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Treacherous Travelers: Emboli

      Presentation

      Simultaneous management of acute cerebrovascular accident and pulmonary embolism poses diagnostic and therapeutic challenges—particularly when the patient has signs hinting at myocardial infarction as well. A 53-year-old African American man presented with symptoms and examination findings consistent with a cerebrovascular accident. The triage electrocardiogram and initial laboratory tests also raised the possibility of myocardial ischemia. A transthoracic echocardiogram (TTE) revealed right ventricular systolic dysfunction. Computed tomography (CT) of the chest disclosed a large mass consistent with a thrombus in the right pulmonary artery. The patient had transient atrial arrhythmia, possible hypercoagulability, and a patent foramen ovale was identified.

      Assessment

      On presentation, the patient had the following vital signs: blood pressure 172/113 mm Hg; heart rate 87 beats per minute; respiratory rate 31 breaths per minute; and temperature 36°C (96.8°F). His oxygen saturation was 95% on 4 L of oxygen by nasal cannula. Jugular venous pressure was 9 cm of water at 45°. He appeared acutely ill and presented with a left gaze preference, dysarthria, and flaccid right hemiplegia. Sensory examination showed right-sided hemineglect. These neurological symptoms were discovered 90 minutes before his arrival, and he was last known to be functional 8 hours before this assessment. His initial score on the National Institutes of Health stroke scale was 21.
      Laboratory testing on arrival showed cardiac troponin T, 0.21 ng/mL (normal, <0.03); creatinine kinase MB, 5.6 ng/mL (normal, <5.0) with a total serum creatinine kinase concentration within the reference range; and an N-terminal brain natriuretic peptide concentration of 2538 pg/mL (normal, 0-900). CT imaging of the brain demonstrated early ischemic changes in the left middle cerebral artery territory without intracranial hemorrhage. Brain and neck CT angiography displayed complete occlusion of the left middle cerebral artery, left ophthalmic artery, left internal carotid artery, and left vertebral artery. The triage electrocardiogram showed normal sinus rhythm with a right bundle branch block, pathologic Q waves in leads III and aVF, and deep T-wave inversions in the anterior leads (Figure 1). The aforementioned TTE showed a left ventricular ejection fraction of 0.73 without obvious wall motion abnormalities, a dilated right heart with severely reduced systolic function, and moderate-to-severely elevated pulmonary artery systolic pressure (64 mm Hg). A saline contrast study for a right-to-left shunt was negative, and use of perflutren protein-type A microspheres as contrast failed to reveal an intracardiac thrombus. Chest CT with contrast illustrated a large pulmonary embolism involving the right main pulmonary artery; interlobar and right lower lobe branch occlusion was noted along with prominent intra-atrial septum bulging (Figure 2). Lower-extremity Doppler imaging was negative for deep vein thrombosis.
      Figure thumbnail gr1
      Figure 1An electrocardiogram obtained on presentation showed a right bundle branch block, pathologic Q waves in leads III and aVF, and deep anterior T-wave inversions.
      Figure thumbnail gr2
      Figure 2Computed tomography of the chest with contrast demonstrated a right main pulmonary artery filling defect (arrowhead) consistent with a large thrombus.

      Diagnosis

      The diagnosis of ischemic stroke was clear. Isolated but marked right ventricular systolic dysfunction was evident on TTE. Therefore, elevation of N-terminal brain natriuretic peptide and cardiac troponin T likely reflected myocardial necrosis secondary to right ventricular pressure overload rather than epicardial coronary vessel ischemia.
      • Walter T.
      • Apfaltrer P.
      • Weilbacher F.
      • et al.
      Predictive value of high-sensitivity troponin I and D-dimer assays for adverse outcome in patients with acute pulmonary embolism.
      While the patient did not present with tachycardia, which is often associated with pulmonary embolus, he was tachypneic and had an alveolar-arterial oxygen gradient of 159 (normal in a 53-year-old man, <18).
      • Bauersachs R.M.
      Clinical presentation of deep vein thrombosis and pulmonary embolism.
      These findings suggested a lung ventilation/perfusion mismatch or a pathological right-to-left shunt.
      Later, transesophageal echocardiogram demonstrated passage of agitated saline from the right to the left atrium after 1 heartbeat, consistent with a large intracardiac shunt (Figure 3). However, it did not show aortic atherosclerotic lesions suggestive of an aortic source for an embolic cerebrovascular accident. The unusually large alveolar-arterial gradient noted on presentation might have stemmed from both a perfusion problem (right-to-left shunt) and a ventilatory problem (pulmonary embolism).
      Figure thumbnail gr3
      Figure 3Transesophageal echocardiography provided a bicaval view of the heart. (A) The arrowhead by Doppler flow velocity indicates flow acceleration (red arrowhead) from RA to LA through a patent foramen ovale (white arrow). (B) After injection into a right upper-extremity intravenous line, saline contrast, in the form of bubbles (red arrowhead), appeared after 1 heartbeat in the LA. LA = left atrium; PFO = patent foramen ovale; RA = right atrium.
      The patient required mechanical ventilatory support for 2 days. A hypercoagulability work-up was negative for the Factor V Leiden mutation and activated protein C resistance. Anticardiolipin antibody and plasma homocysteine assays were normal. An antithrombin III assay showed slightly decreased activity at 80% (normal, 81%-125%).

      Management

      Reports of simultaneous pulmonary embolism and ischemic stroke are exceedingly rare, although pulmonary embolism remains a leading cause of mortality following stroke.
      • Condliffe R.
      • Elliot C.A.
      • Hughes R.J.
      • et al.
      Management dilemmas in acute pulmonary embolism.
      • Omar H.R.
      • Huang C.
      • Miller J.H.
      • Mangar D.
      • Kabemba A.
      • Camporesi E.M.
      Simultaneous pulmonary embolism and cerebrovascular stroke.
      From a neurological perspective, the patient was not a candidate for thrombolytic therapy for his cerebrovascular accident because his presentation was outside the window for effective therapeutic intervention. From a cardiopulmonary perspective, elevated plasma troponin and right ventricular systolic dysfunction in the setting of relative hemodynamic stability suggested a submassive pulmonary embolism, which negated the need for urgent thrombolytic therapy.
      • Matthews J.C.
      • McLaughlin V.
      Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management.
      • Sanchez O.
      • Planquette B.
      • Wermert D.
      • Marié E.
      • Meyer G.
      Massive pulmonary embolism.
      Because serial CT imaging of the brain did not indicate hemorrhagic transformation, treatment with subcutaneous enoxaparin, 1 mg/kg twice daily, was initiated.
      Transient atrial tachycardia, at 150 beats per minute, was noted on telemetry, although making a distinction between atrial flutter and atrial tachycardia was difficult. Atrial arrhythmias may occur from an underlying structural defect or from right atrial stretch, which can be precipitated by submassive pulmonary embolus.
      • Flegel K.M.
      When atrial fibrillation occurs with pulmonary embolism, is it the chicken or the egg?.
      Proposed temporal mechanisms for this patient's simultaneous pulmonary embolism and ischemic cerebrovascular accident are illustrated schematically (Figure 4).
      Figure thumbnail gr4
      Figure 4Possible mechanisms for simultaneous pulmonary embolus (PE) and ischemic cerebrovascular accident (CVA) are illustrated. LH = left heart; RH = right heart.
      The inciting event for this patient's dual diagnosis remains unclear. Possibly, a pulmonary embolism caused elevated right heart pressure and subsequently, paradoxical embolism when a thrombus passed through the patent foramen ovale. Or, a paroxysmal atrial arrhythmia led to a right atrial thrombus and pulmonary embolism with a coincident paradoxical embolism. Finally, the patient may have had a genetic thrombophilia that made him vulnerable to thrombus formation. His results from the antithrombin III assay were just outside the reference range, and further testing would be required before thrombophilia could be absolutely excluded.
      Current guidelines from the American College of Physicians recommend that patients with a provoked stimulus for thrombus formation receive 3 months of therapeutic anticoagulation; indefinite treatment if the pulmonary embolism was unprovoked.
      • Kearon C.
      • Aki E.A.
      • Comerota A.J.
      • et al.
      Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      At the time of discharge to a skilled rehabilitation facility, the patient was to continue anticoagulation with enoxaparin. His National Institutes of Health Stroke Scale score had decreased from 21 to 14.
      A major embolic pathway for cryptogenic ischemic cerebrovascular accident is through a patent foramen ovale, which this patient clearly had. Two major studies, the RESPECT study (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) and the PC-Trial (Randomized Clinical Trial Comparing the Efficacy of Percutaneous Closure of Patent Foramen Ovale with Medical Treatment in Patients with Cryptogenic Embolism) compared percutaneous closure of the patent foramen ovale with the investigational Amplatzer PFO Occluder (St. Jude Medical, Inc, St. Paul, MN) with medical management.
      • Carroll J.D.
      • Saver J.L.
      • Thaler D.E.
      • et al.
      Closure of patent foramen ovale versus medical therapy after cryptogenic stroke.
      • Meier B.
      • Kalesan B.
      • Mattle H.P.
      • et al.
      Percutaneous closure of patent foramen ovale in cryptogenic embolism.
      The results were equivocal regarding the benefit of percutaneous closure because the primary intended endpoint was not met in either study. Therefore, the decision to close a patent foramen ovale, surgically or percutaneously with an occluder device, remains controversial. Each candidate must be assessed with this in mind.
      In summary, our patient was diagnosed simultaneously with acute pulmonary embolism and an ischemic cerebrovascular accident—a highly unusual concurrence. He likely also had paroxysmal atrial arrhythmia, and a patent foramen ovale was discovered upon imaging. The stimulus for formation of the original thrombus and its location could not be determined. We were compelled to think carefully about some of the controversial management decisions we make in the acute medical setting when evidence for therapeutic efficacy is limited. In the absence of definitive guidelines, we decided that life-long anticoagulation was a reasonable course for our patient. If we could be certain the pulmonary embolism was a consequence of a lower-extremity deep vein thrombosis, insertion of an inferior vena cava filter also would be a reasonable option.
      • Condliffe R.
      • Elliot C.A.
      • Hughes R.J.
      • et al.
      Management dilemmas in acute pulmonary embolism.

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