Abstract
We report a case of pulmonary thrombosis and pericardial effusion in a patient receiving clozapine who, later was diagnosed to have primary lung adenocarcinoma with distant metastasis. We discuss management of patients with this simultaneous presentation and current recommendations for evaluation of cancer screening.
Keywords: clozapine, percicardial effusion, pulmonary embolism, thrombosis
Introduction
The incidence of pulmonary thrombosis in patients with pericardial syndromes has been reported to be 4% in the literature1. Usually these present in isolation and are easy to recognize. Their simultaneous presentation has been rarely reported2. We report a case with both pulmonary embolism and pericardial effusion in a patient receiving clozapine who was diagnosed with primary lung adenocarcinoma with distant metastasis three months after initial presentation to our hospital.
Case report
A 53 year old man with a history of schizophrenia presented to our hospital with complaints of chest pain, dyspnea and light headedness. He was diagnosed with schizophrenia at age 21 and was prescribed trihexyphenidyl 2 mg twice a day, cogentin 0.5 mg twice a day, depakote extended release 500 mg once a day and clozapine 600 mg at night for control of his psychosis. He was on clozapine for 3 years until the time he became acutely ill and was admitted to the hospital. There was no history of fevers or upper respiratory tract infection, pneumonia, weight loss, coagulation disorders and long travel, he was a fairly active person and had a ten pack year history of tobacco use.
Physical examination: He had a normal body habitus. He was afebrile, normotensive, no pulsus paradoxus, although tachycardic at 110/ minute and tachypneic maintaining oxygen saturations of 92% on 3 liters/minute of oxygen. He was alert and oriented to time, place and person. There was no jugular venous distension. Both first and second heart sounds were distant. There was decreased bibasilar air entry with no crackles. There was no lower extremity tenderness or swelling.
Laboratory Results: Complete blood count and chemistry panel were normal. Electrocardiogram showed sinus tachycardia and nonspecific ST changes. D-dimer was elevated at 8.1 (normal up to 0.5). Spiral Computed Tomogram of chest was ordered based on the D-dimer results and showed evidence for right upper lobe pulmonary artery thrombosis, small bilateral pleural effusions and moderate pericardial effusion.
Doppler ultrasound of the lower extremities was negative for deep vein thrombosis. Patient was started on high intensity heparin protocol without heparin bolus after getting informed consent in the emergency room from both the patient and his mother. Both patient and his family were explained risks and benefits with special consideration to potential development of hemopericardium. Emergent drainage of pericardial effusion was not deemed necessary then as it was not exhibiting any signs of tamponade on exam.
The next morning, physical exam of the patient revealed blood pressure of 90/60 mm Hg, heart rate of 120/ min, jugular venous distension, distant heart sounds and pulsus peridoxus of 16 mm of Hg consistent with cardiac tamponade physiology. A transthoracic echocardiogram (See figure 1) revealed a moderate size pericardial effusion. There was greater than 40 % respiratory variation in early diastolic flow across the mitral and tricuspid valves. Right atrial systolic invagination was more than 50% of the cardiac cycle consistent with cardiac tamponade. Patient subsequently underwent percutaneous pericardiocentesis which only removed 60 mL of opaque effusion. Temporary drain placement was unsuccessful and the patient underwent surgical pericardial drainage, removing 750 mL. On analysis of the pericardial fluid, it was opaque with 16,300 nucleated cells and 72% neutrophils. Viral, bacterial and fungal cultures were negative. Pericardial fluid and biopsy were negative for acid fast bacilli and malignancy. TSH and rheumatologic panel including erythrocyte sedimentation rate, antinuclear antibody and rheumatoid factor were normal. HIV antibody test was negative. Other causes of venous thromboembolism including factor V Leiden, Protein C and S and anti-phospholipid antibody was normal. Chest, abdominal and pelvis CT were negative for malignancy.
The source of pulmonary embolism and pericarditis was not isolated and clozapine was discontinued on day 2 of hospitalization, due to the concern it may be the etiology. Patient continued to do better and was finally transferred to group home a week later.
Three months after discharge, he presented to the hospital with “disinhibited” behavior and a marked change in personality never observed before. This prompted CT of head which revealed a 3 centimeter mass in left frontal lobe with considerable edema. MRI of head was consistent with the above findings. Later, he underwent CT of chest which revealed a 1.4 cm x 2 cm focal lucency in apex of left lung. CT of abdomen revealed low densities in posterior right lobe of liver. He eventually underwent resection of left frontal lobe mass. The pathological findings were consistent with metastasis from primary lung adenocarcinoma.
Post operation, patient did well. He is now scheduled to see an oncologist for further care.
Discussion
The most common causes of pericardial effusion include acute idiopathic pericarditis, infection, iatrogenic, malignancy, chronic idiopathic effusion, post-acute myocardial infarction, uremia or dialysis, radiation, trauma, collagen vascular diseases, drugs (such as procainamide and hydralazine) and congenital illnesses3,4. The most common risk factors for pulmonary embolism include immobilization, surgery within the last three months, trauma, stroke, history of venous thromboembolism and malignancy5. Other risk factors include obesity, heavy cigarette smoking, fractures of the long bone, oral contraceptive and estrogen replacement, hypertension, stroke, indwelling venous catheters, congestive heart failure, pregnancy, varicose veins, acquired factor deficiency, antiphospholipid antibody syndrome, drugs and inflammatory bowel disease6,7. Causes of combined pericardial effusion and pulmonary embolism include malignancy and connective tissue diseases.
Clozapine, an atypical antipsychotic used against positive and negative symptoms of schizophrenia has been associated with pulmonary embolism (PE), having the second most common cause of death among current clozapine users 8 after death through external causes (accident, homicide and suicide). Review of 67,072 patients registered in the Clozapine National Registry between 1991 and 1993 revealed absolute risk of death from PE was increased by a factor of 5.2 among current clozapine users compared with past users of the medication 8,9. The mechanism by which clozapine can induce thromboembolism is unclear. Drug-induced sedation, obesity and antiphospholipid antibodies leading to increased activity in the coagulation system are the suggested etiological factors10. Except for a history of smoking, our patient did not have any of the above risks factors, in addition he was young and fairly active.
There are few case reports implicating this drug with pericardial effusion. An inflammatory process, possibly an autoimmune type reaction, has been suspected as the cause for clozapine induced pericarditis 11.
A thorough literature search did not reveal a case report of clozapine associated with pulmonary embolism and pericardial effusion in the same patient. None of the other medications which this patient was taking have been implicated in pulmonary thrombosis and/or pericardial effusion.
Management of pericardial effusion revolves around treatment of the underlying etiology. In face of cardiac tamponade, catheter accomplished pericardiocentesis is the procedure of choice in most patients12. Open surgical drainage is preferable in reaccumulated and/or loculated effusions13. Venous thromboembolic disease is managed with intravenous heparin or low molecular weight heparin and warfarin therapy with heparin discontinued on day 5-6 if the INR has been therapeutic for two consecutive days14. Long term anticoagulation with warfarin is continued for atleast 3-6 months. In face of hemodynamically unstable PE, thrombolytic therapy or pulmonary thromboembolectomy with intra-venacaval filters may be used15.
An important treatment dilemma is the simultaneous management of potential catastrophic illnesses-pericardial effusion and pulmonary embolism. Each can present with tachycardia, hypotension and signs of heart failure making diagnosis difficult. Whereas pulmonary embolism would be managed with anticoagulation, it poses significant risk of causing hemorrhagic pericardial effusion. In our case, an attempt was made to treat pulmonary embolism first. When repeat examination revealed tamponade physiology, anticoagulation had to be stopped and pericardiocentesis pursued.
Management of patients with pulmonary emboli in face of larger pericardial effusions is even more challenging. Echocardiographic monitoring of the amount of pericardial fluid is strongly suggested 16. In cases with high probability of cardiac tamponade, pericardial catheter drainage should be used 16. Patients who are hemodynamically unstable are probable candidates for emergency pulmonary thromboembolectomy and pericardiectomy with drain placement and inferior vena caval interruption using total cardiopulmonary bypass and Adams-DeWeese clip17 or Greenfield filter.
The initial diagnoses of PE and pericardial effusion related to clozapine in our patient were that of exclusion. We speculated drug induced autoimmune reaction causing both PE and pericardial effusion to be the probable etiological factor. Unfortunately, he was diagnosed with primary lung adenocarcinoma three months after initial presentation to the hospital. Head CT was not performed previously as it was not clinically warranted given all other investigations were negative.
It is a well known fact pulmonary embolism can precede the diagnosis of malignancy by months to years. In addition, the pericardium is involved in 5-15% of patients with malignant neoplasm18. Pericardial effusions resulting from neoplastic involvement are large and frequently present with tamponade even before the primary lesion is discovered19.
The increased incidence of subsequent malignancy among patients presenting with idiopathic DVT or pulmonary embolism has raised the question of whether extensive screening would be beneficial. The use of extensive screening appeared to increase the incidence of detected malignancies as demonstrated by Monreal et al and Bastounis et al 20,21. However, the incidence of cancer was also increased in the patients with secondary DVT in these studies, so that the relative risk of diagnosing malignancy among patients with unexplained DVT and secondary thrombosis was comparable to other studies. Current guidelines do not recommend aggressive search of malignancy in all patients and suggest that only those with abnormality in one of the the four components of the initial investigation-history, physical examination, basic laboratory testing or chest X-ray undergo further periodic testing 22.
Conclusion
Management of patients with combined pulmonary thrombosis and pericardial effusion is a dilemma. Balancing the risk of anticoagulation and further thrombotic emboli with prevention of tamponade is critical to patient care. Furthermore, identifying both drugs (eg; clozapine) and performing a thorough search for malignancies are prudent for patient care.
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