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Shortness of breath in the postoperative patient
The Journal of Emergency Medicine, Vol. 27, No. 2, pp. 171–177, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/04 $–see front matter
doi:10.1016/j.jemermed.2004.05.001
Case Presentations of the Harvard Emergency Medicine Residency
SHORTNESS OF BREATH IN THE POSTOPERATIVE PATIENT Haritha Challapalli,
MD,*
Samuel Z. Goldhaber, MD,† David F.M. Brown, and Eric S. Nadel, MD*,‡,§
MD,*,‡
*Division of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, †Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, ‡Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, and §Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Reprint Address: Eric S. Nadel, MD, Department of Emergency Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115
Dr. Haritha Challapalli: Today’s case is that of a 33-year-old woman who presented to the Emergency Department (ED) complaining of shortness of breath. The patient noted the sudden onset of dyspnea on exertion and palpitations over the past day. She was seen briefly by her primary care physician, who sent her to the ED for further evaluation. The patient denied pleuritic chest pain or chest pressure, fever, chills, or cough. The patient reported undergoing a recent colectomy with diverting ileostomy in Spain approximately 5 weeks earlier secondary to colonic perforation in the setting of colitis of unknown etiology. She remained hospitalized in Spain for approximately 1 month, and was released 1 week prior, returning to Boston 3 days prior. There was no other significant past medical history. The only medications were lomotil and omeprazole. There were no known drug allergies, and no use of alcohol, tobacco, or illicit substances. Are there any questions about the initial history? Dr. Kriti Bhatia: You mentioned that the patient was recovering from recent surgery, and that she had a recent overseas flight, both risk factors for pulmonary embolism (PE). Did she complain of leg pain or swelling, or have a history of thromboembolic disease? Dr. Challapalli: The patient denied leg pain or swelling, and had no history of PE or deep vein thrombosis (DVT). On physical examination, the patient was awake,
alert and in mild respiratory distress. Vital signs were: blood pressure 92/76 mm Hg, heart rate 122 beats per minute, respiratory rate 20 breaths per minute, oxygen saturation 98% on room air. Examination of the head and neck was unremarkable; there was no jugular venous distension. Cardiac examination revealed a regular tachycardia, without murmurs, rubs or gallops, and normal S1 and S2 sounds. The lungs were clear to auscultation bilaterally, without any rales or rhonchi. The abdomen was soft and nontender, without guarding or rebound. Rectal examination revealed heme negative stool. The lower extremities were warm without clubbing, cyanosis or edema. Neurological examination was nonfocal. Dr. Eric Nadel: Are there any questions regarding the initial presentation or thoughts as to initial differential diagnosis and management? Dr. Medley Gatewood: The patient has risk factors for pulmonary embolism, and a clinical presentation concerning for PE, including dyspnea, tachypnea, and tachycardia. Although reduced oxygen saturation and pleuritic chest pain were not present, my concern for pulmonary embolism is high. If the evaluation for PE is negative, I would consider other etiologies of shortness of breath, including pneumonia, bronchitis, and congestive heart failure. I would initiate the evaluation by obtaining a chest radiograph (CXR), electrocardiogram
Case Presentations of the Harvard Emergency Medicine Residency are coordinated by David F. M. Brown, MD, and Eric S. Nadel, MD, of Harvard University Medical School, Boston, Massachusetts 171
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Figure 1. Electrocardiogram reveals sinus tachycardia, S1Q3T2, T wave inversion V1–V5.
(EKG), complete blood count, electrolytes, creatinine, D-Dimer, and make arrangements for a chest computed tomography (CT) angiogram to evaluate for pulmonary embolism. Dr. David Brown: I agree that the evaluation should focus on establishing the diagnosis of pulmonary embolism given the clinical presentation. Given the high likelihood of PE based on clinical presentation, I would also recommend initiation of anticoagulation while waiting for diagnostic studies to be performed. The chest CT should happen relatively quickly, but occasionally there are delays. In some institutions, ventilation/perfusion V/Q scanning remains the diagnostic modality of choice, and there can be significant delay in obtaining results. This patient has a high pre-test probability for PE, and should have treatment initiated immediately. Dr. Challapalli: A portable chest X-ray revealed no evidence of acute cardiopulmonary disease. A complete blood cell count was normal and a basic metabolic panel
was normal. ELISA D-dimer was elevated at 3767 ng/ ml. The EKG (Figure 1) revealed a sinus tachycardia, with left axis deviation, and a S1Q3T3 pattern with T wave inversion in leads V1–V5. A CT angiogram of the chest (Figures 2 and 3) revealed significant bilateral central pulmonary emboli extending into all lobes. Secondary enlargement of the right ventricle consistent with heart strain was also noted. No evidence of deep vein thrombosis was noted in the pelvis. The patient received a bolus then continuous infusion of unfractionated heparin. Are there thoughts as to further management of this patient? Dr. Kriti Bhatia: I would consider thrombolysis in this patient with bilateral central pulmonary emboli, tachycardia, and mild hypotension. I would immediately obtain an echocardiogram to better delineate the amount of right ventricular strain because right ventricular dysfunction is an independent predictor of subsequent death (1).
Figure 2. Chest CT angiogram reveals bilateral central pulmonary embolism (arrows).
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Figure 3. Chest CT angiogram reveals right ventricular enlargement (arrow).
Dr. Derek Barclay: What are the echocardiographic findings in pulmonary embolism? Dr. Challapalli: Echocardiographic findings of PE include right ventricular (RV) dilatation and hypokinesis, abnormal motion of the interventricular septum, tricuspid regurgitation, lack of collapse of the inferior vena cava during inspiration, and McConnell’s sign: RV hypokinesis with sparing of the RV apex, which has a 94% specificity for PE (1). Cardiology was consulted, and an echocardiogram was performed in the ED, which revealed severe right ventricular enlargement and hypokinesis consistent with severe RV strain. The left ventricle (LV) was hyperdynamic with an ejection fraction (EF) of 70%. All cardiac valves were normal. The estimated pulmonary artery (PA) systolic pressure was elevated at 42 mm Hg. An echogenic density in the area of the region of the right pulmonary artery suggested clot. In consultation with Cardiology, the patient was admitted to the coronary care unit (CCU) for close monitoring and possible thrombolysis. Over the first 6 h in the CCU, there were a few episodes of hypotension with systolic blood pressures down to 70 mm Hg, which were treated successfully with intravenous normal saline boluses. Over the next 12 h the patients’ vital signs improved; she was transferred to the floor 24 h later and was discharged home on hospital day 5, at which time her heart rate was 80 bpm and her oxygen saturation was 97% on room air. Dr. Sarah Tibbetts: Would you discuss the standard
indications for thrombolysis and its concomitant risks and contraindications? Dr. Challapalli: Standard indications for thrombolysis include hypotension, significant hypoxemia, and massive pulmonary embolism. Complications of thrombolysis include intracranial bleeding and other significant bleeding. Absolute contraindications include active internal bleeding, major active external bleeding, recent neurosurgery (⬍ 8 weeks), recent hepatic or renal biopsy, recent ocular surgery (⬍ 8 weeks), and diabetic retinopathy with recent hemorrhage. Relative contraindications include major trauma, recent surgery, recent major vessel puncture, immediately postpartum, uncontrolled hypertension at time of thrombolysis, recent prolonged cardiopulmonary resuscitation, current pregnancy, and central nervous system cancer (2). Dr. Nadel: The diagnosis of pulmonary embolism was made in a timely fashion based on high clinical suspicion, and the early management was appropriate as anticoagulation with unfractionated heparin was initiated. It seems that although administration of thrombolytic agents was considered, none was given in the ED or CCU. Patients with pulmonary embolism and hemodynamic instability or severe respiratory distress are often considered candidates for thrombolysis. Whereas this patient remained hemodynamically stable after the initial fluid bolus, patients with evidence of right heart strain are also known to have higher mortality. Should thrombolytic agents be more strongly considered in patients such as this? I am interested to hear the thoughts of Dr.
174
Goldhaber, from our thromboembolism service, regarding the decision to administer or withhold thrombolytic agents in this patient. Can you please comment on the current recommendations regarding management of submassive pulmonary embolism? Dr. Samuel Z. Goldhaber: Anticoagulation remains the cornerstone of therapy for massive and submassive pulmonary embolism. The Food and Drug Administration approved recombinant human tissue plasminogen activator (rt–PA), also called alteplase, in 1990 for thrombolysis of massive pulmonary embolism. The approved dose is 100 mg as a continuous infusion over 2 h, without concomitant heparin. Whereas clear-cut recommendations exist to administer thrombolysis to patients with massive pulmonary embolism, the role of these agents in patients with submassive illness remains controversial and uncertain. We suffer from a lack of data to resolve this question. Over the past 30 years, 10 randomized trials have studied thrombolysis plus anticoagulation versus anticoagulation alone in a total of only 717 patients. Meta-analysis shows a trend toward a 25% reduction in mortality, but the confidence intervals are wide, and this trend is not statistically significant. On the other hand, it is certain from meta-analysis that the major bleeding rate doubles in patients receiving thrombolysis. In 1993, a multi-centered United States trial randomized 101 hemodynamically stable patients to recombinant tissue plasminogen activator (rt–PA) followed by heparin versus heparin alone (3). PE did not recur among rt–PA patients, but there were five recurrences, including two fatalities, among heparin-alone patients within the ensuing 14 days (p ⫽ 0.06). On echocardiogram, right ventricular wall motion improved in more than twice as many rt–PA compared with heparin-alone patients. The rapid reversal of right ventricular dysfunction provides a mechanism to explain the potential reduction in mortality from PE. In 2003, the MAPPET-3 group compared rt–PA plus heparin versus heparin alone in a double-blind trial of 256 PE patients with right ventricular dysfunction but without hypotension or shock (2). This is the largest thrombolysis trial ever undertaken. The primary endpoint was death or escalation of therapy, defined as the need for catecholamine infusion, open-label thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or emergency embolectomy. Of 256 patients enrolled, 118 were randomly assigned to receive heparin plus alteplase and 138 to receive heparin plus placebo. The incidence of the primary end point was significantly higher in the heparin-plus-placebo group than in the heparin-plus-alteplase group (p ⫽ 0.006), and the probability of 30-day event-free survival was higher in the heparin-plus-alteplase group (p ⫽ 0.005). This difference was due to the
H. Challapalli et al.
higher incidence of treatment escalation in the heparinplus-placebo group (24.6% vs. 10.2%, respectively, p ⫽ 0.004) (Figure 4). Most of the difference favoring rt–PA came from the “soft” endpoint of open-label thrombolysis. No intracranial hemorrhage occurred. In a registry of 2454 patients with PE, 304 received thrombolysis, of whom 3.0% had intracranial bleeding (4). This high bleeding rate points out how much more difficult it is to achieve a satisfactory level of safety in the context of “real life” clinical practice compared with the artificial environment of a highly monitored and regulated controlled clinical trial. The key to successful management of patients with submassive pulmonary embolism is rapid and accurate risk stratification. Physical examination, electrocardiogram, chest X-ray, CT scan, and echocardiogram can provide evidence of right ventricular dysfunction, a key prognostic marker of high risk and increased major adverse clinical events. On physical examination, clues to right heart failure include distended jugular veins, an accentuated pulmonic heart sound, and a tricuspid regurgitation murmur. The electrocardiogram may show a new complete or incomplete right bundle branch block or a classic S1Q3T3 pattern, but more often will demonstrate a less commonly recognized sign of right ventricular strain, T wave inversion in leads V1–V4. The chest X-ray may show enlarged pulmonary arteries, especially an enlarged right descending pulmonary artery, indicating pulmonary arterial hypertension. The cardiac phase of the chest CT scan may show that the right ventricle is as large as the left ventricle, indicating right ventricular dilatation due to right ventricular dysfunction. On echocardiography, moderate or severe right ventricular hypokinesis, pulmonary hypertension, a patent foramen ovale, and free-floating right-heart thrombus are markers for a high risk of death or recurrent PE. The most recent development in prognostication is the use of biomarkers such as troponin elevation, which indicates right ventricular microinfarction, and elevations of pro-BNP and BNP, which indicate right ventricular shear stress due to right ventricular overload (5–9) (Figure 5). Elevations in cardiac biomarkers reflect an increased likelihood that the hospital course will be complicated despite immediate treatment with anticoagulation. However, biomarkers are not useful in patients who present with cardiogenic shock due to massive PE (Figure 6). These patients require emergency thrombolysis or embolectomy. I would have treated this patient with thrombolysis. She presented 5 weeks after general abdominal surgery. This time frame is well beyond the 2-week window during which thrombolysis may cause excessive bleeding at the surgical site. She had episodic systemic arterial hypotension during her first hospital night, which is an
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Figure 4. Kaplan–Meier estimates of the probability of event-free survival among patients with acute submassive pulmonary embolism, according to treatment with heparin plus alteplase or heparin plus placebo. (Reprinted with permission from Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus atleplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50.)
obviously ominous sign. Furthermore, the echocardiogram showed she was suffering from severe heart failure due to right ventricular dysfunction, a precursor to death from pulmonary embolism.
Nevertheless, she improved clinically with conservative management. There remains clinical equipoise concerning optimal management in submassive pulmonary embolism because clinical trials to date do not mandate
Figure 5. Mechanism of cardiac biomarker level elevation in pulmonary embolism. RV, right ventricular. (Reprinted with permission from Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108:2191– 4.)
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Figure 6. Pulmonary embolism management strategy. RV, right ventricular. (Reprinted with permission from Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108:2191– 4.)
thrombolysis. The best solution to this dilemma is a definitive clinical trial with hard clinical endpoints such as death, recurrent pulmonary embolism, and development of cardiogenic shock. Stavros Konstantinides of Germany, the Principal Investigator of MAPPET–3, is planning such a trial (Figure 7). It will enroll 1100 patients in an international effort and will test the thrombolytic agent, tenecteplase. Until that trial is completed, we can expect marked divergence of practice patterns. Dr. Medley Gatewood: What is the current role of
echocardiography in the diagnosis and treatment of pulmonary embolism? Dr. Goldhaber: For diagnosis, echocardiography helps detect conditions that mimic PE, such as myocardial infarction, aortic dissection, or pericardial tamponade. The transesophageal approach is an alternative for patients with poor image quality of the right ventricle. Overall, the majority of patients with pulmonary embolism will have normal echocardiograms (1). Echocardiography has also emerged as the single most useful tool for risk stratification. Right ventricular
Figure 7. Randomized trial being planned to test thrombolysis in submassive pulmonary embolism.
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dysfunction is an independent predictor for an increased likelihood of dying from pulmonary embolism. Systolic function of the right ventricle is assessed by qualitatively examining the motion of the right ventricular free wall. Right ventricular dilatation is present when the enddiastolic size of the right ventricle equals or exceeds the size of the left ventricle. Indirect signs of right ventricular pressure overload include a tricuspid regurgitant velocity of more than 2.6 m/s, a congested inferior vena cava with a lack of inspiratory collapse, or a flattened interventricular septum, with paradoxical systolic motion toward the left ventricle (1). Dr. Benjamin Sun: This patient was given fluid boluses for hypotension despite a high degree of RV dyskinesia and overload. Would you recommend early pressors in such a patient? Dr. Goldhaber: Pressors are fine as a temporizing strategy. Once you start thinking about pressors, however, this is a warning sign to think about the underlying reason why pressors are required. In patients with pulmonary embolism, it is usually a sign of the onset of cardiogenic shock. In the old days, we never gave thrombolysis until patients had failed high dose pressors. This was a big mistake. By that time, profound cardiogenic shock and multisystem organ failure had ensued, making survival unlikely. Thrombolytic agents then would be given under these desperate circumstances, or patients would be transferred to cardiac surgeons for emergent embolectomy, and such patients would inevitably die. As a consequence, both thrombolysis and surgical embolectomy got undeservedly bad reputations as therapeutic strategies.
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Dr. Nadel: Thank you for your comments, Dr. Goldhaber. Although this patient did well with conservative therapy, it seems that we should consider administration of intravenous thrombolytic therapy in similar situations in the future.
REFERENCES 1. Goldhaber S. Echocardiography in the management of pulmonary embolism. Ann Intern Med 2002;136:691–700. 2. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators, Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus atleplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50. 3. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341:507–11. 4. 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. 5. Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108: 2191– 4. 6. Konstantinides S, Geibel A, Olschewski M, et al. Importance of cardiac troponins I and T in risk stratification of patients with acute pulmonary embolism. Circulation 2002;106:1263– 8. 7. Kucher N, Printzen G, Doernhoefer T, Windecker S, Meier B, Hess OM. Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Circulation 2003;107: 1576 – 8. 8. ten Wolde M, Tulevski II, Mulder JW, et al. Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism. Circulation 2003;107:2082– 4. 9. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of BNP in acute pulmonary embolism. Circulation 2003;107:2545–7.
doi:10.1016/j.jemermed.2004.05.001
Case Presentations of the Harvard Emergency Medicine Residency
SHORTNESS OF BREATH IN THE POSTOPERATIVE PATIENT Haritha Challapalli,
MD,*
Samuel Z. Goldhaber, MD,† David F.M. Brown, and Eric S. Nadel, MD*,‡,§
MD,*,‡
*Division of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, †Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, ‡Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, and §Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Reprint Address: Eric S. Nadel, MD, Department of Emergency Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115
Dr. Haritha Challapalli: Today’s case is that of a 33-year-old woman who presented to the Emergency Department (ED) complaining of shortness of breath. The patient noted the sudden onset of dyspnea on exertion and palpitations over the past day. She was seen briefly by her primary care physician, who sent her to the ED for further evaluation. The patient denied pleuritic chest pain or chest pressure, fever, chills, or cough. The patient reported undergoing a recent colectomy with diverting ileostomy in Spain approximately 5 weeks earlier secondary to colonic perforation in the setting of colitis of unknown etiology. She remained hospitalized in Spain for approximately 1 month, and was released 1 week prior, returning to Boston 3 days prior. There was no other significant past medical history. The only medications were lomotil and omeprazole. There were no known drug allergies, and no use of alcohol, tobacco, or illicit substances. Are there any questions about the initial history? Dr. Kriti Bhatia: You mentioned that the patient was recovering from recent surgery, and that she had a recent overseas flight, both risk factors for pulmonary embolism (PE). Did she complain of leg pain or swelling, or have a history of thromboembolic disease? Dr. Challapalli: The patient denied leg pain or swelling, and had no history of PE or deep vein thrombosis (DVT). On physical examination, the patient was awake,
alert and in mild respiratory distress. Vital signs were: blood pressure 92/76 mm Hg, heart rate 122 beats per minute, respiratory rate 20 breaths per minute, oxygen saturation 98% on room air. Examination of the head and neck was unremarkable; there was no jugular venous distension. Cardiac examination revealed a regular tachycardia, without murmurs, rubs or gallops, and normal S1 and S2 sounds. The lungs were clear to auscultation bilaterally, without any rales or rhonchi. The abdomen was soft and nontender, without guarding or rebound. Rectal examination revealed heme negative stool. The lower extremities were warm without clubbing, cyanosis or edema. Neurological examination was nonfocal. Dr. Eric Nadel: Are there any questions regarding the initial presentation or thoughts as to initial differential diagnosis and management? Dr. Medley Gatewood: The patient has risk factors for pulmonary embolism, and a clinical presentation concerning for PE, including dyspnea, tachypnea, and tachycardia. Although reduced oxygen saturation and pleuritic chest pain were not present, my concern for pulmonary embolism is high. If the evaluation for PE is negative, I would consider other etiologies of shortness of breath, including pneumonia, bronchitis, and congestive heart failure. I would initiate the evaluation by obtaining a chest radiograph (CXR), electrocardiogram
Case Presentations of the Harvard Emergency Medicine Residency are coordinated by David F. M. Brown, MD, and Eric S. Nadel, MD, of Harvard University Medical School, Boston, Massachusetts 171
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Figure 1. Electrocardiogram reveals sinus tachycardia, S1Q3T2, T wave inversion V1–V5.
(EKG), complete blood count, electrolytes, creatinine, D-Dimer, and make arrangements for a chest computed tomography (CT) angiogram to evaluate for pulmonary embolism. Dr. David Brown: I agree that the evaluation should focus on establishing the diagnosis of pulmonary embolism given the clinical presentation. Given the high likelihood of PE based on clinical presentation, I would also recommend initiation of anticoagulation while waiting for diagnostic studies to be performed. The chest CT should happen relatively quickly, but occasionally there are delays. In some institutions, ventilation/perfusion V/Q scanning remains the diagnostic modality of choice, and there can be significant delay in obtaining results. This patient has a high pre-test probability for PE, and should have treatment initiated immediately. Dr. Challapalli: A portable chest X-ray revealed no evidence of acute cardiopulmonary disease. A complete blood cell count was normal and a basic metabolic panel
was normal. ELISA D-dimer was elevated at 3767 ng/ ml. The EKG (Figure 1) revealed a sinus tachycardia, with left axis deviation, and a S1Q3T3 pattern with T wave inversion in leads V1–V5. A CT angiogram of the chest (Figures 2 and 3) revealed significant bilateral central pulmonary emboli extending into all lobes. Secondary enlargement of the right ventricle consistent with heart strain was also noted. No evidence of deep vein thrombosis was noted in the pelvis. The patient received a bolus then continuous infusion of unfractionated heparin. Are there thoughts as to further management of this patient? Dr. Kriti Bhatia: I would consider thrombolysis in this patient with bilateral central pulmonary emboli, tachycardia, and mild hypotension. I would immediately obtain an echocardiogram to better delineate the amount of right ventricular strain because right ventricular dysfunction is an independent predictor of subsequent death (1).
Figure 2. Chest CT angiogram reveals bilateral central pulmonary embolism (arrows).
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Figure 3. Chest CT angiogram reveals right ventricular enlargement (arrow).
Dr. Derek Barclay: What are the echocardiographic findings in pulmonary embolism? Dr. Challapalli: Echocardiographic findings of PE include right ventricular (RV) dilatation and hypokinesis, abnormal motion of the interventricular septum, tricuspid regurgitation, lack of collapse of the inferior vena cava during inspiration, and McConnell’s sign: RV hypokinesis with sparing of the RV apex, which has a 94% specificity for PE (1). Cardiology was consulted, and an echocardiogram was performed in the ED, which revealed severe right ventricular enlargement and hypokinesis consistent with severe RV strain. The left ventricle (LV) was hyperdynamic with an ejection fraction (EF) of 70%. All cardiac valves were normal. The estimated pulmonary artery (PA) systolic pressure was elevated at 42 mm Hg. An echogenic density in the area of the region of the right pulmonary artery suggested clot. In consultation with Cardiology, the patient was admitted to the coronary care unit (CCU) for close monitoring and possible thrombolysis. Over the first 6 h in the CCU, there were a few episodes of hypotension with systolic blood pressures down to 70 mm Hg, which were treated successfully with intravenous normal saline boluses. Over the next 12 h the patients’ vital signs improved; she was transferred to the floor 24 h later and was discharged home on hospital day 5, at which time her heart rate was 80 bpm and her oxygen saturation was 97% on room air. Dr. Sarah Tibbetts: Would you discuss the standard
indications for thrombolysis and its concomitant risks and contraindications? Dr. Challapalli: Standard indications for thrombolysis include hypotension, significant hypoxemia, and massive pulmonary embolism. Complications of thrombolysis include intracranial bleeding and other significant bleeding. Absolute contraindications include active internal bleeding, major active external bleeding, recent neurosurgery (⬍ 8 weeks), recent hepatic or renal biopsy, recent ocular surgery (⬍ 8 weeks), and diabetic retinopathy with recent hemorrhage. Relative contraindications include major trauma, recent surgery, recent major vessel puncture, immediately postpartum, uncontrolled hypertension at time of thrombolysis, recent prolonged cardiopulmonary resuscitation, current pregnancy, and central nervous system cancer (2). Dr. Nadel: The diagnosis of pulmonary embolism was made in a timely fashion based on high clinical suspicion, and the early management was appropriate as anticoagulation with unfractionated heparin was initiated. It seems that although administration of thrombolytic agents was considered, none was given in the ED or CCU. Patients with pulmonary embolism and hemodynamic instability or severe respiratory distress are often considered candidates for thrombolysis. Whereas this patient remained hemodynamically stable after the initial fluid bolus, patients with evidence of right heart strain are also known to have higher mortality. Should thrombolytic agents be more strongly considered in patients such as this? I am interested to hear the thoughts of Dr.
174
Goldhaber, from our thromboembolism service, regarding the decision to administer or withhold thrombolytic agents in this patient. Can you please comment on the current recommendations regarding management of submassive pulmonary embolism? Dr. Samuel Z. Goldhaber: Anticoagulation remains the cornerstone of therapy for massive and submassive pulmonary embolism. The Food and Drug Administration approved recombinant human tissue plasminogen activator (rt–PA), also called alteplase, in 1990 for thrombolysis of massive pulmonary embolism. The approved dose is 100 mg as a continuous infusion over 2 h, without concomitant heparin. Whereas clear-cut recommendations exist to administer thrombolysis to patients with massive pulmonary embolism, the role of these agents in patients with submassive illness remains controversial and uncertain. We suffer from a lack of data to resolve this question. Over the past 30 years, 10 randomized trials have studied thrombolysis plus anticoagulation versus anticoagulation alone in a total of only 717 patients. Meta-analysis shows a trend toward a 25% reduction in mortality, but the confidence intervals are wide, and this trend is not statistically significant. On the other hand, it is certain from meta-analysis that the major bleeding rate doubles in patients receiving thrombolysis. In 1993, a multi-centered United States trial randomized 101 hemodynamically stable patients to recombinant tissue plasminogen activator (rt–PA) followed by heparin versus heparin alone (3). PE did not recur among rt–PA patients, but there were five recurrences, including two fatalities, among heparin-alone patients within the ensuing 14 days (p ⫽ 0.06). On echocardiogram, right ventricular wall motion improved in more than twice as many rt–PA compared with heparin-alone patients. The rapid reversal of right ventricular dysfunction provides a mechanism to explain the potential reduction in mortality from PE. In 2003, the MAPPET-3 group compared rt–PA plus heparin versus heparin alone in a double-blind trial of 256 PE patients with right ventricular dysfunction but without hypotension or shock (2). This is the largest thrombolysis trial ever undertaken. The primary endpoint was death or escalation of therapy, defined as the need for catecholamine infusion, open-label thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or emergency embolectomy. Of 256 patients enrolled, 118 were randomly assigned to receive heparin plus alteplase and 138 to receive heparin plus placebo. The incidence of the primary end point was significantly higher in the heparin-plus-placebo group than in the heparin-plus-alteplase group (p ⫽ 0.006), and the probability of 30-day event-free survival was higher in the heparin-plus-alteplase group (p ⫽ 0.005). This difference was due to the
H. Challapalli et al.
higher incidence of treatment escalation in the heparinplus-placebo group (24.6% vs. 10.2%, respectively, p ⫽ 0.004) (Figure 4). Most of the difference favoring rt–PA came from the “soft” endpoint of open-label thrombolysis. No intracranial hemorrhage occurred. In a registry of 2454 patients with PE, 304 received thrombolysis, of whom 3.0% had intracranial bleeding (4). This high bleeding rate points out how much more difficult it is to achieve a satisfactory level of safety in the context of “real life” clinical practice compared with the artificial environment of a highly monitored and regulated controlled clinical trial. The key to successful management of patients with submassive pulmonary embolism is rapid and accurate risk stratification. Physical examination, electrocardiogram, chest X-ray, CT scan, and echocardiogram can provide evidence of right ventricular dysfunction, a key prognostic marker of high risk and increased major adverse clinical events. On physical examination, clues to right heart failure include distended jugular veins, an accentuated pulmonic heart sound, and a tricuspid regurgitation murmur. The electrocardiogram may show a new complete or incomplete right bundle branch block or a classic S1Q3T3 pattern, but more often will demonstrate a less commonly recognized sign of right ventricular strain, T wave inversion in leads V1–V4. The chest X-ray may show enlarged pulmonary arteries, especially an enlarged right descending pulmonary artery, indicating pulmonary arterial hypertension. The cardiac phase of the chest CT scan may show that the right ventricle is as large as the left ventricle, indicating right ventricular dilatation due to right ventricular dysfunction. On echocardiography, moderate or severe right ventricular hypokinesis, pulmonary hypertension, a patent foramen ovale, and free-floating right-heart thrombus are markers for a high risk of death or recurrent PE. The most recent development in prognostication is the use of biomarkers such as troponin elevation, which indicates right ventricular microinfarction, and elevations of pro-BNP and BNP, which indicate right ventricular shear stress due to right ventricular overload (5–9) (Figure 5). Elevations in cardiac biomarkers reflect an increased likelihood that the hospital course will be complicated despite immediate treatment with anticoagulation. However, biomarkers are not useful in patients who present with cardiogenic shock due to massive PE (Figure 6). These patients require emergency thrombolysis or embolectomy. I would have treated this patient with thrombolysis. She presented 5 weeks after general abdominal surgery. This time frame is well beyond the 2-week window during which thrombolysis may cause excessive bleeding at the surgical site. She had episodic systemic arterial hypotension during her first hospital night, which is an
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175
Figure 4. Kaplan–Meier estimates of the probability of event-free survival among patients with acute submassive pulmonary embolism, according to treatment with heparin plus alteplase or heparin plus placebo. (Reprinted with permission from Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus atleplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50.)
obviously ominous sign. Furthermore, the echocardiogram showed she was suffering from severe heart failure due to right ventricular dysfunction, a precursor to death from pulmonary embolism.
Nevertheless, she improved clinically with conservative management. There remains clinical equipoise concerning optimal management in submassive pulmonary embolism because clinical trials to date do not mandate
Figure 5. Mechanism of cardiac biomarker level elevation in pulmonary embolism. RV, right ventricular. (Reprinted with permission from Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108:2191– 4.)
176
H. Challapalli et al.
Figure 6. Pulmonary embolism management strategy. RV, right ventricular. (Reprinted with permission from Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108:2191– 4.)
thrombolysis. The best solution to this dilemma is a definitive clinical trial with hard clinical endpoints such as death, recurrent pulmonary embolism, and development of cardiogenic shock. Stavros Konstantinides of Germany, the Principal Investigator of MAPPET–3, is planning such a trial (Figure 7). It will enroll 1100 patients in an international effort and will test the thrombolytic agent, tenecteplase. Until that trial is completed, we can expect marked divergence of practice patterns. Dr. Medley Gatewood: What is the current role of
echocardiography in the diagnosis and treatment of pulmonary embolism? Dr. Goldhaber: For diagnosis, echocardiography helps detect conditions that mimic PE, such as myocardial infarction, aortic dissection, or pericardial tamponade. The transesophageal approach is an alternative for patients with poor image quality of the right ventricle. Overall, the majority of patients with pulmonary embolism will have normal echocardiograms (1). Echocardiography has also emerged as the single most useful tool for risk stratification. Right ventricular
Figure 7. Randomized trial being planned to test thrombolysis in submassive pulmonary embolism.
Shortness of Breath
dysfunction is an independent predictor for an increased likelihood of dying from pulmonary embolism. Systolic function of the right ventricle is assessed by qualitatively examining the motion of the right ventricular free wall. Right ventricular dilatation is present when the enddiastolic size of the right ventricle equals or exceeds the size of the left ventricle. Indirect signs of right ventricular pressure overload include a tricuspid regurgitant velocity of more than 2.6 m/s, a congested inferior vena cava with a lack of inspiratory collapse, or a flattened interventricular septum, with paradoxical systolic motion toward the left ventricle (1). Dr. Benjamin Sun: This patient was given fluid boluses for hypotension despite a high degree of RV dyskinesia and overload. Would you recommend early pressors in such a patient? Dr. Goldhaber: Pressors are fine as a temporizing strategy. Once you start thinking about pressors, however, this is a warning sign to think about the underlying reason why pressors are required. In patients with pulmonary embolism, it is usually a sign of the onset of cardiogenic shock. In the old days, we never gave thrombolysis until patients had failed high dose pressors. This was a big mistake. By that time, profound cardiogenic shock and multisystem organ failure had ensued, making survival unlikely. Thrombolytic agents then would be given under these desperate circumstances, or patients would be transferred to cardiac surgeons for emergent embolectomy, and such patients would inevitably die. As a consequence, both thrombolysis and surgical embolectomy got undeservedly bad reputations as therapeutic strategies.
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Dr. Nadel: Thank you for your comments, Dr. Goldhaber. Although this patient did well with conservative therapy, it seems that we should consider administration of intravenous thrombolytic therapy in similar situations in the future.
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