By Kunal Karani, MS4, University of Cincinnati College of Medicine
Interventional Radiology uses innovative tools to treat a variety of medical conditions. One tool that medical students are likely familiar with from a diagnostic standpoint, but less so a therapeutic standpoint, is ultrasound. Ultrasound is a reliable, inexpensive and safe diagnostic imaging modality. However, the benefits of ultrasound technology also extend into therapeutic applications. The use of ultrasound technology has made its way into hospitals and outpatient centers as an option to treat a variety of medical illnesses such as thrombo-occlusive diseases and cancer. Further research is being performed on sonothrombolysis, ultrasound ablation and other therapeutic applications.
Mechanism of Therapeutic US:
Ultrasound exerts therapeutic effects in many ways. Mechanisms that unify the various applications of ultrasound include: stable and inertial cavitation, streaming from cavitation, heating and acoustic radiation force. Sonothrombolysis is an application of ultrasound that employs these mechanisms to improve clot lysis. Ultrasound energy imparts momentum to tissue through absorption and scattering mechanisms to generate a resultant force known as acoustic radiation force (1). Radiation force causes fluid mixing to allow a thrombolytic drug to penetrate a clot and additionally removes clot degradation products (2-4). Ultrasound energy also creates vapor cavities (also called microbubbles or cavitation nuclei) in fluids–a mechanism called cavitation (5). Cavitation can be either inertial or stable. In inertial cavitation, the expansion and collapse of bubbles creates a liquid jet that can be used to mechanically damage a clot (5). In stable cavitation, microbubbles oscillate in size without collapsing (6,7). Stable cavitation generates a microstreaming effect of the surrounding fluid to cause fluid mixing that hastens enzymatic fibrinolysis by enhancing the penetration of both rt-PA and plasminogen into clots (6,7). Cavitation nuclei can be further induced by the use of clinical ultrasound contrast agents (6,7).
High intensity focused ultrasound (HIFU) is another application of ultrasound that provides non-invasive heating and ablation of tissues to treat a variety of conditions. The HIFU source can be placed outside of the body to treat abnormalities in the liver, kidney, breast, uterus, pancreas, brain and bone, or in the rectum to treat the prostate (14-19). HIFU directs ultrasonic energy at the target site to induce necrosis, avoiding overlying tissue in the propagating ultrasound wave fields. A typical analogy to describe HIFU is that of a magnifying glass that concentrates the sun’s rays to burn an object. Both ultrasound and MRI may guide HIFU therapy.
Applications of Therapeutic US:
Deep Vein Thrombosis/Pulmonary Embolism
An ultrasound-assisted thrombolysis catheter exemplifies clinical use of sonothrombolysis. The catheter is typically composed of a multi-side hole drug infuser with a core of ultrasound elements and treats peripheral arterial disease (8), stroke (9), deep venous thrombosis (DVT) (10) and pulmonary embolism (PE) (11). Many medical students may have already seen the use of ultrasound-assisted thrombolysis catheters for the treatment of DVT during their IR rotations. Now, medical students will increasingly see this technology used for PE. A randomized control trial analyzed 59 patients with acute pulmonary embolism who were either treated with the EKOS ultrasound catheter system (Bothell, WA, USA) and rt-PA, or rt-PA alone. The study concluded that ultrasound-assisted thrombolysis was the superior treatment versus anticoagulation at 24 hours, without an increased bleeding risk (12). A retrospective study comprised of 45 patients with submassive PE found both a clinically significant and statistically significant decrease of mean pulmonary artery pressure with no readmissions for PE 30 days post-discharge in the patients treated with ultrasound (13). Ischemic stroke patients may also benefit from sonothrombolysis, as its potential as an adjuvant to thrombolytic drug therapy is currently a major area of research.
HIFU procedures typically require only a single session with the patient either fully conscious or lightly sedated. Clinical HIFU data most strongly supports its use in prostate cancer (18,19). Two indications for the use of HIFU in prostate cancer are validated today: 1. Primary care treatment (for patients with localized prostate cancer for whom radical prostatectomies are not an option due to age over 70, life expectancy less than 10 years, major co-morbidities which preclude studies or the simple refusal on the part of the patient to undergo surgery) and 2. External Beam Radiation Therapy Failure (20).
MRI-guided HIFU directed at the thalamus is now an FDA approved for essential tremor treatment. A double-blind control trial involving 76 patients with essential tremor who had not responded to medication therapy was performed (21). Fifty-six of the randomly selected patients that were treated with MRI-guided HIFU showed nearly a 50 percent improvement in their tremors and motor function three months after treatment compared to their baseline score. At 12 months post-procedure, the treatment group retained a 40 percent improvement compared to baseline. Patients in the sham treatment group showed a lack of improvement or worsening of symptoms.
Targeted Drug Delivery
Biological barriers open through use of ultrasound mediated cavitation—a mechanism termed sonoporation—that allows for targeted delivery of drugs (22-24). For example, Kotopoulis et al treated patients with pancreatic adenocarcinoma with a commercial clinical ultrasound scanner following standard chemotherapy treatment with gemcitabine (24). An ultrasound contrast agent was injected intravascularly during the treatment to induce sonoporation. The patients in the study received a significantly greater number of treatment cycles versus those who did not receive ultrasound therapy, thus creating the potential for a prolonged quality of life (24). Considerable laboratory research has also focused on liposomes and microbubbles that carry drugs that can be acted upon ultrasound to release drugs at a targeted location.
The research behind the therapeutic ultrasound is teeming, as this article merely scratches the surface. In conclusion, interventional radiologists will use more of therapeutic ultrasound in the future as evidence in the literature grows.
For additional information, please see references below.
- Nyborg WL (1953). Acoustic Streaming Due to Attenuated Plane Waves. J Acoust Soc Am, 25:68.
- Francis CW, Blinc A, Lee S, Cox C (1995). Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator into Clots. Ultrasound Med Biol, 21:419–424.
- Acconcia C, Leung BYC, Hynynen K, Goertz DE (2013). Interactions Between Ultrasound Stimulated Microbubbles and Fibrin Clots. Appl Phys Lett, 103:053701.
- Chuang YH, Cheng PW, Li PC (2013). Combining Radiation Force with Cavitation for Enhanced Sonothrombolysis. IEEE Trans Ultrason Ferroelectr Freq Control, 60(1):97-104.
- Weiss HL, Selvaraj P, Okita K, Matsumoto Y, Voie A, Hoelscher T, Szeri AJ (2013). Mechanical Clot Damage from Cavitation During Sonothrombolysis. J Acoust Soc Am, 133:3159.
- Datta S, Coussios C-C, Ammi AY, Mast TD, de Courten-Myers GM, Holland CK (2008). Ultrasound-enhanced Thrombolysis Using Definity as a Cavitation Nucleation Agent. Ultrasound Med Biol, 34:1421–1433.
- Sutton JT, Haworth KJ, Pyne-Geithman G, Holland CK (2013). Ultrasound-mediated Drug Delivery for Cardiovascular Disease. Expert Opin Drug Deliv, 10:573-592.
- Greenberg R, Ivancev K, Ouriel K (1999). High Frequency Ultrasound Thrombolysis: Phase I Results. Am J Cardiol, 84:42.
- The IMS II Trial Investigators (2007). The Interventional Management of Stroke (IMS) II study. Stroke, 38:2127–2135.
- Raabe RA (2006). Ultrasound Facilitated Thrombolysis in Treating DVT. Endovascular Today, 4:1–14.
- Engelberger RP, Kucher N (2014). Ultrasound-assisted Thrombolysis for Acute Pulmonary Embolism: A Systematic Review. Eur Heart, J 35:758–764.
- Kucher N, Boekstegers P, Müller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greid M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Greunwald H, Empen K, Baumgartner I (2013). Randomized, Controlled Trial of Ultrasound-assisted Catheter-directed Thrombolysis for Acute Intermediate-risk Pulmonary Embolism. Circulation, 129:479-486.
- Bagla S, Smirniotopoulos JB, van Breda A, Sheridan MJ, Sterling KM. (2015). Ultrasound-Accelerated Catheter-Directed Thrombolysis for Acute Submassive Pulmonary Embolism. JVIR, 26:1001-1006.
- Al-Bataineh O, Jenne J, Huber P (2012). Clinical and Future Applications of High Intensity Focused Ultrasound in Cancer. Cancer Treat Rev, 38:346-353.
- Orsi F, Arnone P, Chen W, Zhang L (2010). High Intensity Focused Ultrasound Ablation: a New Therapeutic Option for Solid Tumors. J Cancer Res Ther, 6:414-420.
- Wu F, Wang ZB, Chen WZ, Zou JZ, Bai J, Zhu H, Li KQ, Jin CB, Xie FL, Su HB (2005). Advanced Hepatocellular Carcinoma: Treatment with High- intensity Focused Ultrasound Ablation Combined with Transcatheter Arterial Embolization. Radiol, 235:659–667.
- Wu F, Wang ZB, Chen WZ, Zou JZ, Bai J, Zhu H, Li KQ, Jin CB, Xie FL, Su HB (2005). Feasibility of US-guided High-intensity Focused Ultrasound Treatment in Patients With Advanced Pancreatic Cancer: Initial Experience. Radiol, 236:1034-1040.
- Jácome-Pita F, Sánchez-Salas R, Barret E, Amaruch N, Gonzalez-Enguita C, Cathelineau, X (2014). Focal Therapy in Prostate Cancer: The Current Situation.E Cancer Medical Science, 8:435.
- Bankhead C (2016). Cautious Optimism for HIFU in Prostate Cancer—Radical Treatment Avoided for 2 years in 90% of Patients. MedPage Today.
- AURO (2009). The Association of Italian Urologists: Guidelines, Prostate Cancer PCa.
- Elias WJ, Lipsman N, Ondo WG, et al (2016). A Randomized Trial of Focused Ultrasound Thalamatomy for Essential Tremor. N Engl J Med, 375:730-739
- Kaddur K, Palanchon P, Tranquart F, Pichon C, Bouakaz A (2007). Sonopermeabilization: Therapeutic Alternative With Ultrasound and Microbubbles. Radiol, 88:1777–1786.
- Tang H, Wang CCJ, Blankschtein D, Langer R (2002). An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport. Pharm Res. 19:1160–1169.
- Kotopoulis S, Dimcevski G, Helge Gilja O, Hoem D, Postema M (2013). Treatment of Human Pancreatic Cancer Using Combined Ultrasound, Microbubbles, and Gemcitabine: A Clinical Case Study. Medical Physics, 40:072902-n/a.
For a comprehensive text on therapeutic ultrasound:
Escoffre J, Bouakaz A, Ohio Library and Information Network. Therapeutic Ultrasound. Vol 880. 1st 2016 ed. Cham: Springer; 2016;2015;.