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82-Year-Old Man With Recurrent Syncope

  • Emmanouil S. Brilakis
    Affiliations
    Resident in Internal Medicine, Mayo Graduate School of Medicine, Mayo Clinic Rochester, Rochester, Minn
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  • A. Jamil Tajik
    Correspondence
    Address reprint requests and correspondence to A. Jamil Tajik, MD, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905
    Affiliations
    Adviser to resident and Consultant in Cardiovascular Diseases and Internal Medicine, Mayo Clinic Rochester, Rochester, Minn
    Search for articles by this author
      An 82-year-old man with coronary artery disease and a myelodysplastic syndrome sought medical assessment because of a 3-week history of chest tightness and dyspnea on exertion. He denied having orthopnea or paroxysmal nocturnal dyspnea but had recently noticed lower extremity swelling and progressive fatigue. His medications (atenolol, nifedipine, isosorbide mononitrate, and aspirin) had not been changed. On physical examination, he appeared pale. His blood pressure was 120/60 mm Hg, and his pulse rate was 78/min and regular. Jugular venous pressure was approximately 10 mm Hg (conversion of jugular venous pressure from centimeters of water to millimeters of mercury is accomplished by dividing centimeters of water by 1.36). Cardiac examination revealed a grade 2/6 early peaking systolic ejection murmur along the upper left sternal border. His lungs were clear on auscultation and percussion. The spleen was enlarged, and a grade 1 to 2 symmetric bilateral pitting edema of the lower extremities was present.
      • 1.
        Which one of the following would be most helpful in explaining this patient's symptoms?
        • a.
          Transthoracic echocardiography
        • b.
          Electrocardiography
        • c.
          Thyroid-stimulating hormone level
        • d.
          Arterial blood gas (ABG) analysis
        • e.
          Complete blood cell count
      Unstable angina is defined as (1) crescendo angina (more frequent, severe, or prolonged), (2) new-onset angina <2 months), or (3) angina at rest. Our patient's symptoms, which began 3 weeks earlier, are typical of angina; therefore, he has unstable angina. Unstable angina is caused by an imbalance between myocardial oxygen supply and demand. Causes of decreased myocardial oxygen supply include severe coronary artery stenosis, ruptured plaque with thrombus formation, hypotension, anemia, and hypoxemia. Causes of increased myocardial oxygen demand include fever, infection, hypertension, aortic stenosis, tachyarrhythmia, emotional stress, and thyrotoxicosis. In patients with unstable angina, identifying the presence of any of the aforementioned conditions is crucial before performing coronary angiography.
      Echocardiography is the test of choice for diagnosing and quantifying aortic stenosis. Severe aortic stenosis can precipitate angina, but it is unlikely in this patient because of the low intensity and early peaking systolic murmur and the preserved S2. An electrocardiogram could reveal ischemic ST or T-wave changes, but these are nonspecific for a particular cause of ischemia. An extremely low thyroid-stimulating hormone level is highly suggestive of thyrotoxicosis, which can increase the workload of the heart by producing a high output state. However, no indications in the patient's history (eg, heat intolerance, weight loss, or diarrhea) or findings on the physical examination (eye, skin, or thyroid changes) suggest a thyroid disorder. Hypoxemia, which could be detected by ABG analysis, is unlikely because findings on the lung examination were normal. A complete blood cell count is the most helpful test in our patient, who has a history of a myelodysplastic syndrome and appears pale. Anemia could explain the new-onset angina, the fatigue, and the dyspnea on exertion.
      A Coombs test revealed that the patient had hemolytic anemia (hemoglobin level, 7.5 g/dL). The exertional angina resolved with packed erythrocyte transfusions. Corticosteroid therapy was unsuccessful; 2 weeks later, the patient underwent an uneventful splenectomy. The first postoperative day he experienced syncope while walking. Findings on physical examination, including vital signs and neurologic assessment, were unchanged from baseline. He remained in bed the rest of the day and was asymptomatic. On the second postoperative day, the syncope recurred.
      • 2.
        Which one is the least probable cause of the patient's 2 syncopal episodes?
        • a.
          Orthostatic hypotension
        • b.
          Transient ischemic attack (TIA)
        • c.
          Myocardial infarction (MI)
        • d.
          Dysrhythmia
        • e.
          Pulmonary embolism (PE)
      Syncope is a sudden temporary loss of consciousness associated with a loss of postural tone with spontaneous recovery; electrical or chemical cardioversion is unnecessary.
      • Kapoor WN
      Syncope and hypotension.
      The causes can be cardiac or noncardiac. Cardiac abnormalities that may cause cerebral ischemia by decreasing cardiac output include dysrhythmias, obstruction of right ventricular outflow (eg, PE) or left ventricular outflow (eg, aortic stenosis, hypertrophic obstructive cardiomyopathy), and pump failure. Noncardiac causes include orthostatic hypotension, neurologic diseases (eg, migraine, seizure, TIA), and reflex-mediated vasomotor instability (eg, vasovagal syncope or carotid sinus hypersensitivity).
      • Kapoor WN
      Syncope and hypotension.
      Orthostatic hypotension is very likely in this elderly man who is recovering from major surgery and is taking 3 blood pressure–lowering medications (atenolol, nifedipine, and isosorbide mononitrate). A TIA in conjunction with syncope is almost always associated with vertebrobasilar insufficiency and concurrent neurologic symptoms, most frequently vertigo, ataxia, and paresthesias.
      • Kapoor WN
      Syncope and hypotension.
      Because of the absence of neurologic symptoms or signs in our patient, TIA is the least likely diagnosis. MI is possible (known coronary artery disease), but he was receiving β- blockers perioperatively and had no chest pain. Both tachydysrhythmias and bradydysrhythmias may occur intermittently, and prolonged electrocardiographic monitoring is necessary for detection. PE can manifest with syncope due to right ventricular outflow obstruction, especially when it is massive.
      • Bell WR
      • Simon TL
      • De Mets DL
      The clinical features of sub-massive and massive pulmonary emboli.
      Our patient had risk factors for PE (advanced age, recent surgery)
      • Silverstcin MD
      • Hcit JA
      • Mohr DN
      • Petterson TM
      • O'Fallon WM
      • Melton III, U
      Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.
      • Fcdullo PF
      • Moser KM
      Advances in acute pulmonary embolism and chronic pulmonary hypertension.
      and had received no deep venous thrombosis (DVT) prophylaxis. He had no other suggestive symptoms (eg, dyspnea or pleuritic chest pain) or signs (eg, unilateral edema of the extremities, increased intensity of the S2, or an S 4), but the diagnosis of PE cannot be confirmed or excluded on the basis of history or physical examination findings alone.
      • Kapoor WN
      Syncope and hypotension.
      Pulse oximetry while the patient was breathing room air showed an oxygen saturation of 95%. Electrocardiographic findings were unchanged from baseline. While he received 2 L of supplemental oxygen, ABG analysis revealed an arterial oxygen pressure (PaO2) of 123 mm Hg, a carbon dioxide pressure (PCO2) of 38 mm Hg, and a pH of 7.45. Chest radiographic findings were normal. The creatine kinase (CK) level was 158 U/L (reference range, 52–336 U/L), with a CK-MB of 1.7 ng/mL (reference, 4.3 ng/mL or lower). On the third postoperative morning, the patient had shortness of breath. His blood pressure was 110/50 mm Hg, heart rate was 82/min, respiratory rate was 20/min, and oxygen saturation was 84% while he was breathing 2 L of supplemental oxygen. Jugular venous pressure was 16 mm Hg. The S2 was loud, and basilar end-inspiratory crackles were detected bilaterally. When the patient tried to stand, he suddenly lost consciousness. Systolic blood pressure decreased to 70 mm Hg, heart rate was 120/min, and oxygen saturation was 73%. He soon recovered consciousness but had severe dyspnea and diaphoresis.
      • 3.
        Which one of the following is least appropriate as immediate action in this patient?
        • a.
          Intravenous administration of normal saline
        • b.
          Oxygen administration
        • c.
          Trendelenburg position
        • d.
          Intravenous administration of 10,000 U of unfractionated heparin
        • e.
          Pericardiocentesis
      The patient was in shock and had an increased jugular venous pressure; the differential diagnosis includes PE, acute MI involving the right ventricle, tension pneumothorax, tamponade, valvular obstruction (eg, thrombosis of an artificial valve), and atrial myxoma causing ventricular outflow obstruction. If we assume that the same underlying disease caused all 3 syncopal episodes, then acute MI would be unlikely because of the normal electrocardiographic findings and the normal CK level. Tension pneumothorax would have been detected by chest radiography. No pericardial friction rub or pulsus paradoxus was present to suggest tamponade. Cardiac myxomas are extremely rare. Therefore, PE is the most likely diagnosis. The recurrent syncopal episodes could be attributed to successive thrombus detachment from the site of formation and embolization to the branches of the pulmonary artery.
      Rapid administration of normal saline, oxygen supplementation, and Trendelenburg position should be implemented as soon as possible to provide better brain oxygenation. Even though the patient would be at increased risk of bleeding (prior surgery), intravenous administration of heparin would be reasonable because PE is the most likely diagnosis. Pericardiocentesis should be delayed until echocardiography confirms tamponade. The patient was given 10,000 U of unfractionated heparin intravenously and was transferred to the intensive care unit because he remained hypotensive.
      • 4.
        Which one of the following would be least useful in the management of our patient?
        • a.
          Electrocardiography
        • b.
          Plasma d-dimer level
        • c.
          Chest radiography
        • d.
          Echocardiography
        • e.
          ABG analysis
      Electrocardiography would show Q waves, ST-segment elevation, or T -wave inversion, suggestive of acute MI. Low voltage and electrical altemans would suggest a pericardial effusion, which could cause tamponade. Sinus tachycardia, S1Q3T3 pattern (prominence of S wave in lead I, Q wave in lead III, and T-wave inversion in lead III), right bundle branch block, and right axis deviation would raise suspicion for PE.
      • Coldhaber SZ
      Pulmonary embolism.
      d- Dimer levels are increased for at least 1 week postoperatively and therefore would be increased in our patient whether or not he had PE. Chest radiography would detect tension pneumothorax. Enlargement of the cardiac silhouette with a “water bottle” configuration would suggest a pericardial effusion. Wester-mark sign (focal oligemia), “Hampton hump” (wedge-shaped density above the diaphragm), or normal chest radiographic findings would imply PE.
      • Coldhaber SZ
      Pulmonary embolism.
      An echocardiogram would readily reveal a pericardial effusion or regional wall motion abnormalities consistent with an ML Right ventricular dilatation and hypokinesis, abnormal interventricular septal motion, tricuspid valve regurgitation, and pulmonary artery dilatation are echocardiographic findings that are indicative of PE. Occasionally, the diagnosis of PE can be established if a thrombus is visualized.
      • Coldhaber SZ
      Pulmonary embolism.
      ABG analysis would offer little diagnostic help because it cannot exclude PE,
      • Stein PD
      • Goldhabcr SZ
      • Henry JW
      • Miller AC
      Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism.
      but it could aid in determining the need for oxygen administration or intubation.
      ABG analysis, while the patient was breathing 5 L of oxygen through a face mask, showed a Pao2 of 44 mm Hg, Pco2 of 36 mm Hg, and pH of 7.46. An electrocardiogram showed sinus tachycardia. The patient's blood pressure soon stabilized at 110/70 mm Hg. Emergency bedside echocardiography revealed dilatation and hypokinesis of the right ventricle and an enlarged right atrium. Pulmonary artery pressure was 72 mm Hg (Doppler ultrasonography), and moderate tricuspid regurgitation was present. No thrombus was visualized, and the inferior vena cava did not collapse with inspiration. These observations prompted enhanced electron-beam computed tomography of the chest, which confirmed the clinical diagnosis of PE.
      • 5.
        Which one of the following would be the least appropriate next step in the patient's management?
        • a.
          Intravenous administration of unfractionated heparin
        • b.
          Subcutaneous administration of unfractionated heparin
        • c.
          Administration of low-molecular-weight heparin (LMWH)
        • d.
          Placement of an inferior vena cava filter
        • e.
          Use of tissue-type plasminogen activator
      An adjusted dose of intravenous or subcutaneous unfractionated heparin has been the standard treatment for PE,
      • Hyers TM
      • Agnelli G
      • Hull RD
      • et al.
      Antithrombotic therapy for venous thromboembolic disease.
      but a fixed subcutaneous dose of LMWH was recently proved to be equally effective and safe,
      • Weitz JI
      Low-molccular-weight heparins.
      The patient's recent surgery is a relative contraindication to anticoagulation. Placement of an inferior vena cava filter could prevent recurrent PE, and thus anticoagulation could be avoided. Tissue-type plasminogen activator has been used for thrombolysis in patients with PE.
      • Dalen JE
      • Alpert JS
      • Hirsch J
      Thrombolytic therapy for pulmonary embolism: is it effective? is it safe? when is it indicated?.
      Thrombolysis provides faster improvement in pulmonary perfusion and right ventricular function than does heparin alone. However, thrombolysis does not reduce mortality and is associated with an increased risk of bleeding (including intracranial hemorrhage) compared with heparin. Thrombolysis (or embolectomy) is indicated in patients with massive PE and hypotension, in the absence of contraindications.
      • Dalen JE
      • Alpert JS
      • Hirsch J
      Thrombolytic therapy for pulmonary embolism: is it effective? is it safe? when is it indicated?.
      Even though our patient was hypotensive, he had a high risk of bleeding because of recent surgery. Therefore, thrombolysis would be the least appropriate management option.
      The patient received unfractionated heparin, and warfarin was instituted on the same day. No bleeding occurred, and he remained hemodynamically stable. Heparin was discontinued 1 week later, when the international normalized ratio had been in the therapeutic range (between 2 and 3) for 2 days. The patient was discharged from the hospital with instructions to continue taking warfarin for the next 6 months, with a goal international normalized ratio between 2 and 3. Nine months later, he was doing well, with no recurrence of thromboembolism or anemia.

      Discussion

      This case illustrates the difficulty and challenge of diagnosing PE. During the first 2 syncopal episodes, the patient had no other symptoms or signs suggestive of PE. This is not surprising because in 1 study, 24 (26%) of 92 patients with fatal PE were previously asymptomatic.10 In our patient, PE was considered unlikely until his third syncopal episode, when dyspnea and signs of pulmonary hypertension appeared.
      Syncope can be the manifesting sign of PE; in various studies, 8% to 13% of patients with PE had syncope. Syncope is usually caused by massive PE. Bell et al2 reported that syncope occurred in 20% of the 197 patients with massive PE vs only 4% of the 130 patients with submassive PE (P<.001) (massive PE was defined as filling defects or obstruction of 2 or more lobar arteries). PE manifesting as syncope has a worse prognosis. Morgenthaler and Ryu
      • Morgenthaler TI
      • Ryu JH
      Clinical characteristics of fatal pulmonary embolism in a referral hospital.
      reported that 27% of patients with autopsy-proven PE had experienced syncope. Thus, massive PE is likely to manifest as syncope and cause death. Syncope should alert the clinician to the possibility of PE, even in the absence of other signs and symptoms. If PE is confirmed, the occurrence of syncope should be viewed as an adverse prognostic factor.
      The presence of risk factors should increase the suspicion for PE.
      • Silverstcin MD
      • Hcit JA
      • Mohr DN
      • Petterson TM
      • O'Fallon WM
      • Melton III, U
      Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.
      Our patient was elderly and had undergone surgery recently. Other risk factors include previous thromboembolism, trauma, hip or pelvic fracture, malignancy, congestive heart failure, obesity, prolonged immobilization, pregnancy and the postpartum period, oral contraceptive use, nephrotic syndrome, inflammatory bowel disease, and hereditary disorders (activated protein C resistance, prothrombin 20210 G to A mutation, deficiency of protein C or protein S, and others). 3,4
      The need for DVT prophylaxis in patients at risk cannot be overemphasized; if our patient had received DVT prophylaxis, his risk for PE may have been reduced. The 3 major prophylaxis approaches are subcutaneous heparin (unfractionated or LMWH), warfarin, and mechanical devices (graduated compression stockings and pneumatic compression devices).
      • Fcdullo PF
      • Moser KM
      Advances in acute pulmonary embolism and chronic pulmonary hypertension.
      The contraindications to their use are severe peripheral arterial disease, lower extremity compartment syndromes, and cutaneous lesions such as bums or infections.
      • Fcdullo PF
      • Moser KM
      Advances in acute pulmonary embolism and chronic pulmonary hypertension.
      DVT prophylaxis has been proved to be both effective and safe, and with long-term use, it could reduce PE-related morbidity and mortality.
      • Fcdullo PF
      • Moser KM
      Advances in acute pulmonary embolism and chronic pulmonary hypertension.
      Plasma d-dimer is a plasmin-derived degradation product of cross-linked fibrin. Determination of the d-dimer level is being evaluated as an exclusionary test for DVT and PE. It is sensitive but not specific; in 1 study, only 22% of the patients without thromboembolic disease had a d-dimer level lower than the critical cutoff value.
      • Fcdullo PF
      • Moser KM
      Advances in acute pulmonary embolism and chronic pulmonary hypertension.
      Therefore, the d-dimer test is best used for patients with suspected PE who have no coexisting systemic illness.' It was useless in our patient who had recently undergone surgery.
      Normal results on ABG analysis have also been proposed as an exclusionary test for PE. However, analysis of data from PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis)
      • PIOPED Investigators
      Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED).
      demonstrated that, with various combinations of a PAO2 of 80 mm Hg or more, a Pco2 of 35 mm Hg or higher, and an alveolar-arterial oxygen gradient (PAO2 – PAO2) of 20 mm Hg or less, PE could not be excluded in 38% of patients with no cardiopulmonary disease and in 14% of patients with prior cardiopulmonary disease.
      • Stein PD
      • Goldhabcr SZ
      • Henry JW
      • Miller AC
      Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism.
      Thus, normal results on ABG analysis are of insufficient discriminant value to permit exclusion of PE.
      After our patient's third syncopal episode, based on clinical suspicion, we administered heparin intravenously before the diagnosis of PE was confirmed. Immediate treatment of suspected PE has not been standardized. The decision should be made individually in light of the speed with which diagnostic test results can be obtained, the level of likelihood of suspected acute PE, the severity of the suspected acute PE, the cardiopulmonary status of the patient, and the potential risk of bleeding due to heparin therapy. Massive PE was strongly suspected in our patient, and his cardiopulmonary reserve was considered poor. If anticoagulation is unacceptable, an inferior vena cava filter would be indicated. If he had not undergone surgery and had remained hypotensive, thrombolytic therapy could have been given.
      Electron-beam computed tomography was used to confirm the diagnosis of PE in our patient. Results of a ventilation-perfusion scan, the traditional diagnostic tool for PE, are indeterminate in up to 75% of cases.
      • PIOPED Investigators
      Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED).
      In 1 study, electron-beam computed tomography compared with angiography, which is still the “gold standard” for the diagnosis of PE, had a sensitivity of 65% and a specificity of 97%; sensitivity for central emboli was 88%.
      • Teigen CH
      • Maus TP
      • Shccdy n, PF
      • et al.
      Pulmonary embolism: diagnosis with contrast-enhanced electron-beam CT and comparison with pulmonary angiography.
      Use of LMWH for the management of PE is increasing. Two trials of LMWH vs unfractionated heparin in the treatment of PE found similar efficacy and bleeding complications.
      • Weitz JI
      Low-molccular-weight heparins.
      LMWH produces a more predictable anticoagulant response than does unfractionated heparin. As a result, LMWH can be administered at weight-adjusted doses, on an outpatient basis, without monitoring of the activated partial thromboplastin time.
      • Weitz JI
      Low-molccular-weight heparins.
      In addition, heparininduced thrombocytopenia and, possibly, osteoporosis occur less frequently with LMWH.
      • Weitz JI
      Low-molccular-weight heparins.
      In our patient, intravenous unfractionated heparin was preferred over LMWH because of ongoing hospitalization. Unfractionated heparin has a shorter half-life (60 minutes), and its action can be reversed faster if bleeding occurs.'
      In summary, increased application of DVT prophylaxis may reduce the incidence of PE. A high index of suspicion could lead to earlier and more frequent diagnoses of PE with improved outcomes.

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        Syncope and hypotension.
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        • Simon TL
        • De Mets DL
        The clinical features of sub-massive and massive pulmonary emboli.
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        • Silverstcin MD
        • Hcit JA
        • Mohr DN
        • Petterson TM
        • O'Fallon WM
        • Melton III, U
        Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.
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        • Moser KM
        Advances in acute pulmonary embolism and chronic pulmonary hypertension.
        Adv Intern Med. 1997; 42: 67-104
        • Coldhaber SZ
        Pulmonary embolism.
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        • Miller AC
        Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism.
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        • et al.
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        Low-molccular-weight heparins.
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        Thrombolytic therapy for pulmonary embolism: is it effective? is it safe? when is it indicated?.
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        Clinical characteristics of fatal pulmonary embolism in a referral hospital.
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