Therapeutic Intra Vascular Ultrasound (TIVUS)



Fig. 10.1
The TIVUS™ System (Console and Multidirectional Catheter) (Printed with permission from Cardiosonic)



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Fig. 10.2
Fluoroscopic image of the multidirectional TIVUS™ Catheter in the renal artery introduced over a 0.014″ guidewire (Printed with permission from Cardiosonic)


The Multidirectional TIVUS™ Catheter is composed of three ultrasonic elements, which emit ultrasonic energy simultaneously. A gradual distancing mechanism is operated via a designated lever on the handle. The lever deploys three petals between the ultrasonic elements, and thus positions the ultrasonic elements at a safe distance from the renal artery wall. The catheter design (multiple ultrasonic elements and the distancing mechanism) facilitates and simplifies the procedure. Bilateral denervation is achieved by delivering US energy in up to three locations within each renal artery.

The TIVUS™ System contains several integrated safety mechanisms as part of the TIVUS™ console, for example:

1.

Temperature Sensor (thermistor): Measures the blood temperature near the catheter tip and turns off the excitation if the blood temperature exceeds the maximal pre-set temperature.

 

2.

Distance Sensor and Control: The ultrasound transducer receives ultrasonic echo feedback from the tissue and evaluates the distance from artery wall; this prevents potential thermal damage to the artery wall. If the ultrasound transducer is sensed to be too close to the artery wall, excitation will not be enabled.

 

In accordance with the general advantages of ultrasonic hyperthermia, the TIVUS™ System may offer several beneficial characteristics:



  • Inducing a remote thermal effect in tissues adjacent to vascular lumen.


  • The TIVUS™ transducer is positioned intra-luminally and does not touch the arterial wall, thus preventing direct thermal or mechanical effect.


  • The catheter system allows continuous cooling of the transducers and the vessel wall by preserving uninterrupted maintenance of renal blood flow.


  • Real-time feedback enables a monitored yet robust treatment.


  • The flexibility of the Multidirectional TIVUS™ enables circumferential treatment in short renal arteries.


  • Absence of any interaction of the ultrasound waves with metal allows treatment of previously stented segments, not otherwise possible with RF energy.



Mechanism of Action


The TIVUS™ System uses high intensity US to induce thermal effect to target nerves, and is intended for renal denervation. US is a widely accepted energy source for hyperthermia therapy in various organs [2]. The TIVUS™ System, comprised of a catheter-mounted ultrasonic transducer and a console, generates high intensity, non-focused ultrasonic energy which can be delivered percutaneously to tissues adjacent to blood vessels of varying diameters (Fig. 10.3a).

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Fig. 10.3
Renal denervation using the TIVUS™ system: (a) Catheter positioning in a renal artery. (b) Transverse section of a peripheral artery. (c) Thermal effect to connective tissue and nerves following TIVUS™ treatment (dark line), illustration of the TIVUS™ ultrasonic transducers and the path of the ultrasonic energy beam, as well as the inner artery spared layers and intact endothelium. (d) Thermal effect distance per ultrasonic beam frequency (Printed with permission from Cardiosonic)

In contrast to low intensity US applied for imaging, where tissue heating is negligible, the US energy generated by the TIVUS™ System is absorbed into the tissue and transformed into heat, thus resulting in a thermal effect on the target tissue and nerves. The other ultrasonic effects on tissue (such as cavitation or streaming) are insignificant. Figure 10.4 illustrates the intensity and frequency range of the TIVUS™ system in comparison to other ultrasonic medical modalities. It is noteworthy that while Cardiosonic’s US element frequency is at a higher range similar to imaging modalities, the intensity is somewhat higher than physical therapy devices and significantly lower than High Intensity Focused Ultrasound (HIFU) products, mostly used in oncological therapies. During treatment, the catheter is placed at a distance from the artery wall, therefore preventing mechanical damage to the artery wall and allowing cooling of the ultrasonic transducer as well as vascular intima by renal blood flow. The ultrasonic energy is absorbed by the tissues adjacent to the artery, which is heated to 50–80 °C. Heating a tissue beyond 50 °C causes irreversible denaturation of protein (eg. collagen) and other thermal effects, resulting in remote damage to the outer artery wall layers and perivascular tissue, while avoiding damage to the vessel’s intimal layer. Thermal damage to the media, if present, is negligible. When US is applied to nerves located in the adventitial and perivascular layers, heating of nerve cells and their supporting tissue results in axonal degeneration and cell death (Fig. 10.3c) [2, 6, 11]. Heating causes irreversible damage and blockage of unmyelinated nerve fibres above 47 °C and of myelinated nerve fibres above 58 °C [11]. The depth of penetration and hence absorption of US energy, depends on the beam frequency; as the frequency rises, the depth of penetration decreases (Fig. 10.3d).

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Fig. 10.4
Medical ultrasonic modalities (Printed with permission from Cardiosonic)


TIVUS™ Pre-clinical and Clinical Data



Animal Studies


Cardiosonic conducted a series of feasibility experiments (swine model) followed by seven animal studies which included 34 treated animals testing various sets of treatment parameters. The animal testing included assessments of safety and performance as well as comparison to an existing RF based technology. 30-day and 45-day safety and performance controlled studies were conducted which included a total of 19 animals treated with different sets of treatment parameters. Analysis revealed no statistically significant renal function alteration, normal angiographic appearance of the renal arteries, and mostly no treatment related renal artery luminal narrowing of >20 % or other abnormalities on histopathological examination. Performance measures resulted in Nor-Epinephrine (NE) concentration lowered by approximately 50 % compared with a standardized reference level (range: 42–93 %).


Clinical Experience-Unidirectional TIVUS


TIVUS I is a First-In-Man (FIM) multicenter study conducted across centres in Australia, Europe and Israel in order to evaluate the TIVUS™ System safety and performance. The study included patients with essential hypertension with Office Systolic Blood Pressure (OSBP) ≥160 mmHg, despite treatment with more than three antihypertensive medications, including a diuretic. In addition, the clinical experience includes patients treated under a compassionate use program for severe resistant hypertension associated with impaired renal function or previously implanted renal artery stent. Overall a total of 18 patients were successfully treated at six investigational sites worldwide. Safety and feasibility have been demonstrated by virtue of absence of device related complications and reduction in blood pressure measurements.

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Jun 20, 2017 | Posted by in NEPHROLOGY | Comments Off on Therapeutic Intra Vascular Ultrasound (TIVUS)

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