Pathophysiological mechanisms of high-intensity focused ultrasound-mediated vascular occlusion and relevance to non-invasive fetal surgery.

High-intensity focused ultrasound (HIFU) is a non-invasive technology, which can be used occlude blood vessels in the body. Both the theory underlying and practical process of blood vessel occlusion are still under development and relatively sparse in vivo experimental and therapeutic data exist. HIFU would however provide an alternative to surgery, particularly in circumstances where serious complications inherent to surgery outweigh the potential benefits. Accordingly, the HIFU technique would be of particular utility for fetal and placental interventions, where open or endoscopic surgery is fraught with difficulty and likelihood of complications including premature delivery. This assumes that HIFU could be shown to safely and effectively occlude blood vessels in utero. To understand these mechanisms more fully, we present a review of relevant cross-specialty literature on the topic of vascular HIFU and suggest an integrative mechanism taking into account clinical, physical and engineering considerations through which HIFU may produce vascular occlusion. This model may aid in the design of HIFU protocols to further develop this area, and might be adapted to provide a non-invasive therapy for conditions in fetal medicine where vascular occlusion is beneficial.

Sliding window dual gradient echo (SW-dGRE): T1 and proton resonance frequency (PRF) calibration for temperature imaging in polyacrylamide gel.

The aim of the work is to evaluate a magnetic resonance imaging (MRI) thermometry sequence suitable for targeting of focused ultrasound (FUS) when used in vascular occlusion studies. A sliding window dual gradient echo (SW-dGRE) sequence was used. This sequence has the capability of monitoring both T1 relaxation and phase changes, which vary with temperature. Preliminary work involved quantification of the changes in T1 relaxation time with temperature and obtaining the PRF shift coefficient in polyacrylamide gel as it underwent an exothermic reaction during polymerization (avoiding the use of an external heat source). Temperature changes were visualized using thermal maps acquired with the sequence. For FUS guidance a thermal imaging technique is required with a temporal resolution <5 s, a spatial resolution of approximately 1 mm and a temperature resolution of approximately 5 degrees C. The sequence was optimized to improve the CNR (contrast to noise ratio) and SNR (signal to noise ratio) in the phase and magnitude images respectively. The PRF coefficient obtained for the polyacrylamide gel was -9.98 +/- 0.24 ppb degrees C(-1), whilst deltaT1 and temperature change were related by a proportionality factor, the T1 temperature coefficient, of 102.3 +/- 2.9 ms degrees C(-1). The sequence produces an image at every 1.4 s interval. In both magnitude and phase data, the in-plane resolution is +/- 1.2 mm and the temperature resolution is approximately 2 degrees C. The advantage of this sequence is that the temperature obtained from the magnitude data can be confirmed independently using the phase data and vice versa. Thus the sequence can essentially be crosschecked.

Preclinical development of noninvasive vascular occlusion with focused ultrasonic surgery for fetal therapy.

OBJECTIVE: This study was undertaken to investigate the ability of focused ultrasonic surgery to occlude blood flow in vivo. STUDY DESIGN: A 5-mm linear track exposure of 1.7-MHz focused ultrasound was applied across the femoral vessels for 5 seconds. Free field spatial peak intensities in the range of 1,000 to 4,660 W x cm(-2) were used. Vascular occlusion was confirmed after demonstration of an absent distal arterial pulse and an absent flow signal on magnetic resonance angiography and subtracted (after minus before) contrast-enhanced dual-echo steady-state sequences. RESULTS: The minimum intensity for consistent vascular occlusion was 1,690 W x cm(-2) at a focal depth of 5 mm when the transducer was moved at 1 mm x s(-1) orthogonal to the direction of blood flow. CONCLUSIONS: This study demonstrates that focused ultrasonic surgery can achieve reproducible vascular occlusion in vivo. Potential obstetric applications include noninvasive ultrasonographically guided occlusion of placental vessels mediating interfetal transfusion in monochorionic twins.

Preliminary results of a phase I dose escalation clinical trial using focused ultrasound in the treatment of localised tumours.

OBJECTIVE: The primary aim of this phase I trial was to assess the tolerance of cancer patients to focused ultrasound (FUS) treatment in a variety of different sites and to document any associated acute or delayed toxicity. This would appear to be the first time that treatment has been given without sedation or anaesthesia. METHODS: Patients with advanced and/or metastatic disease were eligible for entry into this study. Previous work has established that an in situ ablative intensity (AI) of 1500 W/cm2 Isp for 1 s achieves coagulative necrosis at the focal spot. Ultrasonic exposures of 25-100% of AI for 1 s were delivered to preselected tissue volumes. Pain questionnaires recording any side effects were completed by the patient and the investigator separately. Ultrasound images of the target volume were taken before, immediately after, and 1 week after treatment. RESULTS: A total of 14 patients have been entered into this study to date. Seven patients were treated at their primary site and seven received treatment to one of their metastases. No treatment needed to be stopped because of pain. Eight of the 14 patients did not complain of any side effect during or after the treatment. One patient complained of mild, and two of moderate pain during the week following treatment. One patient developed an asymptomatic blister on the skin. CONCLUSION: Focused ultrasound is a safe, well-tolerated and non-invasive method of delivering ablative thermal energy to selected tumours. More clinical trials are needed to assess the role of this modality in the treatment of cancer.

Vascular occlusion using focused ultrasound surgery for use in fetal medicine.

OBJECTIVE: Focused ultrasound surgery (FUS) is being developed clinically for the non-invasive treatment of soft tissue tumours of the prostate, bladder, liver, kidney, muscle and breast. In the work described in this paper, the application of FUS is extended to investigate the potential to induce vascular occlusion, with the aim of applying the technique to problems in fetal medicine and oncology. METHODS: In this feasibility study the occlusion of femoral blood flow in vivo is demonstrated using an array of multiple single exposures of 1.7 MHz focused ultrasound. These were placed in two rows of four lesions at a focal depth of 5 mm. The 4660-W cm-2 (free field spatial peak intensity) 2-s exposures were placed 2 mm apart. Vascular patency was assessed using a Siemens Vision (1.5T) magnetic resonance (MR) imaging scanner with an extremity coil, and intravenous gadolinium contrast agent. FLASH and FISP MR sequences were used to obtain full 3D data sets providing information on soft tissue damage and perfusion. RESULTS AND CONCLUSION: Total vascular occlusion was achieved in four of nine cases and significant vascular disruption in five of nine cases. Refinement of the FUS technique and long-term studies are now indicated prior to initial clinical application in fetal medicine.

A 3-D finite-element model for computation of temperature profiles and regions of thermal damage during focused ultrasound surgery exposures.

Although there have been numerous models implemented for modeling thermal diffusion effects during focused ultrasound surgery (FUS), most have limited themselves to representing simple situations for which analytical solutions and the use of cylindrical geometries sufficed. For modeling single lesion formation and the heating patterns from a single exposure, good results were achieved in comparison with experimental results for predicting lesion size, shape and location. However, these types of approaches are insufficient when considering the heating of multiple sites with FUS exposures when the time interval between exposures is short. In such cases, the heat dissipation patterns from initial exposures in the lesion array formation can play a significant role in the heating patterns for later exposures. Understanding the effects of adjacent lesion formation, such as this, requires a three-dimensional (3-D) representation of the bioheat equation. Thus, we have developed a 3-D finite-element representation for modeling the thermal diffusion effects during FUS exposures in clinically relevant tissue volumes. The strength of this approach over past methods is its ability to represent arbitrarily shaped 3-D situations. Initial simulations have allowed calculation of the temperature distribution as a function of time for adjacent FUS exposures in excised bovine liver, with the individually computed point temperatures comparing favorably with published measurements. In addition to modeling these temperature distributions, the model was implemented in conjunction with an algorithm for calculating the thermal dose as a way of predicting lesion shape. Although used extensively in conventional hyperthermia applications, this thermal dose criterion has only been applied in a limited number of simulations in FUS for comparison with experimental measurements. In this study, simulations were run for focal depths 2 and 3 cm below the surface of pig's liver, using multiple intensity levels and exposure times. The results also compare favorably to published in vitro experimental measurements, which bodes well for future application to more complex problems, such as the modeling of multiple lesion arrays within complex anatomical geometries.

High-intensity focused ultrasound ablation of the kidney in a large animal model.

The purpose of this study was to establish the feasibility of noninvasive treatment of small renal tumors with high-intensity focused ultrasound (HIFU). A 1.69-MHz extracorporeal HIFU transducer of 150-mm focal length was used. In vitro experiments with excised porcine kidneys allowed determination of suitable exposure parameters to be tested in vivo. For short exposure times (< 2 seconds), the minimum energy required to produce acute thermal damage was 500 +/- 100 Wcm-2 per second. Porcine kidneys (N = 18) were treated in vivo at a depth of 40 mm from the skin surface, with acute damage detected in 13. Damage was macroscopically and histologically discrete and confined to the target area within the kidney. Skin induration was observed after treatment in nine cases, and there was one skin burn. Transducer developments to prevent this morbidity and to improve energy deposition within the target are discussed.

A feasibility study for the non-invasive treatment of superficial bladder tumours with focused ultrasound.

OBJECTIVE: To determine whether high-intensity focused ultrasound can be used to ablate bladder wall tissue using a transabdominal approach in a large animal model, and whether it can be developed as a non-invasive treatment for superficial bladder tumours. MATERIALS AND METHODS: The bladder wall of 25 large white pigs was treated with a 1.7 MHz extracorporeal focused-bowl ultrasonic transducer. Animals were killed either 2 h, 3 days or 4 weeks after treatment and the bladder wall examined macroscopically and histologically. RESULTS: Acute bladder wall damage was detected in 15 of 16 animals at 2 h and in all six animals examined after 3 days. Areas of healing were seen in 10 of 12 animals at 4 weeks. Histological analysis of the treated areas revealed that the urothelium was denuded within 2 h and was associated with an acute inflammatory response in the bladder wall. At 4 weeks, the urothelium had regenerated over a maturing scar. CONCLUSIONS: Focused ultrasound can be used successfully to destroy regions of the bladder wall in a large animal model in vivo.