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Intraosseous Administration of Thrombolytics for Pulmonary Embolism
The Journal of Emergency Medicine, Vol. 45, No. 6, pp. e197–e200, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2013.05.057
Clinical Communications: Adults INTRAOSSEOUS ADMINISTRATION OF THROMBOLYTICS FOR PULMONARY EMBOLISM Taylor R. Spencer, MD, MPH Department of Emergency Medicine, Albany Medical Center, Albany, NY 12208 Reprint Address: Taylor R. Spencer, MD, MPH, Department of Emergency Medicine, Albany Medical Center, MC-139, Albany, NY 12208
, Abstract—Background: Massive pulmonary embolism is associated with cardiac dysfunction and ischemia, hemodynamic collapse, and significant potential for death. The American College of Chest Physicians and American College of Emergency Physicians each supports thrombolytic administration to hemodynamically unstable patients with acute pulmonary embolism. Objectives: In the resuscitation of patients with massive pulmonary embolism and obstructive shock, difficulty with vascular access can hinder care. Alternative options may facilitate delivery of thrombolytics and enhance patient management. Case Report: The case presented is a 36-year-old woman with massive pulmonary embolism associated with hemodynamic instability. She was treated with thrombolytics through a tibial intraosseous line. Conclusions: To the best of our knowledge, this is the first identified case of a patient not in cardiac arrest in whom thrombolytics were administered via an intraosseous line. Similarly, we believe this is also the first reported case of thrombolytics delivered via an intraosseous line for massive pulmonary embolism in the United States. Ó 2013 Elsevier Inc.
decreased cardiac output, hypotension, end-organ hypoperfusion, and ultimately, cardiac arrest may ensue. RV dysfunction and ischemia in acute pulmonary embolism are associated with an increased risk of death, even in the absence of initial hemodynamic abnormalities (1–5). Thrombolytics may correct this underlying pathophysiology. For example, Goldhaber et al. demonstrated rapidly improved RV wall movement and tricuspid regurgitation on echocardiography after tissue plasminogen activator therapy (4). Other investigators have similarly found that thrombolytics improve cardiac function (6–8). But clear evidence of a survival benefit for thrombolytics remains elusive (9,10). Despite this uncertainty, the American College of Chest Physicians (ACCP) and the American College of Emergency Physicians (ACEP) currently support thrombolytic administration for hemodynamically unstable patients with acute pulmonary embolism (Grade of evidence – 1B for ACCP, Level B recommendation for ACEP) (11,12). In emergent resuscitation, intraosseous access is an accepted alternative to central line or large-bore peripheral access. Most drugs given in emergency care by peripheral or central access can also be administered by intraosseous access, although there is scant literature on delivering thrombolytics in this way.
, Keywords—pulmonary embolism; thrombolysis; intraosseous infusion; resuscitation; obstructive shock
INTRODUCTION With massive pulmonary embolism, an abrupt rise in pulmonary artery pressure increases right ventricular (RV) afterload and precipitates acute RV failure. Subsequently, cardiac ischemia, decreased left ventricular preload,
CASE REPORT A 36-year-old woman presented to the Emergency Department (ED) with 1 day of acute-onset dyspnea and
RECEIVED: 7 March 2013; ACCEPTED: 19 May 2013 e197
e198
nonpleuritic chest pressure. Associated symptoms included nausea and sore throat. She denied edema, fevers, or cough. She had no history of similar episodes. The patient’s past medical history included multiple sclerosis and chronic lower-extremity lymphedema. The medication list included baclofen, duloxetine, methylphenidate, nitrofurantoin, olopatadine drops, levonorgestrelethinyl estradiol, solifenacin, and a bowel regimen including polyethylene glycol, magnesium hydroxide, and sodium phosphate enema. She denied tobacco use or recent travel. The patient lived in a nursing facility. Vital signs revealed a heart rate of 135 beats/min, blood pressure of 192/131 mm Hg, respiratory rate of 24 breaths/min, oxygen saturation of 98% on 3 L oxygen, and a temperature of 36.06 C (96.9 F). She was uncomfortable and visibly dyspneic, with moderate respiratory distress. No jugular venous distention or carotid bruit was identified. Lungs were clear to auscultation without retractions, but mildly decreased at the bases. Her cardiac examination showed tachycardia without murmurs or rub. Prominent bilateral lower extremity edema extended above the knees with mild pitting. Homan’s sign or palpable cords were not appreciated.
Figure 1. Initial electrocardiogram.
T. R. Spencer
Electrocardiogram (ECG) revealed sinus tachycardia of 156 beats/min with normal intervals. ST depressions in inferolateral leads were noted, with S1, Q3 noted, but no T3. There was no right bundle branch block or T-wave inversions (Figure 1). Her blood counts were notable for a white blood cell count of 17.3 103/mL without left shift, and her comprehensive metabolic panel was unremarkable except for mildly elevated liver function tests. Troponin was elevated at 0.166 ng/mL. Emergent contrast computed tomography (CT) imaging of the chest identified extensive bilateral pulmonary embolism (Figure 2). A large saddle embolus extended into the upper and lower lobe branches of the right and left pulmonary arteries. Bedside echocardiography with tricuspid regurgitation and a dilatated right ventricle indicated pulmonary hypertension and right heart failure, as well as severely reduced global cardiac contractility. The acute regurgitation was rated as mild-moderate, with peak gradient in systole of 36.2 mm Hg, suggesting elevated right ventricular systolic pressure. There was concern for an atrial thrombus, as a large (1-cm diameter) mobile density could be seen in the right atrium and traversing the
IO Thrombolytics for PE
e199
Figure 2. Computed tomography confirmation of extensive pulmonary embolism.
tricuspid valve. A possible coronary sinus thrombus was also visualized. While in the ED, the patient became progressively more tachycardic, with a heart rate exceeding 150 beats/min, and her systolic blood pressure dropped to 70 mm Hg. Intravenous fluid resuscitation with normal saline was initiated, but her peripheral intravenous line became dislodged, and additional attempts at peripheral access were unsuccessful. Given her hemodynamic instability and need for thrombolytic therapy, immediate access was warranted. We considered central line access, but each of the possible sites posed significant potential challenges and hazards. The patient was intolerant of Trendelenberg positioning for internal jugular access secondary to her respiratory distress. Her morbid obesity and lymphedema precluded femoral access. The subclavian site would not offer compressibility should hemorrhage develop after thrombolysis. Given these limitations and the time requirements for central line placement, intraosseous (IO) line was felt to be the best immediate option for emergent access. A left tibial IO line was placed. After a thorough discussion of risks, benefits, and review of potential contraindications, alteplase was administered through the IO line at 100 mg over 2 h. There were no complications of the alteplase administration through the IO line. She was subsequently transferred to the intensive care unit. In the intensive care unit, the patient was treated with alteplase, heparin infusion, and warfarin. The patient was stabilized over 2 days prior to transfer to the medical floor. No pressors were required. Troponin increased on hospital day 2 to peak at 1.170 ng/mL, and then trended down to the normal range. A repeat ECG on the second hospital day showed persistent but improved sinus tachycardia at 111 beats/min. ST depressions resolved in the lateral leads, but were replaced with precordial T-wave inversion. Serial ECGs showed normal sinus rhythm with persistent nonspecific T-wave abnormalities. No repeat echocardiography or CT was performed. The patient’s international normalized ratio reached therapeutic levels and, on discharge, the patient was pain-free with oxygen
saturation of 96% on room air. She was transferred back to her nursing home on hospital day 7 without new longterm disability. DISCUSSION Literature review identified only three cases of thrombolytics given through an intraosseous line. Valde´s and colleagues reported a case of intraosseous administration of thrombolytics in out-of-hospital massive pulmonary embolism in a 25-year old woman. The patient was in cardiogenic shock and progressed to cardiac arrest. Tenecteplase was given empirically prior to transport to the hospital, and only later was acute bilateral massive pulmonary embolism confirmed on CT pulmonary angiogram. Resuscitation drugs were also given by the intraosseous route, and therapeutic hypothermia was employed. The treatment had good effect, and the patient was discharged from the hospital without significant sequelae after 39 days (13). Landy and colleagues report a second case of intraosseous access for resuscitation in a patient with ventricular fibrillation in France (14). The dysrhythmia was thought to be the result of massive pulmonary embolism based upon echocardiography, and alteplase was administered. This patient had a complicated course post cardiac arrest with multi-system organ failure and wound necrosis, but few neurologic sequelae (14). No other cases of intraosseous thrombolytics for massive pulmonary embolism could be identified in a detailed English literature search. However, a third case of thrombolytics given through an intraosseous line was for myocardial infarction. A 64-year-old man with an out-of-hospital right coronary ST-segment elevation myocardial infarction progressed to recurrent ventricular fibrillation. The ECG showed sinus rhythm, right bundle branch block, ST-segment elevation in the inferior and precordial leads, and ST-segment depression in I and aVL. Electrical defibrillation, aspirin, amiodarone, heparin, clopidogrel, and beta-blocker were also used. The patient had resolution of coronary ischemia and electrical instability without complications and was discharged after 2 days (15).
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T. R. Spencer
The correspondence by Landy and colleagues in Resuscitation (described above) raises concerns about potential complications from intraosseous thrombolytics (14). An extensive necrosis developed at the intraosseous site, perhaps due to local pressure necrosis induced by subcutaneous bleeding at the insertion site. However, thrombolytics were given in conjunction with resuscitation-dose epinephrine, and necrosis could be linked to or exacerbated by epinephrine extravasation and local ischemia (14). Thrombolytics through an intraosseous line is rarely reported in the literature. This case differs from the preceding cases in fundamental ways. The prior cases reported occurred outside of the United States and – at least in the Ruiz-Hornillos et al. and Valde´s et al. cases – by prehospital providers (this is not clarified in the correspondence by Landy et al.) (13–15). Additionally, in this case report, thrombolytics were given to a patient with respiratory distress and radiographically confirmed massive pulmonary embolism with evidence of obstructive shock. However, none of the prior reports of intraosseous thrombolytics to treat confirmed pulmonary embolism involved a patient who had not experienced cardiac arrest. This is believed to be the first reported case of thrombolytics through an intraosseous line in an American hospital setting, and the first in a patient who had not progressed to a cardiac arrest. CONCLUSION A 36-year-old woman with massive pulmonary embolism was treated with thrombolytics through a tibial intraosseous line. Evidence suggests that the patient in this case report had significant potential for mortality, with hypotension and shock having mortality rates of 14% and 23%, respectively (2). Although large peripheral or central venous access would have been preferred, this was not feasible for reasons previously described. This raises the potential use of intraosseous lines to deliver thrombolytics in patients with massive pulmonary embolism. Others have also suggested a possible use in myocardial infarction (15). Additional evidence is warranted to validate uses in these contexts, or in other applications of thrombolytics such as ischemic stroke. Further evaluation is needed to compare the risks and benefits of this alternative route of administration.
Acknowledgments—Dr. Denis Pauze and Dr. C. Christopher King provided uncompensated writing assistance and general support.
REFERENCES 1. Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000;101:2817–22. 2. Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30:1165–71. 3. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 134:479–87. 4. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing rightventricular function and pulmonary perfusion. Lancet 1993;341: 507–11. 5. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–9. 6. Tibbutt DA, Davies JA, Anderson JA, et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. Br Med J 1974;1:343–7. 7. Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the PIOPED Investigators. Chest 1990;97:528–33. 8. Wang Y, Wang C, Yang Y, Pang B. Effect of recombinant singlechain urokinase-type plasminogen activator on experimental pulmonary embolism. Clin Appl Thromb Hemost 2010;16:537–42. 9. Todd JL, Tapson VF. Thrombolytic therapy for acute pulmonary embolism: a critical appraisal. Chest 2009;135:1321–9. 10. Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol 2002;40: 1660–7. 11. Kearon C, Akl EA, Comerota AJ, et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S–94. 12. Fesmire FM, Brown MD, Espinosa JA, et al. American College of Emergency Physicians. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med 2011;57: 628–65275. 13. Valde´s M, Araujo P, de Andre´s C, Sastre E, Martin T. Intraosseous administration of thrombolysis in out-of-hospital massive pulmonary thromboembolism. Emerg Med J 2010;27:641–4. 14. Landy C, Plancade D, Gagnon N, Schaeffer E, Nadaud J, Favier JC. Complication of intraosseous administration of systemic fibrinolysis for a massive pulmonary embolism with cardiac arrest. Resuscitation 2012;83:e149–50. 15. Ruiz-Hornillos PJ, Martı´nez-Ca´mara F, Elizondo M, et al. Systemic fibrinolysis through intraosseous vascular access in ST-segment elevation myocardial infarction. Ann Emerg Med 2011;57:572–4.
http://dx.doi.org/10.1016/j.jemermed.2013.05.057
Clinical Communications: Adults INTRAOSSEOUS ADMINISTRATION OF THROMBOLYTICS FOR PULMONARY EMBOLISM Taylor R. Spencer, MD, MPH Department of Emergency Medicine, Albany Medical Center, Albany, NY 12208 Reprint Address: Taylor R. Spencer, MD, MPH, Department of Emergency Medicine, Albany Medical Center, MC-139, Albany, NY 12208
, Abstract—Background: Massive pulmonary embolism is associated with cardiac dysfunction and ischemia, hemodynamic collapse, and significant potential for death. The American College of Chest Physicians and American College of Emergency Physicians each supports thrombolytic administration to hemodynamically unstable patients with acute pulmonary embolism. Objectives: In the resuscitation of patients with massive pulmonary embolism and obstructive shock, difficulty with vascular access can hinder care. Alternative options may facilitate delivery of thrombolytics and enhance patient management. Case Report: The case presented is a 36-year-old woman with massive pulmonary embolism associated with hemodynamic instability. She was treated with thrombolytics through a tibial intraosseous line. Conclusions: To the best of our knowledge, this is the first identified case of a patient not in cardiac arrest in whom thrombolytics were administered via an intraosseous line. Similarly, we believe this is also the first reported case of thrombolytics delivered via an intraosseous line for massive pulmonary embolism in the United States. Ó 2013 Elsevier Inc.
decreased cardiac output, hypotension, end-organ hypoperfusion, and ultimately, cardiac arrest may ensue. RV dysfunction and ischemia in acute pulmonary embolism are associated with an increased risk of death, even in the absence of initial hemodynamic abnormalities (1–5). Thrombolytics may correct this underlying pathophysiology. For example, Goldhaber et al. demonstrated rapidly improved RV wall movement and tricuspid regurgitation on echocardiography after tissue plasminogen activator therapy (4). Other investigators have similarly found that thrombolytics improve cardiac function (6–8). But clear evidence of a survival benefit for thrombolytics remains elusive (9,10). Despite this uncertainty, the American College of Chest Physicians (ACCP) and the American College of Emergency Physicians (ACEP) currently support thrombolytic administration for hemodynamically unstable patients with acute pulmonary embolism (Grade of evidence – 1B for ACCP, Level B recommendation for ACEP) (11,12). In emergent resuscitation, intraosseous access is an accepted alternative to central line or large-bore peripheral access. Most drugs given in emergency care by peripheral or central access can also be administered by intraosseous access, although there is scant literature on delivering thrombolytics in this way.
, Keywords—pulmonary embolism; thrombolysis; intraosseous infusion; resuscitation; obstructive shock
INTRODUCTION With massive pulmonary embolism, an abrupt rise in pulmonary artery pressure increases right ventricular (RV) afterload and precipitates acute RV failure. Subsequently, cardiac ischemia, decreased left ventricular preload,
CASE REPORT A 36-year-old woman presented to the Emergency Department (ED) with 1 day of acute-onset dyspnea and
RECEIVED: 7 March 2013; ACCEPTED: 19 May 2013 e197
e198
nonpleuritic chest pressure. Associated symptoms included nausea and sore throat. She denied edema, fevers, or cough. She had no history of similar episodes. The patient’s past medical history included multiple sclerosis and chronic lower-extremity lymphedema. The medication list included baclofen, duloxetine, methylphenidate, nitrofurantoin, olopatadine drops, levonorgestrelethinyl estradiol, solifenacin, and a bowel regimen including polyethylene glycol, magnesium hydroxide, and sodium phosphate enema. She denied tobacco use or recent travel. The patient lived in a nursing facility. Vital signs revealed a heart rate of 135 beats/min, blood pressure of 192/131 mm Hg, respiratory rate of 24 breaths/min, oxygen saturation of 98% on 3 L oxygen, and a temperature of 36.06 C (96.9 F). She was uncomfortable and visibly dyspneic, with moderate respiratory distress. No jugular venous distention or carotid bruit was identified. Lungs were clear to auscultation without retractions, but mildly decreased at the bases. Her cardiac examination showed tachycardia without murmurs or rub. Prominent bilateral lower extremity edema extended above the knees with mild pitting. Homan’s sign or palpable cords were not appreciated.
Figure 1. Initial electrocardiogram.
T. R. Spencer
Electrocardiogram (ECG) revealed sinus tachycardia of 156 beats/min with normal intervals. ST depressions in inferolateral leads were noted, with S1, Q3 noted, but no T3. There was no right bundle branch block or T-wave inversions (Figure 1). Her blood counts were notable for a white blood cell count of 17.3 103/mL without left shift, and her comprehensive metabolic panel was unremarkable except for mildly elevated liver function tests. Troponin was elevated at 0.166 ng/mL. Emergent contrast computed tomography (CT) imaging of the chest identified extensive bilateral pulmonary embolism (Figure 2). A large saddle embolus extended into the upper and lower lobe branches of the right and left pulmonary arteries. Bedside echocardiography with tricuspid regurgitation and a dilatated right ventricle indicated pulmonary hypertension and right heart failure, as well as severely reduced global cardiac contractility. The acute regurgitation was rated as mild-moderate, with peak gradient in systole of 36.2 mm Hg, suggesting elevated right ventricular systolic pressure. There was concern for an atrial thrombus, as a large (1-cm diameter) mobile density could be seen in the right atrium and traversing the
IO Thrombolytics for PE
e199
Figure 2. Computed tomography confirmation of extensive pulmonary embolism.
tricuspid valve. A possible coronary sinus thrombus was also visualized. While in the ED, the patient became progressively more tachycardic, with a heart rate exceeding 150 beats/min, and her systolic blood pressure dropped to 70 mm Hg. Intravenous fluid resuscitation with normal saline was initiated, but her peripheral intravenous line became dislodged, and additional attempts at peripheral access were unsuccessful. Given her hemodynamic instability and need for thrombolytic therapy, immediate access was warranted. We considered central line access, but each of the possible sites posed significant potential challenges and hazards. The patient was intolerant of Trendelenberg positioning for internal jugular access secondary to her respiratory distress. Her morbid obesity and lymphedema precluded femoral access. The subclavian site would not offer compressibility should hemorrhage develop after thrombolysis. Given these limitations and the time requirements for central line placement, intraosseous (IO) line was felt to be the best immediate option for emergent access. A left tibial IO line was placed. After a thorough discussion of risks, benefits, and review of potential contraindications, alteplase was administered through the IO line at 100 mg over 2 h. There were no complications of the alteplase administration through the IO line. She was subsequently transferred to the intensive care unit. In the intensive care unit, the patient was treated with alteplase, heparin infusion, and warfarin. The patient was stabilized over 2 days prior to transfer to the medical floor. No pressors were required. Troponin increased on hospital day 2 to peak at 1.170 ng/mL, and then trended down to the normal range. A repeat ECG on the second hospital day showed persistent but improved sinus tachycardia at 111 beats/min. ST depressions resolved in the lateral leads, but were replaced with precordial T-wave inversion. Serial ECGs showed normal sinus rhythm with persistent nonspecific T-wave abnormalities. No repeat echocardiography or CT was performed. The patient’s international normalized ratio reached therapeutic levels and, on discharge, the patient was pain-free with oxygen
saturation of 96% on room air. She was transferred back to her nursing home on hospital day 7 without new longterm disability. DISCUSSION Literature review identified only three cases of thrombolytics given through an intraosseous line. Valde´s and colleagues reported a case of intraosseous administration of thrombolytics in out-of-hospital massive pulmonary embolism in a 25-year old woman. The patient was in cardiogenic shock and progressed to cardiac arrest. Tenecteplase was given empirically prior to transport to the hospital, and only later was acute bilateral massive pulmonary embolism confirmed on CT pulmonary angiogram. Resuscitation drugs were also given by the intraosseous route, and therapeutic hypothermia was employed. The treatment had good effect, and the patient was discharged from the hospital without significant sequelae after 39 days (13). Landy and colleagues report a second case of intraosseous access for resuscitation in a patient with ventricular fibrillation in France (14). The dysrhythmia was thought to be the result of massive pulmonary embolism based upon echocardiography, and alteplase was administered. This patient had a complicated course post cardiac arrest with multi-system organ failure and wound necrosis, but few neurologic sequelae (14). No other cases of intraosseous thrombolytics for massive pulmonary embolism could be identified in a detailed English literature search. However, a third case of thrombolytics given through an intraosseous line was for myocardial infarction. A 64-year-old man with an out-of-hospital right coronary ST-segment elevation myocardial infarction progressed to recurrent ventricular fibrillation. The ECG showed sinus rhythm, right bundle branch block, ST-segment elevation in the inferior and precordial leads, and ST-segment depression in I and aVL. Electrical defibrillation, aspirin, amiodarone, heparin, clopidogrel, and beta-blocker were also used. The patient had resolution of coronary ischemia and electrical instability without complications and was discharged after 2 days (15).
e200
T. R. Spencer
The correspondence by Landy and colleagues in Resuscitation (described above) raises concerns about potential complications from intraosseous thrombolytics (14). An extensive necrosis developed at the intraosseous site, perhaps due to local pressure necrosis induced by subcutaneous bleeding at the insertion site. However, thrombolytics were given in conjunction with resuscitation-dose epinephrine, and necrosis could be linked to or exacerbated by epinephrine extravasation and local ischemia (14). Thrombolytics through an intraosseous line is rarely reported in the literature. This case differs from the preceding cases in fundamental ways. The prior cases reported occurred outside of the United States and – at least in the Ruiz-Hornillos et al. and Valde´s et al. cases – by prehospital providers (this is not clarified in the correspondence by Landy et al.) (13–15). Additionally, in this case report, thrombolytics were given to a patient with respiratory distress and radiographically confirmed massive pulmonary embolism with evidence of obstructive shock. However, none of the prior reports of intraosseous thrombolytics to treat confirmed pulmonary embolism involved a patient who had not experienced cardiac arrest. This is believed to be the first reported case of thrombolytics through an intraosseous line in an American hospital setting, and the first in a patient who had not progressed to a cardiac arrest. CONCLUSION A 36-year-old woman with massive pulmonary embolism was treated with thrombolytics through a tibial intraosseous line. Evidence suggests that the patient in this case report had significant potential for mortality, with hypotension and shock having mortality rates of 14% and 23%, respectively (2). Although large peripheral or central venous access would have been preferred, this was not feasible for reasons previously described. This raises the potential use of intraosseous lines to deliver thrombolytics in patients with massive pulmonary embolism. Others have also suggested a possible use in myocardial infarction (15). Additional evidence is warranted to validate uses in these contexts, or in other applications of thrombolytics such as ischemic stroke. Further evaluation is needed to compare the risks and benefits of this alternative route of administration.
Acknowledgments—Dr. Denis Pauze and Dr. C. Christopher King provided uncompensated writing assistance and general support.
REFERENCES 1. Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000;101:2817–22. 2. Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30:1165–71. 3. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 134:479–87. 4. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing rightventricular function and pulmonary perfusion. Lancet 1993;341: 507–11. 5. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–9. 6. Tibbutt DA, Davies JA, Anderson JA, et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. Br Med J 1974;1:343–7. 7. Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the PIOPED Investigators. Chest 1990;97:528–33. 8. Wang Y, Wang C, Yang Y, Pang B. Effect of recombinant singlechain urokinase-type plasminogen activator on experimental pulmonary embolism. Clin Appl Thromb Hemost 2010;16:537–42. 9. Todd JL, Tapson VF. Thrombolytic therapy for acute pulmonary embolism: a critical appraisal. Chest 2009;135:1321–9. 10. Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol 2002;40: 1660–7. 11. Kearon C, Akl EA, Comerota AJ, et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S–94. 12. Fesmire FM, Brown MD, Espinosa JA, et al. American College of Emergency Physicians. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med 2011;57: 628–65275. 13. Valde´s M, Araujo P, de Andre´s C, Sastre E, Martin T. Intraosseous administration of thrombolysis in out-of-hospital massive pulmonary thromboembolism. Emerg Med J 2010;27:641–4. 14. Landy C, Plancade D, Gagnon N, Schaeffer E, Nadaud J, Favier JC. Complication of intraosseous administration of systemic fibrinolysis for a massive pulmonary embolism with cardiac arrest. Resuscitation 2012;83:e149–50. 15. Ruiz-Hornillos PJ, Martı´nez-Ca´mara F, Elizondo M, et al. Systemic fibrinolysis through intraosseous vascular access in ST-segment elevation myocardial infarction. Ann Emerg Med 2011;57:572–4.