NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

Show details

Sonicated human serum microspheres

Sonicated HSM
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: May 27, 2008.

Chemical name:Sonicated human serum microspheres
Abbreviated name:Sonicated HSM
Synonym:Albunex®, Infoson®
Agent Category:Albumin
Target:Non-targeted agent, blood pool
Target Category:Passive nonspecific filling of cardiac chambers
Method of detection:Ultrasound (US)
Source of signal/contrast:Air-filled microbubble
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Non-human primates
  • Checkbox Humans

Background

[PubMed]

Sonicated human serum microspheres (HSM) is a preparation of air-filled HSM that was developed as an ultrasound (US) contrast agent for use in echocardiography to enhance US images (1). In the United States, sonicated HSM was approved by the Food and Drug Administration in 1994 for US contrast enhancement of cardiac ventricular chambers and improvement of endocardial border definition in patients with suboptimal echocardiograms undergoing ventricular function and regional wall motion studies (2). In 1997, sonicated HSM was also approved for use with transvaginal US to assess fallopian tube patency (2). However, it is currently not commercially available for clinical applications.

US contrast agents, or echopharmaceuticals, are designed to change the attenuation (absorption, reflection, and refraction) or impedance (resistance to sound propagation) of sound to enhance the differentiation of the signal (echo) of a target organ from that of the surrounding tissue (3-6). Gas-liquid emulsions (microbubbles or gaseous particles) are highly echogenic invivo because of the nonlinear rarefaction and compression effects that lead to volume pulsations of microbubbles (4, 7, 8). Human serum albumin (HSA), synthetic polymers, and phospholipids have been used to construct the membranes of these bubbles. Microbubble preparations of various formulations have been developed, and their clinical usefulness depends very much on the size and stability of these bubbles in vivo. The current clinical application of these agents is in myocardial contrast echocardiography (MCE) (9).

Air-filled microbubbles stabilized within a galactose matrix were the first commercially available echopharmaceutical (10). However, these microbubbles are not stable enough to pass through the pulmonary capillary bed after a peripheral intravenous injection and can be used only to opacify the right heart chamber. Sonicated HSM was the first US contrast agent approved in the United States for cardiac applications. It consists of air-filled microbubbles stabilized in a thin shell of HSA with a mean diameter of 3.8 ± 2.5 μm (11). Although these air-filled microbubbles are very sensitive to pressure changes with an in vivo half-life (t½) of <1 min, they can pass through the pulmonary capillary bed and reach the left heart chamber. In Europe, air-filled microbubbles stabilized by palmitic acid have been introduced. These air-filled microbubbles are considered the first-generation of echopharmaceuticals. Second-generation echopharmaceuticals use perfluorocarbons to increase the stability of the microbubbles (12).

Sonicated HSM is composed of three protein fractions (1). The carrier protein fraction, which consists of 5% HSA into which the microspheres are dispersed, constitutes over 99.9% of the total protein. The microsphere shell comprises the other two protein fractions: a water-soluble fraction (shell protein 1) and a water-insoluble fraction (shell protein 2).

Synthesis

[PubMed]

Sonicated HSM preparations are produced by sonication of a heated 5% HSA solution (1, 2, 11). The HSA is derived from plasma collected from donors who have been screened and tested. Heat treatment of the serum albumin at 60 °C for 10 h reduces the risk of viral transmission. Sodium acetyl tryptophanate (0.08 mmol) and sodium caprylate (0.08 mmol) are added to 1 g of albumin as stabilizers. Superoxide free radicals, produced by the high temperatures reached during cavitation in the sonication process, cause oxidation and intrachain cross-linking of cysteine residues of the albumin chains (13). Barnhart et al. (1) detected no changes in the surface-charge properties, ultraviolet spectrum, amino acid sequences, or the ability of the albumin molecule to complex with antihuman antibody as a result of the sonication. The commercial preparation is a clear, amber liquid with an upper white layer containing the air-filled microspheres. The preparation must be inverted and gently rotated for approximately 3 min to completely resuspend the microspheres. On resuspension, the liquid becomes opaque, and the concentration of microspheres is 3-5 × 108/ml.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Barnhart et al. (1) studied the in vitro characteristics of sonicated HSM by gel-filtration fast-protein liquid chromatography and found that the integrity of the peptide chain was maintained during the sonication production process. At 5 MHz, sonicated HSM was more echogenic than soft tissues even after being diluted to 0.0003% of the original concentration. Bleeker et al. (14) reported that both the scatter coefficient (absolute measure of US backscatter) and attenuation coefficient at 7.5 MHz (20 °C) for 2.6-μm microbubbles were linearly proportional to the number of microbubbles.

Brayman et al. (15) studied the effect of static pressure on acoustic transmittance of sonicated HSM suspensions in well-aerated, albumin-rich media. They found that the acoustic transmittance of microbubble suspensions was strongly hydrostatic pressure (Ps) dependent. Their data indicated that many of the microbubbles were destroyed at Ps comparable to the invivoPs produced by the heart. Ota et al. (16) found that the echogenicity (pixel videointensity) of sonicated HSM suspensions (800-160,000 microbubbles/ml) decreased with pressurization and that the critical pressure required to reduce the intensity to half of its initial value increased with the logarithm of microbubble concentration. Both acoustic power and transducer frequency appeared to affect the physical properties of the microbubbles and decreased mean videointensity. Chang et al. (17) identified two pressure thresholds (P1 and P2) at which the air-filled microbubbles undergo inertial cavitation (rapid expansion and collapse of microbubbles). The P1 threshold (all microbubbles lost their effective scatter property) of sonicated HSM increased with increasing microbubble concentration. Both P1 and P2 (onset of a more violent inertial cavitation) decreased with increasing number of acoustic cycles. Padial et al. (18) reported that sonicated HSM demonstrated a significant increase in the decay rate of contrast intensity with increasing pulsatile pressure rate (pulsations/min).

Mor-Avi et al. (19) used an in vitro isolated rabbit heart model to show that sonicated HSM did not impair myocardial contractility. In an in vitro pulsatile heart model, Deng et al. (20) reported that the microbubbles were compressed in systole and decompressed in diastole. This produced a corresponding change of the backscatter intensity during the cardiac cycle. Using cultured human coronary artery endothelial cells, Villanueva et al. (21) found that sonicated HSM microbubbles preferentially adhered to inflammatory endothelial extracellular matrix. Their study suggested that MCE with sonicated HSM might be used to study endothelial integrity. In another study using in vitro perfused human placental lobule, Abramowicz et al. (22) found that sonicated HSM could improve visualization of circulation throughout the lobule. They also found that sonicated HSM could be used to image placental bed circulation.

Animal Studies

Rodents

[PubMed]

Acute and chronic toxicity studies of sonicated HSM after i.v. injection in rats showed no change in hematology, blood chemistry, or urinalysis parameters and no gross pathology or histomorphologic findings (1). Studies using 125I-labeled microspheres showed that the plasma t½ in rats was <1 min. More than 80% of the radioactivity was found in the liver at 3 min after i.v. injection, and less than 10% activity remained in the liver after 6 h. After 24 h, 80% of the radioactivity was in the urine.

Walday et al. (23) studied the biodistribution of 125I-labeled sonicated HSM in rats. At 3 min after injection, the percentages of the injected dose (% ID; n = 5) in the liver, lungs, and blood were 59.8, 3.13, and 14.3% ID, respectively. At 90 min, these values changed to 16.5, 0.51, and 12.3% ID, respectively. The decrease in liver activity appeared to follow first-order kinetics with an elimination t½ of 40 min. More than 90% of the microbubbles appeared to be taken up by the liver macrophages (Kupffer cells). At any time point, less than 1.2% ID was recovered in the kidneys. Less than 0.3% was found in the brain or heart. The radioactivity in the bone marrow increased up to a maximum of 3.3% after 30 min. In comparison, 125I-labeled HSA (125I-labeled shells from collapsed microspheres) had significantly different distribution kinetics.

Raeman et al. (24) studied the effect of sonicated HSM on the sensitivity of the lung to US exposure in mice. Each mouse received four 0.05-ml doses of sonicated HSM and was exposed for 5 min to 1.1 MHz of pulsed US (100-Hz repetition frequency) at a peak positive pressure of 2 MPa at the surface of the animal. The mean lung hemorrhage area for animals treated with sonicated HSM was 17.3 ± 4.5 mm2 compared with 19.7 ± 2.5 mm2 for the control (saline-treated) group. The authors concluded that sonicated HSM did not increase the lung damage caused by US exposure. Haggag et al. (25) used Evans blue with fluorescence microscopy, and histologic examination to show that sonicated HSM did not appear to damage the cerebral microvasculature or brain tissue in rats.

Other Non-Primate Mammals

[PubMed]

Barnhart et al. (1) found no acute or chronic toxicity in dogs after intra-arterial injection of sonicated HSM. In addition, after intracoronary injection, sonicated HSM did not significantly change coronary blood flow, left ventricular function, or systemic hemodynamics even in the presence of a critical coronary stenosis. Keller et al. (26) reported that intracoronary injection of sonicated HSM (dose = 0.033 ml/kg) did not significantly change coronary blood flow, left ventricular function, or systemic hemodynamics. In a safety study, Ostensen et al. (27) found that sonicated HSM caused thromboxane-mediated pulmonary hypertension in pigs but not in monkeys or rabbits.

Biodistribution studies of 125I-labeled sonicated HSM in pigs showed that the microbubbles were rapidly cleared from the circulation (23). At 3 min, the percentage of injected dose (n = 3) for the liver, lungs, and blood was 0.29, 103.4, and 6.76% ID, respectively. At 90 min, these values changed to 0.93, 50.8, and 8.39% ID, respectively. Less than 1% ID was observed in most other organs examined. The bone marrow activity was 2.4% ID at 90 min. The study suggested that the high uptake in the pig lungs might be caused by the presence of pulmonary intravascular macrophages. Macrophages are normally not found in rats or humans.

Rovai et al. (28) studied the use of sonicated HSM for myocardial blood flow measurements in 6 mongrel dogs. Each dog received a total dose of 0.4 ml of sonicated HSM (2 × 108 microbubbles/ml). In comparison with 99mTc-HSA, the myocardial mean transit time (without dipyridamole) of sonicated HSM was 2.16 ± 0.59 s, which was much shorter than the 7.98 ± 2.92 s of 99mTc-HSA. With dipyridamole, the values were 1.73 ± 0.59 and 2.73 ± 0.88 s, respectively. The coefficient of variation (measurement reproducibility) for sonicated HSM was higher, 16.5% compared with 9.7% for 99mTc-HSA. The study concluded that although sonicated HSM MCE could be useful for studying the distribution of myocardial perfusion, the coronary blood flow was not adequately quantified. Desir et al. (29) reported that sonicated HSM MCE (doses of 0.25-2 ml; n = 16) could detect the presence of coronary stenoses of variable degrees of severity in dogs. Compared with radioactive microspheres, a consistent underestimation of dipyridamole-induced hyperemia by sonicated HSM MCE was observed. On the basis of sonicated HSM MCE studies in rabbits, Lafitte et al. (30) suggested that the rabbit model showed promise for contrast echocardiographic study of ischemic myocardium.

Non-Human Primates

[PubMed]

After i.v. injection of sonicated HSM in monkeys, Barnhart et al. (1) found no significant acute or chronic toxicity. Ostensen et al. (27) studied the safety of sonicated HSM in 3 cynomolgus monkeys. Each monkey received doses of 0.12, 0.24, and 0.48 ml/kg at 30-min intervals. Sonicated HSM MCE did not cause changes in mean pulmonary arterial pressure, left ventricular pressure, heart rate, femoral arterial blood flow, or mean systemic arterial pressure.

Human Studies

[PubMed]

Feinstein et al. (31) reported on the safety and preliminary efficacy of i.v. injection of sonicated HSM in 71 patients at three medical institutions. Three doses ranging from 0.01 to 0.12 ml/kg of body weight were given, and the efficacy of the sonicated HSM MCE was evaluated by two independent blinded radiologists. No significant changes in vital signs or physical and laboratory data were observed. Adverse reactions were minor and infrequent. Irrespective of the doses, right ventricle opacification (+2 or higher on a scale of 0 to +3) was observed in 88% of cases, and left ventricle opacification was observed in 63%. The degree of opacification appeared to be related to dose and concentration. Similarly, no clinical, hemodynamic, or respiratory adverse reactions were reported by Geny et al. (32) in 20 patients with ischemic heart disease. With doses of 0.08-0.22 ml/kg, left ventricular opacification (+2 or higher) was observed in 74% of the cases. Crouse et al. (33) reported the results of a phase III multicenter trial that involved 175 patients at 8 investigating centers. Overall, 81% of patients had at least moderate left ventricular chamber opacification and endocardial definition was improved in 83%. Both Barnhart et al. (34) and Geny et al. (35) reported that repeated administration of sonicated HSM induced no detectable antibody immune response, no adverse effect on the cellular and humoral immune systems, and no change in the left and right heart hemodynamics.

In a European phase III clinical trial, Voci et al. (36) found that sonicated HSM (two 0.2 ml/kg doses) provided adequate left ventricular opacification in 90% of 40 low-echogenicity patients. In the United States, in a phase III clinical trial involving 254 patients (dose = 0.05 ml/kg), Grayburn et al. (37) reported full or intermediate left ventricular opacification in 55% of cases (rated by the investigators) and endocardial border delineation in 45% of cases. In comparison, for 2% dodecafluoropentane emulsion (a second-generation US agent; dose = 0.05 ml/kg), left ventricular opacification and endocardial border delineation were obtained in 83% and 88% of cases, respectively. The total adverse event rate was 6.3%, with taste alteration (2.7%) and vasodilation (2%) the most common adverse reactions.

Holte et al. (38) reported the use of sonicated HSM as an intrafallopian US contrast agent for determining fallopian tube patency (hysterosalpingo contrast sonography; HyCoSy) in 7 patients. Sonicated HSM in doses of 0.5-0.9 ml was injected transcervically. No serious adverse reactions were observed. Agreement between HyCoSy and postoperative testing was found in 12 of 14 Fallopian tubes. Boudghene et al. (39) studied HyCoSy in 23 patients and found similar efficacy compared with standard conventional hysterosalpingography.

Various studies [PubMed] have found that sonicated HSM appears to be a clinically useful US contrast agent for ventricular and myocardial opacification.

NIH Support

NIH P32 HL07502, K08-HL-01833, R29-HL-38345.

References

1.
Barnhart J., Levene H., Villapando E., Maniquis J., Fernandez J., Rice S., Jablonski E., Gjoen T., Tolleshaug H. Characteristics of Albunex: air-filled albumin microspheres for echocardiography contrast enhancement Invest Radiol 1990. 25Suppl 1S162–4. [PubMed: 2126533]
  • 2. Albunex, albumin (human) 5%, sonicated package insert Part No. 50047/RS. 1997, Mallinckrodt Medical Inc.
  • 3.
    Morawski A.M., Lanza G.A., Wickline S.A. Targeted contrast agents for magnetic resonance imaging and ultrasound. Curr Opin Biotechnol. 2005;16(1):89–92. [PubMed: 15722020]
    4.
    Schutt E.G., Klein D.H., Mattrey R.M., Riess J.G. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals. Angew Chem Int Ed Engl. 2003;42(28):3218–35. [PubMed: 12876730]
  • 5. Swanson, D.P., Enhancement agents for ultrasound: Fundamentals, in Pharmaceuticals in Medical Imaging, D.P. Swanson, H.M. Chilton and J.H. Thrall, Editor. 1990, MacMillan Publishing Co., Inc.: New York. p. 682-687.
  • 6. Gobuty, A.H., Perspectives in ultrasound contrast agents, in Contrast media: Biologic effects and clinical application, Z. Parvez, R. Moncada and M. Sovak, Editor. 1987, CRC: Boca Raton, Florida. p. 145-155.
  • 7.
    Averkiou M., Powers J., Skyba D., Bruce M., Jensen S. Ultrasound contrast imaging research. Ultrasound Q. 2003;19(1):27–37. [PubMed: 12970614]
    8.
    Miller A.P., Nanda N.C. Contrast echocardiography: new agents. Ultrasound Med Biol. 2004;30(4):425–34. [PubMed: 15121243]
    9.
    Murthy T.H., Li P., Locvicchio E., Baisch C., Dairywala I., Armstrong W.F., Vannan M. Real-time myocardial blood flow imaging in normal human beings with the use of myocardial contrast echocardiography. J Am Soc Echocardiogr. 2001;14(7):698–705. [PubMed: 11447415]
    10.
    Correas J.M., Bridal L., Lesavre A., Mejean A., Claudon M., Helenon O. Ultrasound contrast agents: properties, principles of action, tolerance, and artifacts. Eur Radiol. 2001;11(8):1316–28. [PubMed: 11519538]
  • 11. Summary of safety and efectiveness data of Albunex, PMA number P900059/Supplement 004. 1997: Mallinckrodt, Inc. p. 1-28.
  • 12.
    Mattrey R.F. Sonographic enhancement of Doppler signals and perfused tissues with perfluorooctylbromide Invest Radiol 1990. 25Suppl 1S158–9. [PubMed: 2283238]
    13.
    Watkin K.L., McDonald M.A. Multi-modal contrast agents: a first step Acad Radiol 2002. 9Suppl 2S285–9. [PubMed: 12188250]
    14.
    Bleeker H.J., Shung K.K., Barnhart J.L. Ultrasonic characterization of Albunex, a new contrast agent. J Acoust Soc Am. 1990;87(4):1792–1797.
    15.
    Brayman A.A., Azadniv M., Miller M.W., Meltzer R.S. Effect of static pressure on acoustic transmittance of Albunex microbubble suspensions. J Acoust Soc Am. 1996;99(4 Pt 1):2403–8. [PubMed: 8730086]
    16.
    Ota T., Hillman N.D., Craig D., Kisslo J., Smith P.K. Contrast echocardiography: influence of ultrasonic machine settings, mixing conditions, and pressurization on pixel intensity and microsphere size of Albunex solutions in vitro. J Am Soc Echocardiogr. 1997;10(1):31–40. [PubMed: 9046491]
    17.
    Chang P.P., Chen W.S., Mourad P.D., Poliachik S.L., Crum L.A. Thresholds for inertial cavitation in albunex suspensions under pulsed ultrasound conditions. IEEE Trans Ultrason Ferroelectr Freq Control. 2001;48(1):161–70. [PubMed: 11367783]
    18.
    Padial L.R., Chen M.H., Vuille C., Guerrero J.L., Weyman A.E., Picard M.H. Pulsatile pressure affects the disappearance of echocardiographic contrast agents. J Am Soc Echocardiogr. 1995;8(3):285–92. [PubMed: 7640022]
    19.
    Mor-Avi V., Shroff S.G., Robinson K.A., Cholley B.P., Ng A.F., Lang R.M. Echocardiographic contrast agents and left ventricular contractility: evaluation using an isolated rabbit heart model. J Am Soc Echocardiogr. 1996;9(4):452–61. [PubMed: 8827628]
    20.
    Deng Y., Li C., Chang Q. Effect of pressure on intracardiac backscatter from microbubbles. J Tongji Med Univ. 2001;21(3):246–8. [PubMed: 12539591]
    21.
    Villanueva F.S., Jankowski R.J., Manaugh C., Wagner W.R. Albumin microbubble adherence to human coronary endothelium: implications for assessment of endothelial function using myocardial contrast echocardiography. J Am Coll Cardiol. 1997;30(3):689–93. [PubMed: 9283527]
    22.
    Abramowicz J.S., Phillips D.B., Jessee L.N., Levene H., Parker K.J., Miller R.K. Sonographic investigation of flow patterns in the perfused human placenta and their modulation by vasoactive agents with enhanced visualization by the ultrasound contrast agent Albunex. J Clin Ultrasound. 1999;27(9):513–22. [PubMed: 10525213]
    23.
    Walday P., Tolleshaug H., Gjoen T., Kindberg G.M., Berg T., Skotland T., Holtz E. Biodistributions of air-filled albumin microspheres in rats and pigs. Biochem J. 1994;299(Pt 2):437–43. [PMC free article: PMC1138291] [PubMed: 8172604]
    24.
    Raeman C.H., Dalecki D., Child S.Z., Meltzer R.S., Carstensen E.L. Albunex Does Not Increase the Sensitivity of the Lung to Pulsed Ultrasound. Echocardiography. 1997;14(6 Pt 1):553–558. [PubMed: 11174994]
    25.
    Haggag K.J., Russell D., Walday P., Skiphamn A., Torvik A. Air-filled ultrasound contrast agents do not damage the cerebral microvasculature or brain tissue in rats. Invest Radiol. 1998;33(3):129–35. [PubMed: 9525750]
    26.
    Keller M.W., Glasheen W., Kaul S. Albunex: a safe and effective commercially produced agent for myocardial contrast echocardiography. J Am Soc Echocardiogr. 1989;2(1):48–52. [PubMed: 2627424]
    27.
    Ostensen J., Hede R., Myreng Y., Ege T., Holtz E. Intravenous injection of Albunex microspheres causes thromboxane mediated pulmonary hypertension in pigs, but not in monkeys or rabbits. Acta Physiol Scand. 1992;144(3):307–15. [PubMed: 1533987]
    28.
    Rovai D., Ghelardini G., Trivella M.G., Bjorklund G., Nevola E., Taddei L., Distante A., L'Abbate A. Intracoronary air-filled albumin microspheres for myocardial blood flow measurement. J Am Coll Cardiol. 1993;22(7):2014–21. [PubMed: 8245361]
    29.
    Desir R.M., Cheirif J., Bolli R., Zoghbi W.A., Hoyt B.D., Quinones M.A. Assessment of regional myocardial perfusion with myocardial contrast echocardiography in a canine model of varying degrees of coronary stenosis. Am Heart J. 1994;127(1):56–63. [PubMed: 8273756]
    30.
    Lafitte S., Laffort P., Rovai D., Alzieu P., Bonoron S., Besse P., Roudaut R. Assessment of Left Ventricular Area at Risk by Myocardial Contrast Two-Dimensional Echocardiography: An Evaluation of a New Animal Model. Echocardiography. 1998;15(6):563–574. [PubMed: 11175080]
    31.
    Feinstein S.B., Cheirif J., Ten Cate F.J., Silverman P.R., Heidenreich P.A., Dick C., Desir R.M., Armstrong W.F., Quinones M.A., Shah P.M. Safety and efficacy of a new transpulmonary ultrasound contrast agent: initial multicenter clinical results. J Am Coll Cardiol. 1990;16(2):316–24. [PubMed: 2197312]
    32.
    Geny B., Mettauer B., Muan B., Bischoff P., Epailly E., Piquard F., Eisenmann B., Haberey P. Safety and efficacy of a new transpulmonary echo contrast agent in echocardiographic studies in patients. J Am Coll Cardiol. 1993;22(4):1193–8. [PubMed: 8409060]
    33.
    Crouse L.J., Cheirif J., Hanly D.E., Kisslo J.A., Labovitz A.J., Raichlen J.S., Schutz R.W., Shah P.M., Smith M.D. Opacification and border delineation improvement in patients with suboptimal endocardial border definition in routine echocardiography: results of the Phase III Albunex Multicenter Trial. J Am Coll Cardiol. 1993;22(5):1494–500. [PubMed: 8227810]
    34.
    Barnhart J.L., Harada M., Lyle L.R., Saravis C.A. Immunologic reactions of human recipients to repeated exposures to Albunex microspheres Invest Radiol 1991. 26Suppl 1S192–3. [PubMed: 1808126]
    35.
    Geny B., Bischoff P., Muan B., Piquard F., Thiranos J.C., Epailly E., Lambrechs M., Juelsrud-Vebner A., Eisenmann B., Haberey P. Safety of a new transpulmonary echocontrast agent (Albunex) in repeated echocardiographic studies in patients. Clin Cardiol. 1997;20(2):111–5. [PubMed: 9034639]
    36.
    Voci P., Muan B., Morris H., Marelli C., Narbuvold H., Testa G., Marino B. Assessment of left ventricular systolic function in low-echogenic patients by intravenous Infoson injection during dopamine echocardiography. An open, phase III trial. Cardiologia. 1997;42(5):495–501. [PubMed: 9225493]
    37.
    Grayburn P.A., Weiss J.L., Hack T.C., Klodas E., Raichlen J.S., Vannan M.A., Klein A.L., Kitzman D.W., Chrysant S.G., Cohen J.L., Abrahamson D., Foster E., Perez J.E., Aurigemma G.P., Panza J.A., Picard M.H., Byrd B.F., Segar D.S., Jacobson S.A., Sahn D.J., DeMaria A.N. Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms. J Am Coll Cardiol. 1998;32(1):230–6. [PubMed: 9669275]
    38.
    Holte J., Rasmussen C., Morris H. First clinical experience with sonicated human serum albumin (Albunex) as an intrafallopian ultrasound contrast medium. Ultrasound Obstet Gynecol. 1995;6(1):62–5. [PubMed: 8528806]
    39.
    Boudghene F.P., Bazot M., Robert Y., Perrot N., Rocourt N., Antoine J.M., Morris H., Leroy J.L., Uzan S., Bigot J.M. Assessment of Fallopian tube patency by HyCoSy: comparison of a positive contrast agent with saline solution. Ultrasound Obstet Gynecol. 2001;18(5):525–30. [PubMed: 11844177]
    PubReader format: click here to try

    Views

    Search MICAD

    Limit my Search:


    Related information

    • PMC
      PubMed Central citations
    • PubMed
      Links to pubmed

    Related citations in PubMed

    See reviews...See all...

    Recent Activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...