Case 17-2004 — A 42-Year-Old Woman with Cardiac Arrest Several Weeks after an Ankle Fracture
http://www.100md.com
《新英格兰医药杂志》
Presentation of Case
Dr. Vicki E. Noble (Emergency Medicine): A 42-year-old woman was admitted to the emergency department of this hospital after cardiac arrest with pulseless electrical activity.
Approximately two weeks before admission, she had fractured her ankle when slipping on the ice. A closed reduction was performed, and a short leg cast was applied. According to her husband, on the evening of admission, the woman stood up from the couch, said she had chest pain and shortness of breath, and collapsed, apparently unconscious, with synchronous jerking of her arms and legs. Her husband called emergency medical services; the paramedics found the woman on the floor, conscious, stating that she had chest pain, and somewhat combative. She rapidly became unresponsive, with agonal respirations. The paramedics intubated the trachea. She subsequently became pulseless; two 1-mg doses of epinephrine and one 1-mg dose of atropine were administered intravenously. In transit to the emergency department, she required intermittent cardiopulmonary resuscitation because of further episodes of pulselessness.
The patient had been well before the ankle fracture. One week before admission, her primary care physician had indicated that she had what the husband understood to be "varicose veins"; an ultrasound examination of the lower leg at another hospital was reported to be negative. She was taking hydrocodone plus acetaminophen and ibuprofen as needed for ankle pain, as well as an oral contraceptive. Since the ultrasound examination, she had taken one "baby aspirin" daily.
She had no allergies. She had three young children, who were well. She worked as an administrative assistant at a local college. She had never smoked or drunk alcohol. Her husband could recall no family medical problems, except that her mother had a history of phlebitis.
In the emergency department, the patient remained unresponsive. The temperature was 35.5°C, the blood pressure was 170/123 mm Hg, the heart rate was 154 beats per minute, and the oxygen saturation ranged from 78 to 85 percent while the fraction of inspired oxygen was 1.0. Physical examination revealed no evidence of acute traumatic injury. The pupils were 4 mm in diameter and sluggishly reactive to light. The trachea was midline, and the oropharynx was clear. Both carotid pulses were palpable. The heart and lungs were normal on auscultation. The abdomen was soft and not distended, with normal bowel sounds. The left lower leg was in a cast to the middle of the calf. There was no swelling or edema of either leg. The skin was cool and there was peripheral cyanosis. There was no spontaneous movement of the eyes or the arms and legs and no gag reflex.
Almost immediately after arrival, the woman again became pulseless. Two 1-mg doses of epinephrine, one ampule of 50 percent dextrose in water, and one ampule of sodium bicarbonate were administered. After another three to five minutes of cardiopulmonary resuscitation, the pulse returned. The systolic blood pressure was 60 to 70 mm Hg. Five minutes after arrival, a triple-lumen catheter was placed in the right femoral vein, and a dopamine infusion was titrated to 56 μg per minute to maintain a systolic blood pressure of 130 to 140 mm Hg.
An electrocardiogram showed a ventricular rate of 56 beats per minute, atrioventricular dissociation, a right bundle-branch block, and nonspecific ST-segment abnormalities (Figure 1A). A radiograph of the chest showed that the tip of the endotracheal tube was approximately 1.5 cm above the carina; there was a diffuse infiltrate in the right upper lung lobe (Figure 2).
Figure 1. Electrocardiograms Obtained on Admission to the Emergency Department.
An initial electrocardiogram (Panel A) shows a ventricular rate of 56 beats per minute, atrioventricular dissociation, right bundle-branch block, and nonspecific ST-segment abnormalities (lead V3 is an artifact). Another electrocardiogram (Panel B) shows a ventricular rate of 101 beats per minute and atrial fibrillation, incomplete right bundle-branch block, and nonspecific ST-segment and T-wave abnormalities.
Figure 2. Chest Radiograph Obtained on Admission to the Emergency Department.
There is diffuse consolidation in the right lung, with maximal consolidation in the right upper lobe. The left lung is clear. R denotes right.
Two liters of normal saline were administered, and administration of norepinephrine was started at a dose of 7.5 μg per minute. The blood pressure again dropped, to 80/40 mm Hg, and the oxygen saturation dropped to 70 to 72 percent. Additional laboratory values are shown in Table 1.
Table 1. Laboratory Values.
Another electrocardiogram showed a ventricular rate of 101 beats per minute and atrial fibrillation, with incomplete right bundle-branch block, and nonspecific ST-segment and T-wave abnormalities (Figure 1B). A bedside echocardiogram showed no evidence of pericardial tamponade but revealed possible dilatation of the right ventricle. Additional episodes of pulselessness occurred, necessitating further cardiopulmonary-resuscitation efforts.
Thirty-five minutes after admission, 15 mg of alteplase (a recombinant tissue plasminogen activator) was given as an intravenous bolus, and then 85 mg was infused over a period of 90 minutes. Pulselessness continued for about 20 minutes. At 20 minutes, pulses returned, the oxygen saturation was 80 to 90 percent, and the systolic blood pressure stabilized at 140 mm Hg. Pressor medications were discontinued. There were no more episodes of pulselessness. The patient remained unresponsive and was transferred to the coronary care unit while receiving an infusion of 1300 units of heparin per hour. An echocardiogram showed marked enlargement and hypokinesis of the right ventricle with moderate tricuspid insufficiency; the size and function of the left ventricle were normal (Figure 3A and Figure 3B).
Figure 3. Echocardiograms.
An apical four-chamber view of the heart obtained several hours after admission to the coronary care unit (Panel A) shows dilatation of the right ventricle. The contractility of the right ventricle was poor, and the function of the right ventricular apex was slightly better than that of the base and midventricular portions; these findings are characteristic of pulmonary embolism. Panel B is a spectral Doppler tracing of the tricuspid regurgitant flow, also obtained after admission to the coronary care unit. The peak systolic velocity of the tricuspid regurgitant jet was 2.6 m per second, and the estimated right ventricular systolic pressure was 38 mm Hg (assuming a right atrial pressure of 10 mm Hg). A third echocardiogram, obtained at a follow-up examination 10 days after admission (Panel C), shows the apical four-chamber view of the heart with normalization of the size of the right ventricular cavity and substantial improvement in right ventricular systolic function. LV denotes left ventricle, RV right ventricle, RA right atrium, and LA left atrium.
The patient's trachea was extubated later that day, and her mental status improved, so that she was able to follow commands and talk with her family. An ultrasound examination of the femoral and popliteal veins showed no evidence of thrombosis.
A hypercoagulability evaluation on the third hospital day revealed a mildly elevated homocysteine level of 14.3 μmol per liter (normal, 0 to 12). The IgG anticardiolipin antibody titer was 17.8 IgG phospholipid units (reference range, <15) and there were decreases in functional protein C (52 percent of the normal value ) and protein C antigen (56 percent of the normal value ), but the result of a test for resistance to activated protein C was normal. Treatment with warfarin was initiated on the fourth hospital day.
The patient's hospital course was complicated by the development of acute renal failure (peak creatinine levels of 10.7 mg per deciliter ), epistaxis, and a right-groin hematoma. On the 10th hospital day, she had a tonic–clonic seizure; a computed tomographic (CT) scan of her head showed small left frontal and cerebellar hemorrhages. Antibodies against heparin-platelet factor 4 complexes were detected — a finding consistent with the presence of heparin-induced thrombocytopenia — but the platelet count was normal. Anticoagulation therapy was discontinued. A filter was placed in the inferior vena cava. Administration of phenytoin was begun, and no further seizures occurred.
The patient was discharged to a rehabilitation facility on the 25th hospital day. Two weeks later, she was readmitted to this hospital because of edema in her legs. CT scanning showed a clot that filled the inferior vena cava and extended to the left common iliac vein. Anticoagulation therapy with warfarin and argatroban was instituted. The leg edema resolved, and she was discharged home, with instructions to continue taking warfarin (with a target international normalized ratio of 2 to 3).
Differential Diagnosis
Dr. Eric S. Nadel: May we review the imaging studies?
Dr. Amita Sharma: An anteroposterior chest radiograph was obtained in the emergency department with the use of portable equipment (Figure 2). The tip of the endotracheal tube is 1.5 cm from the top of the carina. The cardiac silhouette is normal, given the anteroposterior projection. There is diffuse consolidation in the right lung, most prominently in the right upper lobe. The left lung is clear. The differential diagnosis of asymmetric consolidation with this appearance includes pulmonary hemorrhage, pneumonia (including aspiration pneumonia), asymmetric pulmonary edema, and pulmonary infarction. A follow-up radiograph obtained 24 hours later showed rapid clearing of the consolidation in the right lung. Therefore, the most likely causes of the consolidation in the right lung are resolving pulmonary hemorrhage or pulmonary edema, since pulmonary infarction and pneumonia would take longer to clear up.
Dr. Mary Etta King: The echocardiogram obtained in the coronary care unit showed dysfunction and enlargement of the right ventricle. In an apical four-chamber view, the left ventricle appears to function normally, but the right ventricle is dilated and contracts poorly (Figure 3A and Video 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). There is preservation of some function at the right ventricular apex. This combination of segmental dysfunction of the right ventricle with preserved apical function is highly specific to acute pulmonary embolus.1 Color Doppler studies show moderate tricuspid regurgitation into the right atrium (Figure 3B and Video 2 of the Supplementary Appendix). The estimated right ventricular systolic pressure, calculated from the peak systolic velocity of the regurgitant tricuspid jet, is 38 mm Hg.
Cross-sectional views from the parasternal window confirmed good left ventricular function with no pericardial effusion, as had been seen on the bedside echocardiogram obtained earlier in the day. The right ventricle was as large as the left ventricle, and the free wall did not contract well. A follow-up study performed 10 days after the first admission showed improvement in right ventricular size and function (Figure 3C and Video 3 of the Supplementary Appendix).
Dr. Nancy Lee Harris (Pathology): Dr. Nadel will discuss the care of this patient in the emergency department, and Dr. Samuel Goldhaber will discuss the management of pulmonary embolism.
Dr. Nadel: Pulseless electrical activity refers to any semiorganized electrical activity that can be seen on the cardiac monitor and is not accompanied by a palpable pulse.2 The term "pulseless electrical activity" has replaced "electromechanical dissociation," which implied a dissociation of the electrical function of the heart from the contractile function. Pulseless electrical activity is often thought of as a state resembling severe shock and without a pulse. Although the terminology has changed, the differential diagnosis has not, and it includes volume depletion, hypoxia, acidosis, hyperkalemia and hypokalemia, hypothermia, ingestion of toxic substances, cardiac tamponade, tension pneumothorax, and both coronary and pulmonary thrombosis. The prognosis for an out-of-hospital cardiac arrest, especially if it involves pulseless electrical activity in particular, is poor; 17 percent of patients who present with cardiac arrest have pulseless electrical activity,3 and of those, 1 to 4 percent survive.4 Treatment of pulseless electrical activity (Table 2) includes administration of epinephrine and atropine, as was performed in this case, and the primary focus is on identification and treatment of the underlying cause.
Table 2. Treatment of Pulseless Electrical Activity.
The clinical presentation of a young woman who has pulseless electrical activity and a cast on her leg and who has recently been evaluated for deep venous thrombosis suggests massive pulmonary embolism. The initial clinical decisions involve the selection of objective diagnostic techniques. Although the measurement of D-dimer levels is often discussed in the evaluation of pulmonary embolism, we believed it would not have helped in this case. We also did not obtain a CT scan or a ventilation–perfusion scan because the patient could not safely leave the intensive-care environment of the emergency department for the performance of these tests. The electrocardiogram revealed an incomplete right-bundle-branch block, and although this abnormality is sometimes found in patients with pulmonary embolism, it is not diagnostic. Rapid bedside echocardiography in the emergency department showed a dilated right ventricle, but this limited study in the setting of cardiopulmonary resuscitation was certainly not diagnostic.
With the presumptive diagnosis of massive pulmonary embolism, we decided to administer intravenous thrombolytic therapy. Is there a role for thrombolysis in patients who have cardiac arrest with pulseless electrical activity? There are certainly many case reports and case series that document high survival rates when thrombolytic agents were administered to patients in cardiac arrest,5 but selection bias makes these reports difficult to interpret. Objective data from two studies6,7 suggest that thrombolysis in undifferentiated cardiac arrest is associated with an increase in the rate of return of spontaneous circulation and an increase in 24-hour survival, but not that it is associated with a clear benefit in terms of long-term outcome. A more recent, randomized, prospective study8 assessed the value of thrombolytic therapy in 233 patients who had cardiac arrest with pulseless electrical activity. One patient survived in the group treated with tissue plasminogen activator; there were no survivors in the control group. There was no difference in the rate of return to spontaneous circulation. The current literature does not support the administration of thrombolytic agents in all cases of undifferentiated pulseless electrical activity and cardiac arrest, but the successful outcome in the patient under discussion and in other case reports and small series suggests that thrombolytic agents should be considered in selected patients. Further research will be required to determine whether administration of these agents in the setting of cardiac arrest will lead to improved outcomes, and whether this therapy will benefit selected patients, such as those with high clinical suspicion for massive pulmonary embolism.
I would like to make one final comment about this case. The decision to continue cardiopulmonary-resuscitation efforts for 15 to 20 minutes after administration of the thrombolytic agent was important in the management of this case. We had several discussions about continuing these efforts. In retrospect, the continuation was critical to the successful outcome in this patient. This experience suggests that when thrombolytic agents are used, some time may be necessary for them to be effective.
Discussion of Management
Dr. Samuel Z. Goldhaber: On October 3, 1930, when John Gibbon, M.D., a surgical research fellow at this hospital, witnessed the collapse of a patient with massive pulmonary embolism after a general surgical operation, Gibbon remained at the patient's bedside overnight and observed her continued clinical deterioration. His chief of surgery, Edward Churchill, M.D., attempted a closed pulmonary embolectomy (Trendelenburg's operation), which was unsuccessful. Gibbon was so devastated by this experience that he devoted the ensuing 23 years to developing a heart–lung machine. On May 6, 1953, he performed the first successful open-heart operation.9
The patient with massive pulmonary embolism whom we are currently discussing was successfully resuscitated with the emergency administration of a thrombolytic agent, despite an initial partial pressure of arterial oxygen of 32 mm Hg and a pH of 6.67. Drs. Gibbon and Churchill would have been proud of this accomplishment.
The case under discussion raises four points to consider when evaluating and treating pulmonary embolism: risk stratification; thrombolysis; alternatives to thrombolysis, including catheter and surgical embolectomy; and the optimal duration and intensity of anticoagulation.
Risk Stratification
If I can provide a single "take-home" lesson, it is the importance of risk stratification in patients with newly diagnosed pulmonary embolism. Pulmonary embolism spans a wide spectrum of severity, from asymptomatic patients with small thrombi to those with life-threatening disease that causes cardiogenic shock, such as the patient under discussion. Treatment options vary so widely that we must assess each patient's prognosis in order to choose appropriately from the menu of therapy. At one extreme, outpatient treatment is safe and feasible in patients at low risk.10 In contrast, patients with impending or ongoing cardiovascular collapse must receive consideration for thrombolysis or embolectomy. Patients whose risk level is between these two extremes will warrant anticoagulation with heparin as a bridge to oral anticoagulation.
Accurate and rapid risk stratification takes into account the clinical presentation, the findings on physical examination, the chest radiograph, the echocardiogram, and, recently, the levels of cardiac biomarkers such as troponin, pro–brain natriuretic peptide, and brain natriuretic peptide.11,12 Typically, the clinical presentation is assessed by the clinician's overall impression. An alternative approach, the Geneva Prognostic Index,13 relies on bedside evaluation and a scoring system of 0 to 8 points. Two points each are given for cancer and for a systemic arterial pressure of less than 100 mm Hg. One point each is given for heart failure, previous deep-vein thrombosis, hypoxemia, and new deep-vein thrombosis that has been confirmed by ultrasound examination. As the point score increases, the likelihood of an adverse outcome (defined as death, recurrent venous thromboembolism, or major bleeding) increases.
In patients with submassive or massive pulmonary embolism, important findings from the physical examination may include the detection of jugular-vein distention, tricuspid regurgitation, and an accentuated pulmonic heart sound — all manifestations of right-sided heart failure. The electrocardiogram was very useful in assessing the patient under discussion, because it showed right bundle-branch block, a classic sign of right ventricular strain in patients with acute pulmonary embolism. The bedside transthoracic echocardiogram is invaluable14 because it may reveal a constellation of findings in major pulmonary embolism (Table 3) and because it can rule out other important diagnoses with radically different treatment, such as pericardial tamponade, aortic dissection, and acute myocardial infarction.
Table 3. Echocardiographic Findings in Major Pulmonary Embolism.
This patient had hypotension, probable heart failure (suggested by the findings on the chest radiograph), possible new deep-vein thrombosis, an abnormal electrocardiogram, repeated episodes of pulseless electrical activity, and possible right ventricular enlargement, with no evidence of cardiac tamponade on the echocardiogram. She clearly falls into a category of extremely high risk for death. Indeed, the question in assessing this patient is not whether she is at high risk but whether a pulmonary embolus is the cause of her problems.
Thrombolysis
For patients identified as being at high risk, such as this woman, thrombolysis should be considered. The thrombolytic regimen approved by the Food and Drug Administration (FDA) is 100 mg of tissue plasminogen activator administered as a continuous infusion over a two-hour period. The principal benefit from thrombolysis is a rapid reversal of right heart failure, which may reduce the risk of death and help ensure a more stable hospital course.15,16 Thrombolysis may also preserve the hemodynamic response to exercise over the long term and improve the patient's quality of life.17 Its potential disadvantage is that it may cause major bleeding, especially intracranial hemorrhage, which may occur in up to 3 percent of patients.18
Embolectomy
High-risk patients who also have a very high risk of hemorrhage from thrombolysis should be considered for embolectomy. Catheter embolectomy may be undertaken with one of several different techniques.19
At Brigham and Women's Hospital, we offer open surgical embolectomy on an around-the-clock basis20 for high-risk patients with preserved systemic arterial pressure. We performed 29 embolectomies during a two-year period, with a survival rate of 89 percent.20 Generally speaking, the decision of whether to use catheter or surgical embolectomy depends on the expertise available at the hospital.
For patients who are stratified as having a high-risk pulmonary embolus, such as this patient, I would recommend a plan of care based on thrombolysis or embolectomy in addition to heparin anticoagulation (Figure 4). In this patient, thrombolysis was dramatically effective, restoring a normal blood pressure within 20 minutes.
Figure 4. Algorithm for the Management of Massive Pulmonary Embolism.
Optimal Duration and Intensity of Anticoagulation
After a patient has been stabilized, we need to consider the optimal duration of oral anticoagulation. Until recently, the standard duration of therapy for pulmonary embolism has been six months.21 Longer-duration anticoagulation decreases the recurrence rate but increases the likelihood of major bleeding.22,23
In a recent double-blind, placebo-controlled trial, my colleagues and I tested a new strategy of indefinite-duration warfarin anticoagulation at a low-intensity INR (1.5 to 2.0) in patients with idiopathic venous thromboembolism who had received an average of approximately six months of standard-intensity anticoagulation, (INR, 2.0 to 3.0). The patients who received long-term low-intensity warfarin had a 64 percent reduction in the rate of recurrent thromboembolic events relative to that in the placebo group, with no increase in major bleeding.24 More than half of all patients with pulmonary embolism will fit into the idiopathic group as defined by this trial, and will benefit from indefinite-duration warfarin (Figure 5).
Figure 5. Optimal Duration and Intensity of Anticoagulation for Pulmonary Embolism.
INR denotes international normalized ratio. This information is from Ridker et al.24
The patient under discussion had deep-vein thrombosis due to an ankle fracture. In the absence of other predisposing factors, she should do well if she receives six months of anticoagulation therapy, despite her near-fatal pulmonary embolism. However, if the presence of antiphospholipid antibodies is confirmed, she should receive anticoagulation at standard intensity for an indefinite duration.25
Dr. Noble: When this patient presented, there was some discussion regarding the dose and rate of thrombolytic therapy for a suspected pulmonary embolus. Are there any data to support bolus therapy in patients with cardiac arrest? What would you recommend as a bolus dose?
Dr. Goldhaber: I think a bolus followed by continuous infusion is superior to the infusion alone, because it offers a faster onset of action. In patients receiving a continuous infusion, my colleagues and I have rarely seen clinical improvement before 45 or 50 minutes had elapsed, and in this patient with a bolus, clinical improvement was seen within 20 minutes. In a recent trial, a 10-mg bolus followed by a 90-mg infusion over the remainder of the two-hour period was used.16 So I think your decision was wise.
Dr. Phillip Rice (Emergency Medicine): How effective is thrombolytic therapy? If it fails, are these patients still candidates for embolectomy?
Dr. Goldhaber: About 80 percent of treated patients will improve with thrombolytic therapy. Those in whom thrombolysis is not effective may be candidates for open surgical embolectomy, but they will have high blood-transfusion requirements.
Dr. David Brown (Emergency Medicine): Do you think that oral direct thrombin inhibitors will replace warfarin?
Dr. Goldhaber: Ximelagatran, an oral direct thrombin inhibitor, looks promising as compared with standard anticoagulation for the management of acute deep venous thrombosis26 and atrial fibrillation27 and the prevention of venous thromboembolism in patients undergoing total knee replacement.28 Its major advantage is that it can be administered in a fixed dose, without a requirement for blood testing for dose adjustment and without raising concerns about drug–drug or drug–food interactions. Its potential disadvantages are the need for twice-daily administration and an observed rise in aminotransferases that is three times as high as normal or higher in 6 to 9 percent of patients during the first six months of administration. The FDA is evaluating the efficacy and safety of ximelagatran as compared with standard therapy.
Dr. Harris: The patient's primary care physician, Dr. Virginia H. Palazzo, has provided us with additional information. Ten days before the patient's presentation to the emergency room, she was seen in her doctor's office with pain and tenderness of the left calf. There was no swelling, and an ultrasound study showed no signs of venous thrombosis. In a telephone conversation with her doctor the next day, the patient said she was improved. At a follow-up visit three days after her second discharge from this hospital, the patient had residual right-sided weakness from her intracerebral hemorrhages. This gradually improved, and she returned to work five months after the cardiac arrest. Eleven months after her illness she was driving, talking normally, and performing all her normal activities. She continued to take warfarin.
Final Diagnosis
Cardiac arrest due to a pulmonary embolus.
Source Information
From the Cardiovascular Division, Department of Medicine (S.Z.G.), and the Department of Emergency Medicine (E.S.N.), Brigham and Women's Hospital; the Departments of Emergency Medicine (E.S.N.), Pediatric Cardiology (M.E.K.), and Radiology (A.S.), Massachusetts General Hospital; and the Departments of Medicine (S.Z.G., E.S.N.), Pediatrics (M.E.K.), and Radiology (A.S.), Harvard Medical School — all in Boston.
References
McConnell MV, Solomon SD, Rayan ME, Come PC, Goldhaber SZ, Lee RT. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 1996;78:469-473.
ACLS provider manual. Dallas: American Heart Association, 2002.
Stueven HA, Aufderheide T, Waite EM, Mateer JR. Electromechanical dissociation: six years prehospital experience. Resuscitation 1989;17:173-182.
Eisenberg MS, Mengert TJ. Cardiac resuscitation. N Engl J Med 2001;344:1304-1313.
Newman DH, Greenwald I, Callaway CW. Cardiac arrest and the role of thrombolytic agents. Ann Emerg Med 2000;35:472-480.
Lederer W, Lichtenberger C, Pechlaner C, Kroesen G, Baubin M. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation 2001;50:71-76.
Bottiger BW, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initial unsuccessful cardiopulmonary resuscitation: a prospective trial. Lancet 2001;357:1583-1585.
Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med 2002;346:1522-1528.
Cohn LH. Fifty years of open-heart surgery. Circulation 2003;107:2168-2170.
Beer JH, Burger M, Gretener S, Bernard-Bagattini S, Bounameaux H. Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients. J Thromb Haemost 2003;1:186-187.
Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108:2191-2194.
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;106:1263-1268.
Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF. Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost 2000;84:548-552.
Goldhaber SZ. Echocardiography in the management of pulmonary embolism. Ann Intern Med 2002;136:691-700.
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;341:507-511.
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-1150.
Sharma GV, Folland ED, McIntyre KM, Sasahara AA. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism. Vasc Med 2000;5:91-95.
Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-1389.
Goldhaber SZ. Integration of catheter thrombectomy into our armamentarium to treat acute pulmonary embolism. Chest 1998;114:1237-1238.
Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation 2002;105:1416-1419.
Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-1665.
Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907.
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434.
Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752-763.
Eriksson H, Wahlander K, Gustafsson D, Welin LT, Frison L, Schulman S. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003;1:41-47.
Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691-1698.
Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703-1712.(Samuel Z. Goldhaber, M.D.)
Dr. Vicki E. Noble (Emergency Medicine): A 42-year-old woman was admitted to the emergency department of this hospital after cardiac arrest with pulseless electrical activity.
Approximately two weeks before admission, she had fractured her ankle when slipping on the ice. A closed reduction was performed, and a short leg cast was applied. According to her husband, on the evening of admission, the woman stood up from the couch, said she had chest pain and shortness of breath, and collapsed, apparently unconscious, with synchronous jerking of her arms and legs. Her husband called emergency medical services; the paramedics found the woman on the floor, conscious, stating that she had chest pain, and somewhat combative. She rapidly became unresponsive, with agonal respirations. The paramedics intubated the trachea. She subsequently became pulseless; two 1-mg doses of epinephrine and one 1-mg dose of atropine were administered intravenously. In transit to the emergency department, she required intermittent cardiopulmonary resuscitation because of further episodes of pulselessness.
The patient had been well before the ankle fracture. One week before admission, her primary care physician had indicated that she had what the husband understood to be "varicose veins"; an ultrasound examination of the lower leg at another hospital was reported to be negative. She was taking hydrocodone plus acetaminophen and ibuprofen as needed for ankle pain, as well as an oral contraceptive. Since the ultrasound examination, she had taken one "baby aspirin" daily.
She had no allergies. She had three young children, who were well. She worked as an administrative assistant at a local college. She had never smoked or drunk alcohol. Her husband could recall no family medical problems, except that her mother had a history of phlebitis.
In the emergency department, the patient remained unresponsive. The temperature was 35.5°C, the blood pressure was 170/123 mm Hg, the heart rate was 154 beats per minute, and the oxygen saturation ranged from 78 to 85 percent while the fraction of inspired oxygen was 1.0. Physical examination revealed no evidence of acute traumatic injury. The pupils were 4 mm in diameter and sluggishly reactive to light. The trachea was midline, and the oropharynx was clear. Both carotid pulses were palpable. The heart and lungs were normal on auscultation. The abdomen was soft and not distended, with normal bowel sounds. The left lower leg was in a cast to the middle of the calf. There was no swelling or edema of either leg. The skin was cool and there was peripheral cyanosis. There was no spontaneous movement of the eyes or the arms and legs and no gag reflex.
Almost immediately after arrival, the woman again became pulseless. Two 1-mg doses of epinephrine, one ampule of 50 percent dextrose in water, and one ampule of sodium bicarbonate were administered. After another three to five minutes of cardiopulmonary resuscitation, the pulse returned. The systolic blood pressure was 60 to 70 mm Hg. Five minutes after arrival, a triple-lumen catheter was placed in the right femoral vein, and a dopamine infusion was titrated to 56 μg per minute to maintain a systolic blood pressure of 130 to 140 mm Hg.
An electrocardiogram showed a ventricular rate of 56 beats per minute, atrioventricular dissociation, a right bundle-branch block, and nonspecific ST-segment abnormalities (Figure 1A). A radiograph of the chest showed that the tip of the endotracheal tube was approximately 1.5 cm above the carina; there was a diffuse infiltrate in the right upper lung lobe (Figure 2).
Figure 1. Electrocardiograms Obtained on Admission to the Emergency Department.
An initial electrocardiogram (Panel A) shows a ventricular rate of 56 beats per minute, atrioventricular dissociation, right bundle-branch block, and nonspecific ST-segment abnormalities (lead V3 is an artifact). Another electrocardiogram (Panel B) shows a ventricular rate of 101 beats per minute and atrial fibrillation, incomplete right bundle-branch block, and nonspecific ST-segment and T-wave abnormalities.
Figure 2. Chest Radiograph Obtained on Admission to the Emergency Department.
There is diffuse consolidation in the right lung, with maximal consolidation in the right upper lobe. The left lung is clear. R denotes right.
Two liters of normal saline were administered, and administration of norepinephrine was started at a dose of 7.5 μg per minute. The blood pressure again dropped, to 80/40 mm Hg, and the oxygen saturation dropped to 70 to 72 percent. Additional laboratory values are shown in Table 1.
Table 1. Laboratory Values.
Another electrocardiogram showed a ventricular rate of 101 beats per minute and atrial fibrillation, with incomplete right bundle-branch block, and nonspecific ST-segment and T-wave abnormalities (Figure 1B). A bedside echocardiogram showed no evidence of pericardial tamponade but revealed possible dilatation of the right ventricle. Additional episodes of pulselessness occurred, necessitating further cardiopulmonary-resuscitation efforts.
Thirty-five minutes after admission, 15 mg of alteplase (a recombinant tissue plasminogen activator) was given as an intravenous bolus, and then 85 mg was infused over a period of 90 minutes. Pulselessness continued for about 20 minutes. At 20 minutes, pulses returned, the oxygen saturation was 80 to 90 percent, and the systolic blood pressure stabilized at 140 mm Hg. Pressor medications were discontinued. There were no more episodes of pulselessness. The patient remained unresponsive and was transferred to the coronary care unit while receiving an infusion of 1300 units of heparin per hour. An echocardiogram showed marked enlargement and hypokinesis of the right ventricle with moderate tricuspid insufficiency; the size and function of the left ventricle were normal (Figure 3A and Figure 3B).
Figure 3. Echocardiograms.
An apical four-chamber view of the heart obtained several hours after admission to the coronary care unit (Panel A) shows dilatation of the right ventricle. The contractility of the right ventricle was poor, and the function of the right ventricular apex was slightly better than that of the base and midventricular portions; these findings are characteristic of pulmonary embolism. Panel B is a spectral Doppler tracing of the tricuspid regurgitant flow, also obtained after admission to the coronary care unit. The peak systolic velocity of the tricuspid regurgitant jet was 2.6 m per second, and the estimated right ventricular systolic pressure was 38 mm Hg (assuming a right atrial pressure of 10 mm Hg). A third echocardiogram, obtained at a follow-up examination 10 days after admission (Panel C), shows the apical four-chamber view of the heart with normalization of the size of the right ventricular cavity and substantial improvement in right ventricular systolic function. LV denotes left ventricle, RV right ventricle, RA right atrium, and LA left atrium.
The patient's trachea was extubated later that day, and her mental status improved, so that she was able to follow commands and talk with her family. An ultrasound examination of the femoral and popliteal veins showed no evidence of thrombosis.
A hypercoagulability evaluation on the third hospital day revealed a mildly elevated homocysteine level of 14.3 μmol per liter (normal, 0 to 12). The IgG anticardiolipin antibody titer was 17.8 IgG phospholipid units (reference range, <15) and there were decreases in functional protein C (52 percent of the normal value ) and protein C antigen (56 percent of the normal value ), but the result of a test for resistance to activated protein C was normal. Treatment with warfarin was initiated on the fourth hospital day.
The patient's hospital course was complicated by the development of acute renal failure (peak creatinine levels of 10.7 mg per deciliter ), epistaxis, and a right-groin hematoma. On the 10th hospital day, she had a tonic–clonic seizure; a computed tomographic (CT) scan of her head showed small left frontal and cerebellar hemorrhages. Antibodies against heparin-platelet factor 4 complexes were detected — a finding consistent with the presence of heparin-induced thrombocytopenia — but the platelet count was normal. Anticoagulation therapy was discontinued. A filter was placed in the inferior vena cava. Administration of phenytoin was begun, and no further seizures occurred.
The patient was discharged to a rehabilitation facility on the 25th hospital day. Two weeks later, she was readmitted to this hospital because of edema in her legs. CT scanning showed a clot that filled the inferior vena cava and extended to the left common iliac vein. Anticoagulation therapy with warfarin and argatroban was instituted. The leg edema resolved, and she was discharged home, with instructions to continue taking warfarin (with a target international normalized ratio of 2 to 3).
Differential Diagnosis
Dr. Eric S. Nadel: May we review the imaging studies?
Dr. Amita Sharma: An anteroposterior chest radiograph was obtained in the emergency department with the use of portable equipment (Figure 2). The tip of the endotracheal tube is 1.5 cm from the top of the carina. The cardiac silhouette is normal, given the anteroposterior projection. There is diffuse consolidation in the right lung, most prominently in the right upper lobe. The left lung is clear. The differential diagnosis of asymmetric consolidation with this appearance includes pulmonary hemorrhage, pneumonia (including aspiration pneumonia), asymmetric pulmonary edema, and pulmonary infarction. A follow-up radiograph obtained 24 hours later showed rapid clearing of the consolidation in the right lung. Therefore, the most likely causes of the consolidation in the right lung are resolving pulmonary hemorrhage or pulmonary edema, since pulmonary infarction and pneumonia would take longer to clear up.
Dr. Mary Etta King: The echocardiogram obtained in the coronary care unit showed dysfunction and enlargement of the right ventricle. In an apical four-chamber view, the left ventricle appears to function normally, but the right ventricle is dilated and contracts poorly (Figure 3A and Video 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). There is preservation of some function at the right ventricular apex. This combination of segmental dysfunction of the right ventricle with preserved apical function is highly specific to acute pulmonary embolus.1 Color Doppler studies show moderate tricuspid regurgitation into the right atrium (Figure 3B and Video 2 of the Supplementary Appendix). The estimated right ventricular systolic pressure, calculated from the peak systolic velocity of the regurgitant tricuspid jet, is 38 mm Hg.
Cross-sectional views from the parasternal window confirmed good left ventricular function with no pericardial effusion, as had been seen on the bedside echocardiogram obtained earlier in the day. The right ventricle was as large as the left ventricle, and the free wall did not contract well. A follow-up study performed 10 days after the first admission showed improvement in right ventricular size and function (Figure 3C and Video 3 of the Supplementary Appendix).
Dr. Nancy Lee Harris (Pathology): Dr. Nadel will discuss the care of this patient in the emergency department, and Dr. Samuel Goldhaber will discuss the management of pulmonary embolism.
Dr. Nadel: Pulseless electrical activity refers to any semiorganized electrical activity that can be seen on the cardiac monitor and is not accompanied by a palpable pulse.2 The term "pulseless electrical activity" has replaced "electromechanical dissociation," which implied a dissociation of the electrical function of the heart from the contractile function. Pulseless electrical activity is often thought of as a state resembling severe shock and without a pulse. Although the terminology has changed, the differential diagnosis has not, and it includes volume depletion, hypoxia, acidosis, hyperkalemia and hypokalemia, hypothermia, ingestion of toxic substances, cardiac tamponade, tension pneumothorax, and both coronary and pulmonary thrombosis. The prognosis for an out-of-hospital cardiac arrest, especially if it involves pulseless electrical activity in particular, is poor; 17 percent of patients who present with cardiac arrest have pulseless electrical activity,3 and of those, 1 to 4 percent survive.4 Treatment of pulseless electrical activity (Table 2) includes administration of epinephrine and atropine, as was performed in this case, and the primary focus is on identification and treatment of the underlying cause.
Table 2. Treatment of Pulseless Electrical Activity.
The clinical presentation of a young woman who has pulseless electrical activity and a cast on her leg and who has recently been evaluated for deep venous thrombosis suggests massive pulmonary embolism. The initial clinical decisions involve the selection of objective diagnostic techniques. Although the measurement of D-dimer levels is often discussed in the evaluation of pulmonary embolism, we believed it would not have helped in this case. We also did not obtain a CT scan or a ventilation–perfusion scan because the patient could not safely leave the intensive-care environment of the emergency department for the performance of these tests. The electrocardiogram revealed an incomplete right-bundle-branch block, and although this abnormality is sometimes found in patients with pulmonary embolism, it is not diagnostic. Rapid bedside echocardiography in the emergency department showed a dilated right ventricle, but this limited study in the setting of cardiopulmonary resuscitation was certainly not diagnostic.
With the presumptive diagnosis of massive pulmonary embolism, we decided to administer intravenous thrombolytic therapy. Is there a role for thrombolysis in patients who have cardiac arrest with pulseless electrical activity? There are certainly many case reports and case series that document high survival rates when thrombolytic agents were administered to patients in cardiac arrest,5 but selection bias makes these reports difficult to interpret. Objective data from two studies6,7 suggest that thrombolysis in undifferentiated cardiac arrest is associated with an increase in the rate of return of spontaneous circulation and an increase in 24-hour survival, but not that it is associated with a clear benefit in terms of long-term outcome. A more recent, randomized, prospective study8 assessed the value of thrombolytic therapy in 233 patients who had cardiac arrest with pulseless electrical activity. One patient survived in the group treated with tissue plasminogen activator; there were no survivors in the control group. There was no difference in the rate of return to spontaneous circulation. The current literature does not support the administration of thrombolytic agents in all cases of undifferentiated pulseless electrical activity and cardiac arrest, but the successful outcome in the patient under discussion and in other case reports and small series suggests that thrombolytic agents should be considered in selected patients. Further research will be required to determine whether administration of these agents in the setting of cardiac arrest will lead to improved outcomes, and whether this therapy will benefit selected patients, such as those with high clinical suspicion for massive pulmonary embolism.
I would like to make one final comment about this case. The decision to continue cardiopulmonary-resuscitation efforts for 15 to 20 minutes after administration of the thrombolytic agent was important in the management of this case. We had several discussions about continuing these efforts. In retrospect, the continuation was critical to the successful outcome in this patient. This experience suggests that when thrombolytic agents are used, some time may be necessary for them to be effective.
Discussion of Management
Dr. Samuel Z. Goldhaber: On October 3, 1930, when John Gibbon, M.D., a surgical research fellow at this hospital, witnessed the collapse of a patient with massive pulmonary embolism after a general surgical operation, Gibbon remained at the patient's bedside overnight and observed her continued clinical deterioration. His chief of surgery, Edward Churchill, M.D., attempted a closed pulmonary embolectomy (Trendelenburg's operation), which was unsuccessful. Gibbon was so devastated by this experience that he devoted the ensuing 23 years to developing a heart–lung machine. On May 6, 1953, he performed the first successful open-heart operation.9
The patient with massive pulmonary embolism whom we are currently discussing was successfully resuscitated with the emergency administration of a thrombolytic agent, despite an initial partial pressure of arterial oxygen of 32 mm Hg and a pH of 6.67. Drs. Gibbon and Churchill would have been proud of this accomplishment.
The case under discussion raises four points to consider when evaluating and treating pulmonary embolism: risk stratification; thrombolysis; alternatives to thrombolysis, including catheter and surgical embolectomy; and the optimal duration and intensity of anticoagulation.
Risk Stratification
If I can provide a single "take-home" lesson, it is the importance of risk stratification in patients with newly diagnosed pulmonary embolism. Pulmonary embolism spans a wide spectrum of severity, from asymptomatic patients with small thrombi to those with life-threatening disease that causes cardiogenic shock, such as the patient under discussion. Treatment options vary so widely that we must assess each patient's prognosis in order to choose appropriately from the menu of therapy. At one extreme, outpatient treatment is safe and feasible in patients at low risk.10 In contrast, patients with impending or ongoing cardiovascular collapse must receive consideration for thrombolysis or embolectomy. Patients whose risk level is between these two extremes will warrant anticoagulation with heparin as a bridge to oral anticoagulation.
Accurate and rapid risk stratification takes into account the clinical presentation, the findings on physical examination, the chest radiograph, the echocardiogram, and, recently, the levels of cardiac biomarkers such as troponin, pro–brain natriuretic peptide, and brain natriuretic peptide.11,12 Typically, the clinical presentation is assessed by the clinician's overall impression. An alternative approach, the Geneva Prognostic Index,13 relies on bedside evaluation and a scoring system of 0 to 8 points. Two points each are given for cancer and for a systemic arterial pressure of less than 100 mm Hg. One point each is given for heart failure, previous deep-vein thrombosis, hypoxemia, and new deep-vein thrombosis that has been confirmed by ultrasound examination. As the point score increases, the likelihood of an adverse outcome (defined as death, recurrent venous thromboembolism, or major bleeding) increases.
In patients with submassive or massive pulmonary embolism, important findings from the physical examination may include the detection of jugular-vein distention, tricuspid regurgitation, and an accentuated pulmonic heart sound — all manifestations of right-sided heart failure. The electrocardiogram was very useful in assessing the patient under discussion, because it showed right bundle-branch block, a classic sign of right ventricular strain in patients with acute pulmonary embolism. The bedside transthoracic echocardiogram is invaluable14 because it may reveal a constellation of findings in major pulmonary embolism (Table 3) and because it can rule out other important diagnoses with radically different treatment, such as pericardial tamponade, aortic dissection, and acute myocardial infarction.
Table 3. Echocardiographic Findings in Major Pulmonary Embolism.
This patient had hypotension, probable heart failure (suggested by the findings on the chest radiograph), possible new deep-vein thrombosis, an abnormal electrocardiogram, repeated episodes of pulseless electrical activity, and possible right ventricular enlargement, with no evidence of cardiac tamponade on the echocardiogram. She clearly falls into a category of extremely high risk for death. Indeed, the question in assessing this patient is not whether she is at high risk but whether a pulmonary embolus is the cause of her problems.
Thrombolysis
For patients identified as being at high risk, such as this woman, thrombolysis should be considered. The thrombolytic regimen approved by the Food and Drug Administration (FDA) is 100 mg of tissue plasminogen activator administered as a continuous infusion over a two-hour period. The principal benefit from thrombolysis is a rapid reversal of right heart failure, which may reduce the risk of death and help ensure a more stable hospital course.15,16 Thrombolysis may also preserve the hemodynamic response to exercise over the long term and improve the patient's quality of life.17 Its potential disadvantage is that it may cause major bleeding, especially intracranial hemorrhage, which may occur in up to 3 percent of patients.18
Embolectomy
High-risk patients who also have a very high risk of hemorrhage from thrombolysis should be considered for embolectomy. Catheter embolectomy may be undertaken with one of several different techniques.19
At Brigham and Women's Hospital, we offer open surgical embolectomy on an around-the-clock basis20 for high-risk patients with preserved systemic arterial pressure. We performed 29 embolectomies during a two-year period, with a survival rate of 89 percent.20 Generally speaking, the decision of whether to use catheter or surgical embolectomy depends on the expertise available at the hospital.
For patients who are stratified as having a high-risk pulmonary embolus, such as this patient, I would recommend a plan of care based on thrombolysis or embolectomy in addition to heparin anticoagulation (Figure 4). In this patient, thrombolysis was dramatically effective, restoring a normal blood pressure within 20 minutes.
Figure 4. Algorithm for the Management of Massive Pulmonary Embolism.
Optimal Duration and Intensity of Anticoagulation
After a patient has been stabilized, we need to consider the optimal duration of oral anticoagulation. Until recently, the standard duration of therapy for pulmonary embolism has been six months.21 Longer-duration anticoagulation decreases the recurrence rate but increases the likelihood of major bleeding.22,23
In a recent double-blind, placebo-controlled trial, my colleagues and I tested a new strategy of indefinite-duration warfarin anticoagulation at a low-intensity INR (1.5 to 2.0) in patients with idiopathic venous thromboembolism who had received an average of approximately six months of standard-intensity anticoagulation, (INR, 2.0 to 3.0). The patients who received long-term low-intensity warfarin had a 64 percent reduction in the rate of recurrent thromboembolic events relative to that in the placebo group, with no increase in major bleeding.24 More than half of all patients with pulmonary embolism will fit into the idiopathic group as defined by this trial, and will benefit from indefinite-duration warfarin (Figure 5).
Figure 5. Optimal Duration and Intensity of Anticoagulation for Pulmonary Embolism.
INR denotes international normalized ratio. This information is from Ridker et al.24
The patient under discussion had deep-vein thrombosis due to an ankle fracture. In the absence of other predisposing factors, she should do well if she receives six months of anticoagulation therapy, despite her near-fatal pulmonary embolism. However, if the presence of antiphospholipid antibodies is confirmed, she should receive anticoagulation at standard intensity for an indefinite duration.25
Dr. Noble: When this patient presented, there was some discussion regarding the dose and rate of thrombolytic therapy for a suspected pulmonary embolus. Are there any data to support bolus therapy in patients with cardiac arrest? What would you recommend as a bolus dose?
Dr. Goldhaber: I think a bolus followed by continuous infusion is superior to the infusion alone, because it offers a faster onset of action. In patients receiving a continuous infusion, my colleagues and I have rarely seen clinical improvement before 45 or 50 minutes had elapsed, and in this patient with a bolus, clinical improvement was seen within 20 minutes. In a recent trial, a 10-mg bolus followed by a 90-mg infusion over the remainder of the two-hour period was used.16 So I think your decision was wise.
Dr. Phillip Rice (Emergency Medicine): How effective is thrombolytic therapy? If it fails, are these patients still candidates for embolectomy?
Dr. Goldhaber: About 80 percent of treated patients will improve with thrombolytic therapy. Those in whom thrombolysis is not effective may be candidates for open surgical embolectomy, but they will have high blood-transfusion requirements.
Dr. David Brown (Emergency Medicine): Do you think that oral direct thrombin inhibitors will replace warfarin?
Dr. Goldhaber: Ximelagatran, an oral direct thrombin inhibitor, looks promising as compared with standard anticoagulation for the management of acute deep venous thrombosis26 and atrial fibrillation27 and the prevention of venous thromboembolism in patients undergoing total knee replacement.28 Its major advantage is that it can be administered in a fixed dose, without a requirement for blood testing for dose adjustment and without raising concerns about drug–drug or drug–food interactions. Its potential disadvantages are the need for twice-daily administration and an observed rise in aminotransferases that is three times as high as normal or higher in 6 to 9 percent of patients during the first six months of administration. The FDA is evaluating the efficacy and safety of ximelagatran as compared with standard therapy.
Dr. Harris: The patient's primary care physician, Dr. Virginia H. Palazzo, has provided us with additional information. Ten days before the patient's presentation to the emergency room, she was seen in her doctor's office with pain and tenderness of the left calf. There was no swelling, and an ultrasound study showed no signs of venous thrombosis. In a telephone conversation with her doctor the next day, the patient said she was improved. At a follow-up visit three days after her second discharge from this hospital, the patient had residual right-sided weakness from her intracerebral hemorrhages. This gradually improved, and she returned to work five months after the cardiac arrest. Eleven months after her illness she was driving, talking normally, and performing all her normal activities. She continued to take warfarin.
Final Diagnosis
Cardiac arrest due to a pulmonary embolus.
Source Information
From the Cardiovascular Division, Department of Medicine (S.Z.G.), and the Department of Emergency Medicine (E.S.N.), Brigham and Women's Hospital; the Departments of Emergency Medicine (E.S.N.), Pediatric Cardiology (M.E.K.), and Radiology (A.S.), Massachusetts General Hospital; and the Departments of Medicine (S.Z.G., E.S.N.), Pediatrics (M.E.K.), and Radiology (A.S.), Harvard Medical School — all in Boston.
References
McConnell MV, Solomon SD, Rayan ME, Come PC, Goldhaber SZ, Lee RT. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 1996;78:469-473.
ACLS provider manual. Dallas: American Heart Association, 2002.
Stueven HA, Aufderheide T, Waite EM, Mateer JR. Electromechanical dissociation: six years prehospital experience. Resuscitation 1989;17:173-182.
Eisenberg MS, Mengert TJ. Cardiac resuscitation. N Engl J Med 2001;344:1304-1313.
Newman DH, Greenwald I, Callaway CW. Cardiac arrest and the role of thrombolytic agents. Ann Emerg Med 2000;35:472-480.
Lederer W, Lichtenberger C, Pechlaner C, Kroesen G, Baubin M. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation 2001;50:71-76.
Bottiger BW, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initial unsuccessful cardiopulmonary resuscitation: a prospective trial. Lancet 2001;357:1583-1585.
Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med 2002;346:1522-1528.
Cohn LH. Fifty years of open-heart surgery. Circulation 2003;107:2168-2170.
Beer JH, Burger M, Gretener S, Bernard-Bagattini S, Bounameaux H. Outpatient treatment of pulmonary embolism is feasible and safe in a substantial proportion of patients. J Thromb Haemost 2003;1:186-187.
Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation 2003;108:2191-2194.
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;106:1263-1268.
Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF. Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost 2000;84:548-552.
Goldhaber SZ. Echocardiography in the management of pulmonary embolism. Ann Intern Med 2002;136:691-700.
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;341:507-511.
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-1150.
Sharma GV, Folland ED, McIntyre KM, Sasahara AA. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism. Vasc Med 2000;5:91-95.
Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-1389.
Goldhaber SZ. Integration of catheter thrombectomy into our armamentarium to treat acute pulmonary embolism. Chest 1998;114:1237-1238.
Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation 2002;105:1416-1419.
Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-1665.
Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907.
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434.
Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752-763.
Eriksson H, Wahlander K, Gustafsson D, Welin LT, Frison L, Schulman S. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003;1:41-47.
Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691-1698.
Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703-1712.(Samuel Z. Goldhaber, M.D.)