Quantitative Assessment of Effectiveness of Ultrasonic Propulsion of Kidney Stones

Abstract

Purpose: Ultrasonic propulsion is an investigative modality to noninvasively image and reposition urinary stones. Our goals were to test safety and effectiveness of new acoustic exposure conditions from a new transducer, and to use simultaneous ureteroscopic and ultrasonic observation to quantify stone repositioning.

Materials and Methods: During operation, ultrasonic propulsion was applied transcutaneously, whereas stone targets were visualized ureteroscopically. Exposures were 350 kHz frequency, ≤200 W/cm² focal intensity, and ≤3-second bursts per push. Ureteroscope and ultrasound (US) videos were recorded. Video clips with and without stone motion were randomized and scored for motion ≥3 mm by independent reviewers blinded to the exposures. Subjects were followed with telephone calls, imaging, and chart review for adverse events.

Results: The investigative treatment was used in 18 subjects and 19 kidneys. A total of 62 stone targets were treated ranging in size from a collection of “dust” to 15 mm. Subjects received an average of 17 ± 14 propulsion bursts (per kidney) for a total average exposure time of 40 ± 40 seconds. Independent reviewers scored at least one stone movement ≥3 mm in 18 of 19 kidneys (95%) from the ureteroscope videos and in 15 of 19 kidneys (79%) from the US videos. This difference was probably because of motion out of the US imaging plane. Treatment repositioned stones in two cases that would have otherwise required basket repositioning. No serious adverse events were observed with the device or procedure.

Conclusions: Ultrasonic propulsion was shown to be safe, and it effectively repositioned stones in 95% of kidneys despite positioning and access restrictions caused by working in an operating room on anesthetized subjects.

Introduction

The management of symptomatic or large kidney stones is primarily surgical,¹ and it is common for fragments to remain after lithotripsy. These residual fragments pose a challenge in the current state of stone treatment. Most spontaneously pass over time, however, the fragments that remain may subsequently grow or become symptomatic. Reported rates of re-intervention for residual stone fragments are as high as 29% after ureteroscopic treatment,^2,3 34% after shockwave lithotripsy,⁴ 26% after percutaneous nephrolithotomy,^5,6 and 30% overall.⁷

Ultrasonic propulsion is a modality developed at the University of Washington (UW) that uses focused bursts of ultrasound (US) energy to reposition kidney stones.⁸ The first in-human clinical feasibility study of this technology demonstrated the potential of this technology to facilitate passage of residual stone fragments, as well as additional clinical applications of dislodging an obstructing stone to relieve pain and differentiating between a single large stone and cluster of stones.⁹ The original probe used in the feasibility study was a commercial curvilinear C5-2 HDI probe (Philips Ultrasound, Bothell, WA) that used a 50-millisecond burst of 2 MHz pulses at a 73% duty cycle. The outcomes achieved with this probe included movement of stones in 14 of 15 subjects, both in clinic and during endoscopic stone treatment in the operating room, movements of ≥3 mm in 8 of 15 subjects, and >30 fragments passed in 4 of 6 postlithotripsy subjects.

Several aspects of the C5-2 probe presented opportunities for improvement. The burst duration and wait time between bursts were limited by the surface heating of the probe, thereby limiting the energy delivered to stone targets the number and effectiveness of each push, and the overall efficiency of successful stone repositioning. Moreover, the short focal length of this probe limited effective energy delivery at deeper depths. Finally, the narrow beam width potentially limited the ability to manipulate groups of fragments vs moving a single fragment at a time.

To address these limitations, a custom probe was subsequently designed to better optimize energy delivery to stone targets. The redesigned probe, referred to as the SC-X probe, uses a water-cooled coupling interface, a broader focal beam width, a longer focal depth, and longer pulse durations. Ex vivo, the SC-X probe design was found to more effectively expel clusters of stone fragments from a 30 mm phantom calix at both 4.5 and 9.5 cm depths, when compared with the original C5-2 probe.¹⁰ Stone composition did not alter the effectiveness ex vivo.¹¹ Based on these data, we expect that the redesigned probe will be more effective at moving stone fragments in vivo.

Previous evaluation of ultrasonic propulsion in human subjects relied on US feedback to assess the success of stone movement. Of note, this carries limitations in accurate assessment of small or out-of-plane movements. We therefore performed a prospective clinical feasibility study to assess the efficacy of the SC-X probe in moving stone targets in human subjects, using endoscopic demonstration of stone movement as the primary endpoint.

Materials and Methods

This was a single center study conducted through the UW with approval from the UW Institutional Review Board and the US Food and Drug Administration through an investigational device exemption. The clinicaltrials.gov number is NCT02028559.

Investigational device

The investigational ultrasonic propulsion system consists of the SC-X therapy probe (Sonic Concepts, Bothell, WA) driven by a function generator (Agilent 33250, Santa Clara, CA) and high-voltage amplifier (ENI AP400B; Electronic Navigation Systems) integrated with a research US platform (VDAS-1; Verasonics, Inc., Redmond, WA) such that real-time image guidance and therapeutic pulse delivery can occur simultaneously using a single handheld probe (Fig. 1a). This is achieved by fitting a P4-2 imaging probe (Philips Ultrasound) with a custom housing within the therapy probe such that the axes are coaligned. A water-circulating coupling head prevents overheating of the probe. The probe has a fixed treatment focus (Fig. 1b, red oval) that requires the operator to visually align the stone target within this focus, but has a longer focal beam and burst duration compared with the C5-2 probe used in the first human clinical trial.⁹

FIG. 1.

(a) Custom handheld ultrasonic propulsion probe with a water-circulating coupling head. The therapy probe (black/silver; marked by arrow) is a single element annulus that supports coaxial alignment of a P4-2 imaging probe (red; marked by arrowhead). The overall probe diameter is 5.5 cm. (b) Ultrasonic propulsion graphical user interface demonstrating real-time imaging. The upper right panel displays the B-mode image. The red oval represents the treatment focus, where a stone must be aligned for the ultrasonic propulsion to be effective. The upper left panel displays the customized “S-mode” image, utilizing color-flow Doppler to make the stone stand out in green. The bottom panel includes all the system settings and system feedback parameters for monitoring operation. Pulses are triggered with a footswitch.

Subjects

Patients with known urolithiasis visible on X-ray, US, or CT who were scheduled for ureteroscopy and laser lithotripsy of at least one renal or ureteral stone were recruited through the UW Kidney Stone Center from November 2017 to February 2019. Patients younger than 18 years, those with a solitary or transplant kidney, those remaining on anticoagulant medications at the time of operative intervention, and those belonging to vulnerable populations (pregnant, homeless, incarcerated, or with intellectual disability) were excluded. Figure 2 provides the steps of the protocol.

FIG. 2.

Steps of the protocol. Light grey indicates research steps and dark grey indicates clinical steps.

Study protocol

Written informed consent was obtained from each subject before entry into the operating room. A screening research US study was performed using the investigational device to determine whether the stones could be visualized and whether an angle was available for pushing the stone in the dorsal lithotomy position. If so, ultrasonic propulsion was then applied transcutaneously under the direction of a sonographer, urologist, and the research team, whereas the stone target was directly visualized ureteroscopically. Laser treatment and irrigation were ceased during each ultrasonic propulsion push attempt.

Stone targets were defined as a single stone or cluster of fragments; a target that was moved to a new calix or that was subsequently fragmented to a smaller collection of stones was considered to be a new, unique target. In this way, multiple targets could be treated in a single kidney, and the ultrasonic propulsion treatment could be applied throughout the lithotripsy procedure. For adherent stones, ultrasonic propulsion was attempted and then these stones were dislodged endoscopically if necessary. Target size was estimated by the treating surgeon with respect to the laser fiber. This method was selected because not all subjects were imaged preoperatively using the same imaging modality (CT, US, or plainfilm), and it additionally allowed for a change in target size generated by the lithotripsy treatment.

The treatment exposure consisted of 350 kHz US frequency, ≤200 W/cm² focal intensity, and ≤3-second bursts per push. There was no limit to the number of push attempts that could be delivered to a kidney, but the maximum exposure duration (summation of the duration of each push) was limited to 10 minutes. Ureteroscope and US videos were recorded.

After operation, each subject was contacted weekly for 3 weeks to capture potential adverse events related to the ultrasonic propulsion treatment. An additional 90-day chart review was conducted to capture any unplanned stone-related events. All subjects had clinical imaging and urologic follow-up as part of their standard of care.

Data analysis

The primary endpoint for this study was successful movement, defined as ≥3 mm, of at least one target stone within the kidney as reported by the independent review of the ureteroscope videos. A 3 mm distance was chosen based on the ability to resolve movement on US (and in ureteroscopy). Secondary outcomes included movement of the target stone on US and occurrence of adverse events. Distance of motion was also measured for each individual push burst, as in clinical practice several bursts might be applied to direct a stone completely out of the kidney, a clinically relevant endpoint.

The research staff filtered all the ureteroscope video clips into an equal number showing stones that received a propulsion burst and stones that did not, and randomized them. The ureteroscope video set was then reviewed for target motion ≥3 mm by three fellowship-trained endourologists blinded to the exposures in each video. The endourologists used their clinical judgment as to whether the stone moved >3 mm in the ureteroscope videos. All US video clips were similarly filtered into an approximately equal number with movement and no movement (as determined by the research team) associated with the ultrasonic propulsion burst, randomized, and reviewed by three additional clinicians. US reviewers included a fellowship-trained endourologist, emergency department physician, and a registered sonographer. A 3 mm reference distance was provided on the US videos. The total distance of each target's movement was quantified from the US videos (where visible).

Results

Demographics

Stone targets and demographic information for enrolled subjects are given in Table 1. Nineteen kidneys in 18 patients underwent ultrasonic propulsion treatment. At least one push attempt was applied to 62 stone targets, which ranged in size from dust-sized particles to 15 mm based on preoperative imaging and intraoperative visualization. Subjects received an average of 17 ± 14 ultrasonic propulsion bursts (range 3–52) with a total average exposure time of 40 ± 40 seconds across all treatment attempts.

Table 1.

Demographic Information and Ultrasonic Propulsion Stone Target Data

Variable	Result
Patients (n)	18
Gender
Female (n)	6
Male (n)	12
Mean age (years) ± SD	58 ± 15
Mean BMI (kg/m2) ± SD	27.8 ± 5.0
Kidneys (n)	19
Right	10
Left	9
Stone targets (n)	62
Size range	Dust: 15 mm
Location
Upper pole	14
Middle pole	28
Lower pole	20
Mean treatment depth by US (cm) ± SD	6.4 ± 1.2

BMI = body mass index; SD = standard deviation; US = ultrasound.

Effectiveness

All 3 blinded reviewers scored a stone movement ≥3 mm from the ureteroscope videos in 18 of 19 kidneys (95%). The video for one case was filmed by a phone camera out of necessity. One reviewer scored movement in this case, but two reviewers reported insufficient video quality to score movement. None of reviewers expressed doubt that any of the motions were >3 mm, and in all but three cases, the stone appeared to move out of the calix past the ureteroscope with a single push burst. On review of the US videos, stone movement ≥3 mm was scored in 15 of 19 kidneys (79%). No stone movement was observed on US in the one case where the ureteroscope video was filmed using a cell phone. The reviewers commented that stones in some cases appeared to move out of the US imaging plane. Figure 3 shows an example of stone movement resulting from a single, <3-second ultrasonic propulsion burst captured simultaneously on US and ureteroscope video. The videos associated with Figure 3 are included as Supplementary Videos ultrasound SV1 and ureteroscopy SV2.

FIG. 3.

Illustration of stone target movement seen on US (a–c) and ureteroscopy (d–f). The yellow arrow indicates the direction of US propagation and acoustic force on the stone. The stone moved out of the calix. US = ultrasound.

Figure 4 provides results from the ureteroscope videos. Each circle shows movement of a single target stone in the 19 kidneys as confirmed by three independent reviewers of the ureteroscope videos. De novo stones, individual fragments, and collections of fragments over a range of sizes were observed to move.

FIG. 4.

Observation of motion from the ureteroscope videos. Each circle shows movement of a single target stone in the 19 kidneys as confirmed by three independent reviewers of the ureteroscope videos. Light grey circles represent movement ≥3 mm. The dark grey circle represents the case where video quality was insufficient to judge movement.

The research staff further reviewed all the US videos (n = 321). We then filtered out the video segments where the stone was attached to tissue (n = 14) as moving attached stones is not the goal in this article, where the patient breathing caused complete misalignment (n = 18) because in our clinical application, the patients awake can hold their breath, and where we were targeting bubbles created by the ureteroscopy (n = 13) because these bubbles will not be present during propulsion in the clinic. Column 3 of Table 2 shows the total number of push bursts and in parentheses the number after this filtering. Videos of cases where it became clear the stone was too large to escape the orifice of the calix were retained because that was not obvious before the push attempt. This left a total of 276 push bursts that were applied. With that total, 53% of all push bursts were reported to result in some level of stone movement, 39% of which resulted in significant stone movement ≥3 mm. In addition, 82% of all stone targets were reported to move with ultrasonic propulsion, 61% of which moved ≥3 mm. The size of these movements ranged from 3.4 to 38.4 mm as measured on US. Significant stone movement ≥3 mm occurred in 30% of lower pole targets (6/20), 68% of midpole targets (19/28), and 43% of upper pole targets (6/14). Stone movements by subject are given in Table 2. The number of push bursts represents the total number attempted with the number after removing video segments with attached stones and cases where the US was misaligned with the target stone in parenthesis.

Table 2.

Summary of Ultrasonic Propulsion Treatment Attempts on 62 Targets in 19 Kidneys

Subject	Stone composition	Total no. of targets	Total no. of push bursts	Greatest movement for each target			Distance moved on US (mm)
				None	<3 mm	>3 mm
1	Not noted	6	12 (9)	3	0	3	4.2–5.5
2	COM/COD	2	10 (9)	1	0	1	Not seen on US
3	COM/UA	3	15 (15)	0	1	2	3.9–38.4
4	CAP	4	24 (20)	1	3	0	<3
5	COD/COM	4	16 (16)	0	3	1	7.6
6	COM	4	9 (9)	0	1	3	8.0–28.9
7	COM	2	13 (4)	0	0	2	6.8–11.5
8	COM/COD	3	13 (12)	1	0	2	9.1–21.7
9	Not noted	3	10 (10)	0	1	2	6.4–27.2
10	COM/CAP	2	5 (5)	0	0	2	8.9–12.0
11	COD/COM	2	8 (8)	1	0	1	Not seen on US
12	COM	4	55 (38)	0	3	1	3.4
13R	COM	2	9 (7)	0	1	1	Not seen on US
13L	COM	4	18 (17)	0	0	4	5.2–11.0
14	COM	7	32 (30)	3	3	1	3.4
15	Struvite	1	3 (3)	0	0	1	5.0–5.7
16	Not noted	4	13 (13)	1	1	2	4.2–16.7
17	COD/COM	2	5 (5)	0	1	1	4.4
18	COM	3	52 (46)	0	2	1	5.7–15.9

In column 3 are the total number of push bursts and in parentheses the number after this filtering.

CAP = calcium phosphate; COD = calcium oxalate dihydrate; COM = calcium oxalate monohydrate; not noted = not explicitly clear to the research team in the recent medical record; UA = uric acid.

Figure 5 provides the complete assessment of motion of the stone targets using the US and ureteroscope videos. The large field of view of the US videos allowed assessment of whether a stone had moved out of the calix and this was confirmed in the ureteroscope video when the operator moved the ureteroscope to find the stone in a new location. Thirteen stone targets in eight subjects were moved entirely out of the targeted calix. In five of six cases, ultrasonic propulsion was unable to detach an attached stone; once detached, all six stones were moved >3 mm with ultrasonic propulsion.

FIG. 5.

Observation of motion from all US and ureteroscope videos. Each circle shows the maximum stone movement measured by review of US videos for the 62 targets. The color of each circle indicates the extent of the movement. The size of each circle represents the target size. Filled circles represent a single target stone, whereas a thatched or speckled pattern identifies a group of stones or dust. The dot location is only generally representative of the stone location.

Safety

Adverse events are summarized in Table 3. Most were considered to be typical sequelae of the ureteroscopic intervention. Skin reddening or other irritation was noted on inspection in seven patients immediately upon completion of the treatment, which resolved spontaneously and was not reported on subsequent 1-week follow-up. One subject reported flank bruising after treatment, possibly related to treatment, which also resolved spontaneously and was not reported at 1-week follow-up. There was no observation of injury to the collecting system wall with the ultrasonic propulsion.

Table 3.

Adverse Events After Ultrasonic Propulsion During Ureteroscopic Laser Lithotripsy of Stones

Events reviewed and considered not related to the US propulsion procedure or device	% (no. of subjects)	Events reviewed and considered related to the US propulsion procedure or device	% (no. of subjects)
Urinary (hematuria)	100 (18)	Skin redness (transient)	33 (6)
Urinary (frequency, urgency, etc.)	72 (13)	Skin bruising	5.5 (1)
Urinary (dysuria, bladder pain)	44 (8)	Skin irritation	5.5 (1)
Urinary (bladder spasms)	17 (3)
Gastrointestinal (diarrhea/constipation)	50 (9)
Gastrointestinal (nausea/vomiting)	33 (6)
Pain (general, flank, kidney, penile)	89 (16)
Other (fatigue, allergy to medications, dry mouth, UTI, headache, atrial fibrillation)	6 (1)

UTI = urinary tract infection.

Treatment observations

In two cases (subjects 9 and 11), ultrasonic repositioning of stone targets obviated the need for a stone basket by repositioning a stone from the lower pole into a more favorable treatment location within the caliceal system. However, in two additional cases, ultrasonic propulsion was not successful in moving the stone, and a basket did have to be deployed. In several cases, exposures generated a “wiggling” motion of the stone targets that were attached to the papillae; these targets were successfully moved ≥3 mm once detached. In only one case (no. 18), was the attached stone (∼2 mm in size) detached (after one push burst). In three subjects (Nos. 1, 10, and 16), stone targets were successfully moved ≥3 mm as de novo stones, and again after further comminution into smaller fragments. However, once fragmented into fine dust (<1 mm in size), targets did not appear to move significantly with ultrasonic propulsion despite visible streaming with the push burst. Finally, there were several cases (Nos. 3, 6, 8, 11, 13, and 18) in which a cluster of multiple stones (as much as six for subject 13) were moved within the same push burst. There was no evidence of damage to the ureteroscope by the ultrasonic propulsion in any case.

Discussion

This article describes the first in-human demonstration of ultrasonic propulsion using a new-generation SC-X therapy probe. Significant stone movement ≥3 mm was confirmed visually with an ureteroscope and on US through independent, blinded review. Successful movement of at least one stone target was seen in 95% of cases. Body mass index or other factors did not prevent successful repositioning in any subjects. In two treatment cases, an unanticipated benefit was that the need for a basket to reposition the stone from the lower pole to a more favorable location for laser lithotripsy was avoided. Moreover, no serious or unanticipated adverse events related to ultrasonic propulsion treatment were noted, which supports previous work demonstrating the safety of this technology in both animal and human studies.^9–14

The high degree of successful target movement in this study is encouraging. It is an improvement from the 67% of cases (8/12, neglecting the de novo cases where stones may have been attached or even submucosal) of >3 mm movement achieved by the previous ultrasonic propulsion probe, which was used to treat stones in clinic and during ureteroscopy.⁹ In addition, the ability to move multiple stone fragments at the same time was demonstrated in at least six cases, an effect that was not observed with the previous probe design.^9,10 Furthermore, these results were obtained with intraoperative challenges of limited subject positioning, uncontrolled respiratory motion, and absence of subject engagement.

Flexibility in patient positioning, such as in the lateral decubitus or prone position, may theoretically expose more potential treatment windows and even further optimize effective treatment in awake patients. In several cases where push attempts were either unsuccessful or met with limited stone motion, the positioning and angle of the therapy beam were suboptimal, resulting in movement of the stone into the wall of the calix rather than toward the infundibulum. This observation was supported by the fact that in two cases, the stone was successfully moved with ultrasonic propulsion after repositioned to a new location (for the purposes of lithotripsy).

Overall, imaging and effectiveness deteriorated over the course of lithotripsy potentially because of air and dust introduced by the ureteroscopy procedure. In one case, there was suspected shielding of the therapy burst by a large, adherent stone, resulting in limited energy delivery to the fragments sitting within the calix.

Although the optimal stone sizes for successful ultrasonic propulsion treatment remain to be defined, we were able to move as much as 7 mm stone targets in this study. Previous trials in human subjects have demonstrated movement of stones as much as 10 mm in size.⁹ The size of the infundibulum and caliceal system is the most likely factor to limit the size of stones able to be repositioned, rather than the force of the push burst.

Most importantly, this study showed stones that were free to move, moved, and movement was typically achieved within a few bursts. However, the full extent of the movement was not always appreciated in the US images, suggesting that actual movement in a clinic setting may be underestimated. This study also provides insight into the broad range of collecting system geometries, and the importance of targeting angle so as to move the stone into an open fluid space rather than into the caliceal wall. Within the clinic, where the anatomy cannot be directly visualized, it will be important to try many angles of approach for a stone that it is not moving. The critical role of the treatment angle is evident by the relative success between targeting stones in the interpolar region compared with the inferior pole region.

It is also important to recognize that the stone may be attached or otherwise confined, which is a condition easily observed with the ureteroscope but not in a clinic application. At present, the pushing bursts have not been successful at dislodging stones (one of six), but we have designed and will be soon implementing new pulses to attempt to dislodge attached stones.

Finally, this study demonstrated how important hydration was, as the dilated collecting space provided better visualization of the stones and a direction to move the stone on US guidance. In ongoing trials to test clinical benefit of ultrasonic propulsion, we encourage subjects to drink water to dilate the collecting space, and we take away confidence from this study that stones that do not move after a few propulsion bursts are attached or otherwise trapped in place and that for the other stones, it is a matter of finding the exit path from the calix.¹⁵

These ongoing trials test the potential benefit of repositioning residual fragments or small stones to facilitate their natural clearance from the kidney or ureterovesical junction and of moving larger stones from an obstructing position in the ureteropelvic junction back into the kidney to relieve pain,¹⁵ With the same probe and system tested here and in the ongoing trials, we have also begun the first human trials to break stones with burst wave lithotripsy¹⁶ and to dislodge or break attached or trapped stones to reposition them.

Conclusions

This study showed a high success of moving stones and stone fragments with the new refined probe design. Ultrasonic propulsion was successfully able to move at least one stone target a distance ≥3 mm in 95% of kidneys under ureteroscopic observation and 79% of kidneys with US observation, without any serious adverse events in human subjects related to the investigational device or procedure. Discrepancy in successful stone movement may be the result of motion out of plane on the US, suggesting that this treatment may be effective even in the absence of positive sonographic feedback in some cases. The results support that ultrasonic propulsion has the potential to be used to relocate stones before lithotripsy, improve stone access during operation, provide feedback on stone attachment, and expel fragments after operation.

Abbreviations Used

BMI

body mass index

CAP

calcium phosphate

COD

calcium oxalate dihydrate

COM

calcium oxalate monohydrate

CT

computed tomography

SD

standard deviation

UA

uric acid

US

ultrasound

UTI

urinary tract infection

UW

University of Washington

Author Disclosure Statement

Barbrina Dunmire, Michael R. Bailey, Bryan W. Cunitz, and Mathew D. Sorensen have equity in and consult for SonoMotion, Inc.

Funding Information

This study was supported by National Institutes of Health P01 DK043881. This article is the result of work supported by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, Washington.

Supplementary Material

Supplementary Video S1

Supplementary Video S2