Skip to main content

Advertisement

Log in

Safety and bio-effects of ultrasound contrast agents

  • Special Issue - Original Article
  • Published:
Medical & Biological Engineering & Computing Aims and scope Submit manuscript

Abstract

The use of gas-filled microbubbles as ultrasound contrast agents raises potential safety concerns for diagnostic ultrasound imaging. A number of biological effects have been seen in experimental systems, including the induction of physiological response to cardiac exposures (premature ventricular contractions) and damage at a microvascular level (microvascular rupture and petechial haemorrhage). The literature indicates that a mechanical index (MI) of 0.4 represents the threshold above which microvascular bio-effects are seen in in vivo studies. Above this value, the extent of biological effects appears to increase rapidly with both increasing in situ peak negative acoustic pressure amplitude and with contrast agent concentration. While there is no proven evidence of harm resulting from clinical use of these agents, caution is recommended when contrast-enhanced imaging is undertaken.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. AIUM (2008) American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound. J Ultrasound Med 27:503–515

    Google Scholar 

  2. Apfel RE, Holland CK (1991) Gauging the likelihood of cavitation from short-pulse, low duty-cycle diagnostic ultrasound. Ultrasound Med Biol 17:179–185

    Article  Google Scholar 

  3. Blomley M, Claudon M, Cosgrove D (2007) WFUMB symposium on ultrasound contrast agents: clinical applications and safety concerns. Ultrasound Med Biol 33:180–186

    Article  Google Scholar 

  4. Brayman AA, Azadniv M, Cox C, Miller MW (1996) Hemolysis of Albunex-supplemented, 40% hematocrit human erythrocytes in vitro by 1 MHz pulsed ultrasound: acoustic pressure and pulse length dependence. Ultrasound Med Biol 22:927–938

    Article  Google Scholar 

  5. Brayman AA, Lizotte LM, Miller MW (1999) Erosion of artificial endothelia in vitro by pulsed ultrasound: acoustic pressure, frequency, membrane orientation and microbubble contrast agent dependence. Ultrasound Med Biol 25:1305–1320

    Article  Google Scholar 

  6. Church CC (1995) The effects of an elastic solid surface layer on the radial pulsations of gas bubbles. J Acoust Soc Am 97:1510–1521

    Article  Google Scholar 

  7. Claudon M, Cosgrove D, Albrecht T et al (2008) Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS)—update 2008. Ultraschall Med 29:28–44

    Article  Google Scholar 

  8. Cosgrove D, Harvey C (2009) Clinical uses of microbubbles in diagnosis and treatment. Med Biol Eng Comput. doi:10.1007/s11517-009-0434-3

  9. Coussios CC, Farny CH, ter Haar GR, Roy R (2007) Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU). Int J Hyperthermia 23:105–120

    Article  Google Scholar 

  10. Dalecki D (2007) WFUMB symposium on ultrasound contrast agents: bioeffects of ultrasound contrast agents in vivo. Ultrasound Med Biol 33:205–213

    Article  Google Scholar 

  11. Dalecki D, Rota C, Raeman CH, Child SZ (2005) Premature cardiac contractions produced by ultrasound and microbubble contrast agents in mice. Acoust Res Lett Online 6:221–226

    Article  Google Scholar 

  12. de Jong N, Cornet R, Lancee CT (1994) Higher harmonics of vibrating gas-filled microspheres, Part one: simulations. Ultrasonics 32:447–453

    Article  Google Scholar 

  13. Duck F (2008) Hazards, risks and safety of diagnostic ultrasound. Med Eng Phys 30:1338–1348

    Article  Google Scholar 

  14. Frenkel V (2008) Ultrasound mediated delivery of drugs and genes to solid tumors. Adv Drug Deliv Rev 60:1193–1208

    Article  Google Scholar 

  15. Frizzell LA, Chen E, Lee C (1994) Effects of pulsed ultrasound on the mouse neonate: hind limb paralysis and lung hemorrhage. Ultrasound Med Biol 20:53–63

    Article  Google Scholar 

  16. Holland CK, Deng CX, Apfel RE, Alderman JL, Fernandez LA, Taylor KJW (1996) Direct evidence of cavitation in vivo from diagnostic ultrasound. Ultrasound Med Biol 22:917–925

    Article  Google Scholar 

  17. Hwang JH, Brayman AA, Reidy MA, Matula TJ, Kimmey MB, Crum LA (2005) Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. Ultrasound Med Biol 31:553–564

    Article  Google Scholar 

  18. Hynynen K (2008) Ultrasound for drug and gene delivery to the brain. Adv Drug Deliv Rev 60:1209–1217

    Article  Google Scholar 

  19. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA (2001) Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220:640–646

    Google Scholar 

  20. IEC62359 (2006) Ultrasonics—field characterization—test methods for the determination of thermal and mechanical indices related to medical diagnostic fields. International Electrotechnical Commission, Geneva

  21. ISO 14971 (2000) Medical devices—application of risk management to medical devices. International Organisation for Standards

  22. Ivey JA, Gardner EA, Fowlkes JB, Rubin JM, Carson PL (1995) Acoustic generation of intra-arterial contrast boluses. Ultrasound Med Biol 21:757–767

    Article  Google Scholar 

  23. Jiménez C, de Gracia R, Aguilera A, Alonso S, Cirugeda A, Benito J, Regojo RM, Aguilar R, Warlters A, Gomez R, Largo C, Selgas R (2008) In situ kidney insonation with microbubble contrast agents does not cause renal tissue damage in a porcine model. J Ultrasound Med 27:1607–1615

    Google Scholar 

  24. Johnson LW, Lozner EC, Johnson S et al (1989) Coronary arteriography 1984–1987: a report of the registry of the Society for Cardiac Angiography and Interventions. I. Results and complications. Cathet Cardiovasc Diagn 17:5–10

    Article  Google Scholar 

  25. Kaneko Y, Maruyama T, Takegami K, Watanabe T, Mitsui H, Hanajiri K, Nagawa H, Matsumoto Y (2005) Use of a microbubble agent to increase the effects of high intensity focused ultrasound on liver tissue. Eur Radiol 15:1415–1420

    Article  Google Scholar 

  26. Killam AL, Greener Y, McFerran BA et al (1998) Lack of bioeffects of ultrasound energy after intravenous administration of FS069 (Optison) in the anesthetized rabbit. J Ultrasound Med 17:349–356

    Google Scholar 

  27. Kobayashi N, Yasu T, Yamada S et al (2002) Endothelial cell injury in venule and capillary induced by contrast ultrasonography. Ultrasound Med Biol 28:949–956

    Article  Google Scholar 

  28. Kobayashi N, Yasu T, Yamada S et al (2003) Influence of contrast ultrasonography with perflutren lipid microspheres on microvessel injury. Circ J 67:630–636

    Article  Google Scholar 

  29. Kudo N, Miyaoka T, Okada K, Niwa K (2002) Study on mechanism of cell damage caused by microbubbles exposed to ultrasound. In: Proceedings of IEEE ultrasonic symposium, pp 1351–1354

  30. Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML (2008) Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent. J Am Coll Cardiol 51:1704–1706

    Article  Google Scholar 

  31. Lafon C, Murillo-Rincon A, Goldenstedt C, Chapelon J-Y, Mithieux F, Owen NR, Cathignol D (2008) Feasibility of using ultrasound contrast agents to increase the size of thermal lesions induced by non-focused transducers: in vitro demonstration in tissue mimicking phantom. Ultrasonics doi:10.1016/j.ultras.2008.07.013

  32. Li P, Cao LQ, Dou CY, Armstrong WR, Miller DL (2003) Impact of myocardial contrast echocardiography on vascular permeability:an in vivo dose response study of delivery mode, ultrasound power and contrast dose. Ultrasound Med Biol 29:1341–1349

    Article  Google Scholar 

  33. Li P, Armstrong WR, Miller DL (2004) Impact of myocardial contrast echocardiography on vascular permeability: comparison of three different contrast agents. Ultrasound Med Biol 30:83–91

    Article  Google Scholar 

  34. Miller DL (2004) Dou Membrane damage thresholds for pulsed or continuous ultrasound in phagocytic cells loaded with contrast agent gas bodies. Ultrasound Med Biol 30:405–411

    Article  Google Scholar 

  35. Miller D (2007) Overview of experimental studies of biological effects of medical ultrasound caused by gas body activation and inertial cavitation. Prog Biophys Mol Biol 93:314–330

    Article  Google Scholar 

  36. Miller DL, Gies RA (1998) Enhancement of ultrasonically-induced hemolysis by perfluorocarbon-based compared to air-based echo-contrast agents. Ultrasound Med Biol 24:285–292

    Article  Google Scholar 

  37. Miller DL, Gies RA (1998) Gas-body-based contrast agent enhances vascular bioeffects of 1.09 MHz ultrasound on mouse intestine. Ultrasound Med Biol 24:1201–1208

    Article  Google Scholar 

  38. Miller DL, Gies RA (2000) The influence of ultrasound frequency and gas-body composition on the contrast agent-medicated enhancement of vascular bioeffects in mouse intestine. Ultrasound Med Biol 26:307–313

    Article  Google Scholar 

  39. Miller DL, Quddus J (2001) Lysis and sonoporation of epidermoid and phagocytic monolayer cells by diagnostic ultrasound activation of contrast agent gas bodies. Ultrasound Med Biol 27:1107–1113

    Article  Google Scholar 

  40. Miller DL, Thomas RM (1995) Ultrasound contrast agents nucleate inertial cavitation activity in vitro. Ultrasound Med Biol 21:1059–1065

    Article  Google Scholar 

  41. Miller DL, Thomas RM (1996) Contrast agent gas bodies enhance hemolysis induced by lithotripter shock waves and high intensity focused ultrasound in whole blood. Ultrasound Med Biol 22:1089–1095

    Article  Google Scholar 

  42. Miller DL, Dou C, Song J (2003) DNA transfer and cell killing in epidermoid cells by diagnostic ultrasound activation of contrast agent gas bodies in vitro. Ultrasound Med Biol 29:601–607

    Article  Google Scholar 

  43. Miller DL, Averkiou MA, Brayman AA, Everbach EC, Holland CK, Wible JH, Wu J (2008) Bio-effects for diagnostic ultrasound contrast agents. J Ultrasound Med 27:311–632

    Google Scholar 

  44. Miller DL, Dou C, Wiggins RC (2008) Frequency dependence of kidney injury induced by contrast aided diagnostic ultrasound in rats. Ultrasound Med Biol 34:1678–1687

    Article  Google Scholar 

  45. Penney DP, Schenk EA, Maltby K, Harman-Raeman C, Child SZ, Carstensen EL (1993) Morphological effects of pulsed ultrasound in the lung. Ultrasound Med Biol 19:127–135

    Article  Google Scholar 

  46. Philipp A, Lauterborn W (1998) Cavitation erosion by single laser-produced bubbles. J Fluid Mech 361:75–116

    Article  MATH  Google Scholar 

  47. Postema M, van Wamel A, Lancee CT, deJong N (2004) Ultrasound-induced encapsulated microbubble phenomena. Ultrasound Med Biol 30:827–840

    Article  Google Scholar 

  48. Price RJ, Skyba DM, Kaul S, Skalak TC (1998) Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation 98:1264–1267

    Google Scholar 

  49. Raeman CH, Dalecki D, Child SZ, Meltzer RS, Carstensen EL (1997) Albunex does not increase the sensitivity of the lung to pulsed ultrasound. Echocardiography 14:553–557

    Article  Google Scholar 

  50. Rahim A, Taylor SL, Bush NL, ter Haar GR, Bamber JC, Porter CD (2006) Physical parameters affecting ultrasound/microbubble mediated gene delivery efficiency in vitro. Ultrasound Med Biol 32:1269–1279

    Article  Google Scholar 

  51. Rahim A, Taylor SL, Bush NL, ter Haar GR, Bamber JC, Porter CD (2006) Spatial and acoustic pressure dependence of microbubble-mediated gene delivery targeted using focused ultrasound. J Gene Med 8:1347–1357

    Article  Google Scholar 

  52. Raisinghani A, Wei KS, Crouse L et al (2003) Myocardial contrast echocardiography (MCE) with triggered ultrasound does not cause premature ventricular complexes: evidence from PB127 MCE studies. J Am Soc Echocardiogr 16:1037–1042

    Article  Google Scholar 

  53. Razansky D, Einziger PD, Adam DR (2006) Enhanced heat deposition using ultrasound contrast agent—modelling and experimental observations. IEEE Trans Ultrason Ferroelectr Freq Control 53:137–147

    Article  Google Scholar 

  54. Sboros V (2008) Response of contrast agents to ultrasound. Adv Drug Deliv Rev 60:1117–1136

    Article  Google Scholar 

  55. Schlachetzki F, Holscher T, Koch HJ et al (2002) Observation on the integrity of the blood-brain barrier after microbubble destruction by diagnostic transcranial color-coded sonography. J Ultrasound Med 21:419–429

    Google Scholar 

  56. Sheikov N, McDannold N, Vykhodtseva N, Jolesz F, Hynynen K (2004) Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound Med Biol 30:979–989

    Article  Google Scholar 

  57. Shigeta K, Itoh K, Ookawara S, Taniguchi N, Omoto K (2004) Endothelial cell injury and platelet aggregation induced by contrast ultrasonography in the rat hepatic sinusoid. J Ultrasound Med 23:29–36

    Google Scholar 

  58. Skyba DM, Price RJ, Linka AZ, Skalak TC, Kaul S (1998) Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 98:290–293

    Google Scholar 

  59. Stieger SM, Caskey CF, Adamson RH, Qin S, Curry FE, Wisner ER, Ferrara KW (2007) Enhancement of vascular permeability with low frequency contrast-enhanced ultrasound in the chorioallantoic membrane model. Radiology 243:112–121

    Article  Google Scholar 

  60. Stride E, Edirisinghe M (2009) Special issue on microbubbles: from contrast enhancement to cancer therapy. Med Biol Eng Comput. doi:10.1007/s11517-009-0510-8

  61. Stride E, Saffari N (2004) The potential for thermal damage posed by microbubble contrast agents. Ultrasonics 42:907–913

    Article  Google Scholar 

  62. Stuart RJ, Ellestad MH (1980) National survey of exercise stress testing facilities. Chest 77:94–97

    Article  Google Scholar 

  63. Tarantal AF, Canfield DR (1994) Ultrasound induced lung hemorrhage in the monkey. Ultrasound Med Biol 20:65–72

    Article  Google Scholar 

  64. Tung Y-S, Liu HL, Wu CC, Ju KC, Chen WS, Lin WL (2006) Contrast agent enhanced ultrasound thermal ablation. Ultrasound Med Biol 32:1103–1110

    Article  Google Scholar 

  65. Umemura S, Kawabata K, Sasaki K (2005) In vivo acceleration of ultrasonic tissue heating by microbubble agent. IEEE Trans Ultrason Ferroelectr Freq Control 52:1690–1698

    Article  Google Scholar 

  66. van Bavel E (2007) Effects of shear stress on endothelial cells: possible relevance for ultrasound applications. Prog Biophys Mol Biol 93:374–383

    Article  Google Scholar 

  67. van der Wouw P, Brauns AC, Bailey SE, Powers JE, Wilde AA (2000) Premature ventricular contractions during triggered imaging with ultrasound contrast. J Am Soc Echocardiogr 13:288–294

    Article  Google Scholar 

  68. Whittingham TA (2007) Medical diagnostic applications and sources. Prog Biophys Mol Biol 93:84–110

    Article  Google Scholar 

  69. Wible JH Jr, Galen KP, Wojdyla JK, Hughes MS, Klibanov AL, Brandenburger GH (2002) Microbubbles induce renal hemorrhage when exposed to diagnostic ultrasound in anesthetized rats. Ultrasound Med Biol 28:1535–1546

    Article  Google Scholar 

  70. Wu J (1998) Temperature rise generated by ultrasound in the presence of contrast agent. Ultrasound Med Biol 24:267–274

    Article  Google Scholar 

  71. Wu J (2002) Theoretical study on shear stress generated by microstreaming surrounding contrast agents attached to living cells. Ultrasound Med Biol 28:125–129

    Article  Google Scholar 

  72. Zachary JF, O’Brien WD (1995) Lung hemorrhage induced by continuous and pulsed wave (diagnostic) ultrasound in mice, rabbits and pigs. Vet Pathol 32:43–54

    Article  Google Scholar 

  73. Zhong P, Zhou Y, Zhu S (2001) Dynamics of bubble oscillation in constrained media and mechanisms of vessel rupture in SWL. Ultrasound Med Biol 27:119–134

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gail ter Haar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

ter Haar, G. Safety and bio-effects of ultrasound contrast agents. Med Biol Eng Comput 47, 893–900 (2009). https://doi.org/10.1007/s11517-009-0507-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11517-009-0507-3

Keywords

Navigation