Enoxaparin sodium

The objective of this study was to describe the clinical course and response to treatment of five patients who developed loculated pleural effusions as complications of pulmonary thromboembolism (PTE). The clinical charts of five patients who had loculated pleural effusions in the course of their PTE were reviewed, with special attention paid to the duration of symptoms before diagnosis, the pleural fluid analysis findings, and the response of the loculations to anticoagulant therapy. In a tertiary care academic medical center, the five patients described in the present study had multiple locules of pleural fluid seen on chest radiographs and thoracic CT scans. In all cases, the diagnosis of PTE had been delayed for at least 2 weeks after symptoms developed. The loculated pleural fluid had led to the mistaken diagnosis of empyema in three cases. The pleural fluid in all cases was exudative, with a predominance of lymphocytes. With anticoagulant therapy, the loculations largely disappeared within the first few days of therapy. Although most pleural effusions secondary to PTE are relatively small and free-flowing, this study demonstrates that PTE can lead to loculated pleural effusions. The loculations occurred in patients who had been symptomatic from their PTE for > 2 weeks. In each instance, the pleural fluid was a lymphocytic exudate. The effusions rapidly resolved with the institution of anticoagulant therapy. PTE should be included in the differential diagnosis of a loculated pleural effusion, particularly if the pleural fluid contains predominantly lymphocytes.

Key words: loculated pleural effusion: pleura; pleural fluid: pulmonary thromboembolism

Abbreviations: PTE = pulmonary thromboembolism; V/Q = ventilation/perfusion

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Pulmonary thromboembolism (PTE) is the disorder most commonly overlooked during the workup of patients with an undiagnosed pleural effusion. (1) It is estimated that at least 250 per 100,000 individuals have a pulmonary thromboembolic event each year. (2) Pleural effusion occurs in 30 to 50% of patients with PTE. (3-6) In most large series of patients with pleural effusions, PTE accounts for < 5% of the pleural effusions. This is likely due to lack of consideration of PTE as the underlying etiology. (1) Supporting this assertion are the results of a postmortem study (7) of 49 patients with pleural effusion from a central Bohemian region in 1988. Pulmonary emboli were found to be the cause of six of the pleural effusions (12.2%), but the diagnosis had been established prior to death in only one of the six patients.

Pleural effusions secondary to PTE are usually free-flowing and are frequently small, with a mean size equal to about 15% of the hemithorax. (3) In the Prospective Investigation of Pulmonary Embolism Diagnosis, (4) 48 of 56 effusions (86%) were manifested only as a blunting of the costophrenic angle, and in no patient did the pleural effusion occupy more than one third of a hemithorax. On occasion, however, there may be a large amount of fluid. (8) The effusions are usually unilateral. (1)

When patients with loculated pleural effusions are evaluated, the most common diagnoses entertained are complicated parapneumonic effusion, a long-standing malignant effusion, or a hemothorax. (1) The differential diagnosis does not usually include PTE. We present five eases of patients with PTE whose chest radiographs and thoracic CT scans showed multiloculated pleural effusions. Interestingly, with the initiation of anticoagulant therapy, the loculated effusions resolved almost completely within several days.

CASE REPORTS

Case 1

A 41-year old man was referred to us with a diagnosis of "atypical pneumonia" in August 1997. Seventeen days before, he had awakened with pleuritic chest pain and dyspnea lasting an hour. When the dyspnea and chest pain recurred 4 days later, he saw a physician who made a diagnosis of pneumonia and prescribed antibiotics. He was referred to us for further evaluation of "atypical pneumonia" when he did not improve.

On hospital admission, he complained of dyspnea on exertion and right-sided pleuritic chest pain. The chest radiograph showed well-marginated, rounded opacities over the right upper and right middle lung fields, linear opacities over the right lower lung field, and a blunted right costophrenic sulcus (Fig 1). The chest CT scan revealed multiloculated pleural effusions associated with atelectasis. Ventilation-perfusion (V/Q) scintigraphy demonstrated multiple wedge shaped segmental perfusion defects in the anterior and posterior segments of the right upper lobe, and in the superior and basal segments of the right lower lobe that were matched with ventilation defects. Echocardiography showed a semi-mobile mass on the posterior wall of the right atrium. Compression ultrasonography findings of the deep veins of the lower extremities were normal. Thoracentesis yielded a clear, yellow lymphocyte-predominant exudate (Table 1) with no organisms and negative cytology.

[FIGURE 1 OMITTED]

Therapy with IV unfractionated heparin was begun for the treatment of PTE. Warfarin (Coumadin; DuPont; Wilmington, DE) was added on the second day, and the patient responded to the treatment rapidly. Both serial chest radiographs (Fig 2) and chest CT scans returned to near normal within 10 days. A control V/Q scintigraphy scan performed 12 days alter hospital admission demonstrated an almost complete resolution of the prior perfusion defects. A follow-up echocardiogram, which was performed on September 2, 1997, disclosed a small decrease in the size of the mass. Arial myxoma was thought to be the source of the emboli. Although a surgical approach was recommended to the patient, he rejected surgery. Subsequent echocardiography, which was performed on March 4, 1998, demonstrated no change in the appearance of the mass. The patient is still receiving treatment with oral anticoagulants, and he has not experienced any recurrences of PTE.

[FIGURE 2 OMITTED]

Case 2

A 43 year-old woman was referred for the evaluation of chest pain in November 1998. Seven days prior to presentation, she had developed sudden-onset left-sided pleuritic chest pain without any other accompanying symptom. When she did not respond to therapy with analgesics, she was transferred to our hospital for further evaluation. On hospital admission, she complained of pleuritic chest pain. The chest radiograph showed a wedge-shaped, pleural-based opacity in the left mid-lung zone and a homogenous opacity occupying the lower one third of the left hemithorax (Fig 3). The chest CT scan revealed multiple loculated collections of pleural fluid with associated underlying atelectasis. Thoracentesis yielded a serosanguineous, lymphocyte-predominant exudate (Table 1) with no organisms and negative cytology. V/Q scintigraphy demonstrated global hypoperfusion of the entire left lung, segmental perfusion defects in the inferior lingular segment of the left upper lobe, and segmental perfusion defects in the anteromediobasal segments of the left lower lobe. Ventilation scintigraphy could not be performed for technical reasons. Compression ultrasonography demonstrated a right popliteal vein thrombosis. Echocardiography findings were normal.

[FIGURE 3 OMITTED]

The patient started receiving therapy with IV unfractionated heparin, and warfarin was added on the second day. Within 5 days of starting treatment, both the chest radiograph and the chest CT scan had improved. Control V/Q scintigraphy performed l0 days post-hospital admission demonstrated almost complete resolution of prior perfusion defects. There were no significant events during the follow-up period of 1 year.

Case 3

A 66-year old unto was transferred to us from a local hospital with a probable diagnosis of empyema in December 2000. Eight days prior to hospital admission, the patient awoke at 2:00 AM with left-sided pleuritic chest pain and dyspnea. The patient was hospitalized with a diagnosis of pneumonia, and during the hospitalization serial chest radiographs and chest CT scans demonstrated loculated collections of pleural fluid. He was referred to our hospital when there was no response to treatment. At the time of admission to our facility, he complained of dyspnea and left-sided pleuritic chest pain. The chest radiograph demonstrated a well-defined pleural-based opacity in the upper two thirds of the left hemithorax and a paracardiac opacity on the left lower hemithorax. The chest CT scan revealed flint the opacities on the chest radiograph were loculated collections of pleural fluid. Spiral CT angiography showed an irregularity of the wall of the superior segmental artery of the left lower lobe and loculated collections of pleural fluid associated with atelectasis in superior and basal segments of the left lower lobe (Fig 4). Thoracentesis revealed a serosanguineous, lymphocyte-predominant exudate (Table 1) with no organisms and negative cytology. V/Q scintigraphy revealed segmental perfusion defects in the lingula and the superior segment of left lower lobe flint matched the ventilation defects. Duplex ultrasonography demonstrated thrombosis of the left femoral vein. Echocardiography findings were normal. The patient was treated with subcutaneous enoxaparin sodium (Clexane; Aventis Pharmaceuticals; Bridgewater, NJ), 1.0 mg/kg twice daily. Warfarin was added on the second hospital day. He improved clinically, roentgenographically, and scintigraphically. The findings of a chest radiograph taken on the 21st day of treatment were normal. No significant events occurred during the follow-up period of 1 year.

[FIGURE 4 OMITTED]

Case 4

A 70-year-old woman was referred to us with a diagnosis of empyema and bronchiectasis in July 2001. Thirty-five days before hospital admission, she had fractured her tibia, which was put into a east on the same day. Twenty days prior to hospital admission, she experienced the sudden onset of left-sided pleuritic chest pain accompanied by dyspnea. She received a diagnosis of myalgia and was prescribed oral analgesics. She was admitted to our hospital when her chest pain and dyspnea persisted. At the time of hospital admission, her left lower extremity remained in a east. The chest radiograph showed a homogenous opacity involving both the middle and lower parts of the left hemithorax, and cardiomegaly. Thoracentesis revealed a serosanguineous, lymphocyte-predominant exudate (Table 1) with no organisms and negative cytology. Spiral CT angiography revealed hypodense plaques in the lumina of both interlobar pulmonary arteries and multiloculated collections of pleural fluid associated with atelectasis of the left lower lobe (Fig 5). Spiral CT angiography of the lower extremity- demonstrated a thrombotic process in the left femoral and popliteal veins, V/Q scintigraphy demonstrated mismatched segmented perfusion defects in the apical segment of right upper lobe, the medial segment of right middle lobe, and the posterior basal segments of right and left lower lobes. The patient was treated with subcutaneous enoxaparin sodium (Clexane), 1.0 mg/kg twice daily. Warfarin was added to the treatment on the second day. There was progressive resolution of the opacities seen on subsequent chest radiographs. By the 10th day of treatment, the chest radiograph findings were almost normal, with only a mild degree of pleural thickening. There were no significant events during the follow-up period of 1 year.

[FIGURE 5 OMITTED]

Case 5

In December 2002, a 64-year-old woman was referred to our department with a diagnosis of empyema. Twenty days previously, she had a sudden onset of right-sided pleuritic chest pain. On the same day, she visited a physician, who hospitalized her with a diagnosis of pneumonia and administered antibiotics. The chest radiographs and chest CT scan demonstrated loculated collections of pleural fluid. When she deteriorated, she was referred to our department, at which time she complained of right-sided pleuritic chest pain. The chest radiograph demonstrated a pleural-based opacity in the right upper hemithorax, a homogenous opacity in both the mid and lower right hemithorax, and blunting of the right costophrenic angle. Thoracentesis revealed a serosanguineous, lymphocyte-predominant exudate (Table 1) with no organisms and negative cytology. Spiral CT angiography revealed hypodense plaques within the lumina of both the right main pulmonary artery and its ascending branch (Fig 6). V/Q scintigraphy demonstrated segmental perfusion defects in the apical and posterior segments of the tight upper lobe, and in the mediobasal and posterobasal segments of the right lower lobe, all with matched ventilation defects. Duplex ultrasonography revealed left femoral vein thrombosis. Echocardiography revealed that the pulmonary artery pressure was approximately 30 mm Hg. The patient was treated with subcutaneous enoxaparin sodium (Clexane). 1.0 mg/kg twice daily. Warfarin was added on the second hospital day. There was progressive resolution of the opacities on successive chest radiographs and the findings of the chest radiograph that was taken after 3 months of treatment were normal. There were no significant events during the follow-up period of 6 months.

[FIGURE 6 OMITTED]

DISCUSSION

The present study describes five patients who developed multiloculated collections of pleural fluid secondary to PTE. In each case, there had been a delay of [greater than or equal to] 2 weeks between the time the patient first became symptomatic and the diagnosis of PTE. The pleural fluid from all patients was a lymphocyte predominant exudate. In each case, the effusion resolved following the institution of anticoagulant therapy.

PTE is believed to he the fourth leading cause of pleural effusion. (1,7) Pleural effusions secondary to pulmonary emboli are typically small and free-flowing. Worsley and associates (4) reviewed the chest radiographs from 1,063 patients who were enrolled in the multicenter Prospective Investigation of Pulmonary Embolism Diagnosis and reported that 36% of the patients had pleural effusions, but that the majority of the effusions were small and caused only blunting of the costophrenic angles. Romero Candeira and associates (8) reviewed the chest radiographs and pleural fluid findings in 60 patients with pulmonary emboli who underwent thoracentesis. They reported that the effusion occupied less than one third of the hemithorax in 80% of their patients. In an earlier study, Bynum and Wilson (3) reported that 51% of 179 patients with pulmonary emboli had pleural effusions and that the mean size of the effusion was only 15% of the hemithorax. Loculation of the pleural fluid was not mentioned in any of these three studies. In the present report, all five patients developed multiple collections of loculated pleural fluid.

The diagnosis of pulmonary embolism is usually made within the first few days after the development of symptoms. In the five cases in the present report, we suspect that the delay in diagnosis allowed the pleural fluid to become loculated. The evidence for PTE was strong in these five cases. In the first patient, there were wedge-shaped perfusion defects and a source for the emboli (ie, a right atrial thrombus). In the second patient, there was a right popliteal vein thrombosis and segmental perfusion defects seen on the lung scan. The last three patients had a demonstrated source for the embolus and positive spiral CT scan findings. The perfusion and ventilation defects were matched in patients 1, 3, and 5. However, it is known that with pulmonary emboli the V/Q defects are commonly matched in patients who are tested > 24 h after the embolic event and in those with concomitant infiltrates. (9)

Loculated pleural effusions typically develop when there is marked inflammation. Such inflammation usually, occurs with pleural infection such as complicated parapneumonic effusions, (10) tuberculosis, (11) or paragonimiasis. (1) Occasionally, loculated pleural effusions occur with hemothorax, (10) postoperatively (10) or with malignancy. (12) Loculated pleural fluid collections may also develop when sclerosing agents are injected intrapleurally in an attempt to create a pleurodesis. (13) To our knowledge, this is the first report of pleural fluid loculation secondary to PTE.

It is believed that fibrin strands within pleural exudates are responsible for creating the loculations. (14) When the pleura is injured, inflammation results and tissue factor-related procoagulant activity is increased such that extravasated plasma forms cross-linked fibrin clots. (14)

Indeed, the intrapleural administration of heparin (15) or urokinase (15,16) will decrease the number of fibrous adhesions when tetracycline is injected intrapleurally. Moreover, the intrapleural injection of streptokinase (17) decreases the number of adhesions with intrapleural infection. Patients with PTE frequently are in a hypercoagulable state and may therefore be more likely, to form the intrapleural fibrin membranes.

An interesting aspect of the present series is the rapid response of the multiple collections of loculated pleural fluid to systemic anticoagulant therapy. Since the loculations are due to fibrous membranes, it is possible that the systemic administration of heparin or warfarin at a minimum prevented the formation of new membranes and possibly even facilitated the breakdown of existing membranes. To our knowledge, the effects of systemic anticoagulation on the formation or resorption of fibrous membranes in the pleural space has not been studied in either animals or humans.

The pleural fluid findings in the present series were compatible with what has been reported in the literature. (8) All the fluids were exudates with a differential cell count that was predominantly lymphocytic. The lymphocyte predominance possibly can be explained by the fact that the patients had been symptomatic for > 2 weeks before the pleural fluid was sampled.

In conclusion, the present study demonstrates that multiloculated collections of pleural fluid can occur with PTE. The occurrence of the loculations appears to be a late event. Accordingly, the diagnosis of PTE should be considered in patients with multiloculated pleural fluid collections along with pleural infection, malignancy, and hemothorax. The observation that the PTE-associated loculations resolved rapidly with systemic anticoagulation raises the possibility that systemic anticoagulation therapy could be effective for patients with loculated pleural fluid secondary to other causes.

* From the Department of Pulmonary Medicine, (Drs. Erkan, Fyndyk, Uzun, and Atycy), Faculty of Medicine, Ondokuz Mavis University, Samsun, Turkey; and Pulmonary Disease Program (Dr. Light), Vanderbilt University, Nashville, TN.

Manuscript received September 18, 2003; revision accepted February 23, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Richard W. Light, MD, FCCP, Saint Thomas Hospital, 4220 Harding Rd, Nashville, TN 37027; e-mail: rlight98@yahoo.com

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