Renal, Hepatic, and Cardiac Enhancement on Doppler and Gray-Scale Sonograms Obtained with EchoGen Thomas Albrecht, MD 1, David O. Cosgrove, MD 1, Jean-M. Correas, MD 2, Loukianos Rallidis, MD 3, Petros Nihoyanopoulos, MD 3, Nayna Patel, MD 1

T ile p'urpose of this phase I study was to assess cardiac, renal, and hepktic enhancement on gray-scale and energy Doppler sonograms

and to assess the safety of the sonogmphic contrast agent perflenapeut emulsion ~in heMthy volunteers. The influences of two different methods of activation of the agent before its injection were compared.

M A T E R I A L S A N D M E T H O D S

Perflenapeut emulsion (EchoGen; Sonus Pharmaceuticals, Bothell, WA) is a microbubble sonographic contrast agent consisting of dodecatluoro- pentane (a perfluorochemical). Dodecafluoropentane has a boiling point of 29.3~ At room temperature, it forms a dispersion of droplets in water. When injected into the human body, the droplets shift phase and form highly echogenic microbubbles with an average diameter of 2-3 p.m. The bubbles are coated by a stabilizing surfactant. Dodecafluoropentane is a highly stable gas with a low water solubility. Microbubble persistence is therefore longer than in agents based on air bubbles. Perflenapeut emul- sion has a calculated mean bubble persistence of 7 min. Dodecafluoro- pentane undergoes no metabolism and is excreted unchanged by the lungs through exhalation.

Eighteen healthy male volunteers were injected intravenously with doses of 0.02-0.15 ml perflenapeut emulsion per kilogram body weight. The agent was activated by one of the two following methods in all volun- teers: (1) injection through a 1.2-I.tm filter (,1 = 7), which produces a pres- sure gradient that facilitates phase shifting, and (2) sonication of the agent immediately before injection using a commercially available sonication device (n = 11).

We performed simultaneous gray-scale B-mode echocardiography (n = 18) as well as gray-scale and energy Doppler sonography of the right kid- ney (n =114) and the liver (gray scale, n = 12; Doppler imaging, n = 9). All scans were recorded on videotapes.

The images of all volunteers were subjectively analyzed for cardiac, renal, and hepatic enhancement on gray-scale images and for renal and

From the 'Department of Radiology, Hammersmith Hospital, Royal Postgraduate Medical School, London, England; 2Sonus Pharmaceuticals, Both- eli, WA; and 3Department of Cardiology, Hammer- smith Hospital, Royal Postgraduate Medical School, London, England. Address reprint requests to T. Albrecht, MD, De- partment of Radiology, Hammersmith Hospital, Royal Postgraduate Medical School, Du Cane Rd., London W12 ONN, Engtand.

Acad Radiol 1996;3:$198--S200 �9 1996, Association of University Radiologists

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hepatic enhancement on energy Doppler sonograms. Quantitative video intensitometry also was performed only in the sonication group. This was done for cardiac enhancement on gray-scale images (n = 7) and for renal (n = 9) and hepatic (n = 4) enhancement on energy Doppler sonograms. For gray-scale quantifica- tion, data were imported into a Macintosh computer using a data translation board. Image software from the National Institutes of Health was used for data analy- sis. Gray-scale measurements were expressed in gray- scale units. Energy Doppler quantification was done with in-house hardware and software on a personal computer [1]. Doppler signal intensity was defined as the number of color pixels in a region of interest times the mean intensity of the color pixels.

RESULTS Subjective Analysis

The results of subjective analysis are summarized in Table 1. In the sonication group, gray-scale and Dop- pler enhancement was consistent in all cases. This included myocardial, renal, and hepatic gray-scale enhancement . In the filter group, the observed effects were not consistent. In particular, myocardial, renal, �9 and hepatic gray-scale enhancement was seen in fewer than half the cases. The observed changes were more marked and longer lasting in the sonication

group.

Quantitative Analysis of the Sonication Group

The results of the quantitative video intensitometry are summarized in Table 2. In the heart, gray-scale enhance- ment of the ventricles was striking in all analyzed volun-

TABLEI: Subjective Assessment of the Presence of Enhancement After Perflenapeut Emulsion Activated by Sonication and Filter

Anatomic Sonographic Sonication Filter Structure Technique

Right ventricle Gray scale 11111 - 6/7 Left ventricle Gray scale 11/11 6/7 Myocardium Gray scale 11/11 3/7 Kidney Energy Doppler 10/10 3/4 Kidney Gray scale 10/10 1/4 Liver ," " Energy Doppler 5/5 114 Liver Gray scale 6a/7 1/4

The numbers on the right of the slash represent the number of volunteers in whom an anatomic structure was sufficiently imaged with the relevant sono- graphic technique.

aHepatic enhancement on gray-scale images was masked by fatty change in one case.

TABLE 2: Quantitative Enhancement After Perflenapeut Emulsion Activated by Sonication

Mean Mean Mean Anatomic Sonographic Signal Duration Time to Structure Techn ique Increase (sec) Peak

(sec)

Right ventricle Gray scale 68 gray-scale 227 14 units

Left ventricle Gray scale 64 gray-scale 350 111 units

Myocardium Gray scale 24 gray-scale 260 140 units

Kidney Energy Doppler 5,350% 393 73

Liver Energy Doppler 1,570% 295 55

teers, lasting up to 11 min (the average enhancement of the left and right ventricles was 64 and 68 gray-scale units, respectively). Myocardial enhancement also was apparent in all analyzed volunteers, with a mean of 24 gray-scale units and lasting up to 9 min. In the kidney, energy Dop- pler enhancement throughout the cortex was dramatic in all volunteers. The average percentage enhancement,

�9 defined as (peak Doppler signal - baseline Doppler sig- nal)/baseline Doppler signal, was 5,350~ and duration was up to 11 min. In the liver, Doppler enhancement was 1,570~ and lasted up to 6 min.

The duration of cardiac, renal, and hepatic enhance- ment and the times to peak enhancement varied consid- erably between volunteers. Dosage had little influence on the observed effects.

Adverse Reactions

Adverse reactions were observed in four of the 18 volunteers. All reactions were mild, short (2-5 rain), and required no medical intervention. They included flushing and light-headedness (n = 4), mild dyspnea (n = 2), and abdominal cramps (n = 1). One volunteer had a mild fever and a slightly raised white blood cell count 24 hr after the injection, but it is unclear whether this was related to the injection of perflenapeut emulsion. No other hematologic or biochemical almormalities were observed. Adverse events tended to be more frequent in the higher dose ranges.

CONCLUSIONS

Perflenapeut emulsion is an effective and safe echo- enhancing agent. Activated by sonication, it provides dra- matic enhancement on color Doppler sonograms and consistent enhancement on gray-scale images of the myo-

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cardium, kidney, and liver. To our knowledge, this is the first report describing consistent enhancement of the myocardium and parenchymal organs on gray-scale sonograms after intravenous injection of a sono- graphic contrast medium in humans. Perflenapeut emulsion has the potential to expand the clinical use

of sonography to perfusion imaging, particularly of the myocardium.

1

REFERENCE

1. Bell DS, Bamber JC, Eckersley RJ. Segmentation and analysis of colour Doppler images of tumour vasculature. Ultrasound Med Biol 1995;21: 635-647.

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