Dr Masaya Tamano, Department of Gastroenterology, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan. Email: firstname.lastname@example.org
Background and Aim: We investigated the utility and safety of contrast-enhanced ultrasonography using Sonazoid in the diagnosis of hepatic hydrothorax.
Methods: The study consisted of seven liver cirrhosis patients with hydrothorax and hydroperitoneum. After obtaining informed consent, Sonazoid was injected intraperitoneally, and enhancement in the peritoneal and pleural cavities was observed.
Results: In all patients, the peritoneal cavity was quickly enhanced after the Sonazoid injection. The pleural cavity was enhanced in five of the seven patients, and these five patients were diagnosed with hepatic hydrothorax. Two patients without enhancement of the pleural cavity were diagnosed with inflammatory hydrothorax.
Conclusions: This is the first report to confirm transdiaphragmatic movement of ascitic fluid into the pleural cavity using contrast-enhanced ultrasonography with Sonazoid. This method can safely detect ascitic flow in real time, and is thus very useful for the diagnosis of hepatic hydrothorax.
Hepatic hydrothorax is defined as the presence of transudative pleural effusion in a patient with cirrhosis of the liver, but with no primary pulmonary or cardiac disease.1 In most patients, such pleural effusion is due to the passage of ascitic fluid into the pleural cavity through defects in the tender portion of the diaphragm.2 However, proposed procedures to detect movement of ascitic fluid into the pleura cavity are complicated and sometimes require harmful materials, such as radioisotopes and indocyanine green.3–5 We previously reported left-sided hepatic hydrothorax diagnosed by contrast-enhanced ultrasonography with an intraperitoneal injection of Levovist (Schering, Berlin, Germany).6 The present study investigated the usefulness and safety of contrast-enhanced ultrasonography using Sonazoid (Daiichi-Sankyo, Tokyo, Japan) in the diagnosis of hepatic hydrothorax.
All study protocols for this clinical investigation were approved by the institutional review board of Dokkyo Medical University, and fully-informed consent about the intraperitoneal injection of Sonazoid was obtained from each patient prior to enrolment.
The study comprised seven patients (3 men and 4 women; mean age: 71.2 years; range: 64–81 years) with clinically-, biochemically-, and ultrasonographically-diagnosed liver cirrhosis. Ascites were diagnosed by ultrasonography, and pleural effusion was diagnosed by chest radiography. Diagnostic puncture of ascites and pleural effusion was performed on all seven patients.
The contrast agent Sonazoid was used at a dose of 0.0015 mL/kg by a manual bolus injection following a flush with 3 mL normal saline solution.
This study used GE LOGIC 7 ultrasonic diagnostic equipment (GE Medical Systems, Milwaukee, WI, USA) with a 4-MHz convex transducer. After visualization of the ascites, the right diaphragm and pleural effusion under normal B-mode scanning from a right intercostal space (4th−6th space, depending on the case), and having confirmed the locus using a contrast-enhanced harmonic mode, Sonazoid was injected through a 21-gauge cannula inserted into the peritoneal cavity. Acoustic power of contrast-enhanced ultrasonography was set to the default setting with a mechanical index of 0.2–0.3; the dynamic range was fixed at 60–65 dB. A single focus point was set at a depth of 6–10 cm. The catheter was inserted into the abdominal cavity from the right subcostal space under ultrasonic guidance. For 10 min immediately after the intraperitoneal injection of Sonazoid, enhancement in the peritoneal and pleural cavities was observed. When Sonazoid enhancement was not seen in the pleural cavity after 10 min, a second examination was performed 2 h later. As Sonazoid was injected under local anesthesia, patients were awake and able to immediately complain of any pain and discomfort. Blood pressure, heart rate and saturation pulse oximetry were measured before, during and immediately after the examination.
Pleural effusion was seen on the right side in all seven patients. The cause of liver cirrhosis was hepatitis C virus in six patients and unknown in one patient. None of the patients had any past history of heart disease, and electrocardiography on admission showed no abnormalities.
After the Sonazoid injection, the echo-free space of the peritoneal cavity immediately showed strong enhancement in all seven patients. Enhancement of the pleural cavity was detected in five of the seven patients. For these five patients, enhancement of the pleural cavity was seen within 1 min after the Sonazoid injection in four patients and approximately 10 min after the injection in one patient (Table 1). Enhancement was seen as turbinated flow from near the diaphragm into the pleural cavity in three of the five patients, and the enhanced area spread throughout the pleural cavity over time. This turbinated enhancement flow appeared to be synchronized with respiration. Figure 1 shows ultrasonography for a patient with turbinated enhancement. Enhancement was seen as numerous hyperechoic spots floating inside the pleural cavity in the remaining two patients.
Table 1. Characteristics of ascitic and pleural fluid and enhancement of the pleural cavity
Attribute of ascitic fluid
Protein ratio pleural/serum
Attribute of pleural fluid
Enhancement of pleural cavity
Time before plural enhancement
SAAG, serum-ascites albumin gradient.
< 1 min
< 1 min
< 1 min
< 1 min
In two of the seven patients, enhancement of the pleural cavity was not seen for 2 h after the Sonazoid injection. Table 1 summarizes enhancement of the pleural cavity and the attributes of ascitic and pleural fluids. The serum-ascites albumin gradient was > 1.1 g/dL for all seven patients, and these ascites were diagnosed as high gradient (transudative) ascites.7 Five patients with enhancement of the pleural cavity did not have pulmonary diseases, and hepatic hydrothorax was confirmed. Pleural fluid in the two patients without enhancement of the pleural cavity was exudate. In these two patients, subsequent examinations confirmed hydrothorax accompanying pleuritis due to pleural mesothelioma in one patient and hydrothorax accompanying pneumonia in the other.
None of the seven patients complained of pain or discomfort during examination. Adverse events in terms of blood pressure, heart rate and saturation pulse oximetry were not seen during or after the examination.
Hepatic hydrothorax is a well-known complication of liver cirrhosis. Pleural effusion accompanying liver cirrhosis is usually right sided (66%), but may be bilateral (17%) or left-sided (17%).8 Although the pathogenesis of hepatic hydrothorax is not fully understood, peritoneo-pleural communication is suggested as one of the significant causes.9 Hepatic hydrothorax can be seen in the absence of ascites due to the negative intrathoracic pressure during breathing, drawing the peritoneal fluid through diaphragmatic defects into the pleural cavity. Radioisotopes3,4 and indocyanine green5 are useful for detecting the transdiaphragmatic passage of ascitic fluid into the pleural cavity. Direct demonstration of a diaphragmatic defect with non-invasive imaging techniques, such as magnetic resonance imaging, is extremely difficult, as the defect itself is usually quite small.10 A method allowing direct observation of the diaphragm by thoracoscopy has been reported,11 but is not generally performed because of the highly invasive nature of the procedure.
Ultrasonography contrast agent is used mainly for intravascular signal enhancement, but can also be used for non-vascular imaging of body cavities, such as the urinary bladder,12 uterine cavity13 or peritoneal cavity.14 Sonazoid is a second-generation microbubble agent for ultrasonography, comprising perfluorobutane microbubbles with a median diameter of 2–3 µm. Sonazoid is reconstituted with 2 mL sterile water for injection.15
In the present study, we tried to detect the movement of ascitic fluid into the pleural space by ultrasonography with Sonazoid. The appropriate dosage for an intraperitoneal injection of Sonazoid has not been determined, so we used the dosage applied in intravenous infusion. As a result, the passage of the contrast agent from the peritoneal cavity to the pleural space was clearly demonstrated only several seconds to 10 min after Sonazoid injection in five patients. These five patients were all diagnosed with hepatic hydrothorax. Moreover, movement of ascitic fluid into the pleural cavity was observed in real time. Ultrasonography contrast agent injected into the abdominal cavity reportedly spreads uniformly in approximately 8 min.14 Enhancement of the pleural cavity was observed within 1 min after Sonazoid injection in four of five patients in this study because the injection point was near the right diaphragm.
Velocity of ascitic fluid movement into the pleural cavity is reportedly proportional to the pressure difference between the pleural and peritoneal cavities.16 We therefore supposed the following from the results of this study. In three of the five patients diagnosed with hepatic hydrothorax and showing turbinated enhancement, a large pressure difference between the pleural and peritoneal cavities caused a large volume of Sonazoid to move into the pleural cavity. A small pressure difference probably caused slower diffusion of Sonazoid in the two patients with enhancement spots. However, these speculations are difficult to prove as pressure measurements within the peritoneal or pleural cavity were not actually performed in this study. In the left-sided hepatic hydrothorax that we previously reported, Levovist, the ultrasonography contrast agent, was seen as jet flow synchronized with heartbeat inside the pleural cavity. In the present right-sided hepatic hydrothorax, Sonazoid was seen as turbinated flow synchronized with respiration in three of the five patients and as hyperechoic spots diffused inside the pleural cavity in the other two patients, representing a very interesting finding.
None of the seven patients experienced any complications during or after the examination.
This is the first report to show transdiaphragmatic movement of ascitic fluid into the pleural cavity using contrast-enhanced ultrasonography with Sonazoid. This method can safely detect ascitic flow in real time, and thus, is very useful for the diagnosis of hepatic hydrothorax.