Acoustic Hemostasis Research Articles

Technology development for acoustic hemostasis

In trauma cases, the often immediate (and necessary) requirement is to stop uncontrolled bleeding; indeed, in combat, more than 50% of deaths result from exsanguination. With the development of ultrasound image-guided High Intensity Focused Ultrasound (HIFU) devices, “Acoustic Hemostasis” is not only possible but has the ability to terminate uncontrolled bleeding as well as for many applications of considerable benefit to medicine. In this lecture, various technology development devices and methodologies will be described that have the potential for commercial development for a wide variety of medical indications.

Computational study of acoustic streaming and heating during acoustic hemostasis

High intensity focused ultrasound (HIFU) has many applications ranging from thermal ablation of cancer to hemostasis. Although focused ultrasound can seal a bleeding site, physical mechanism of acoustic hemostasis is not fully understood yet. To understand better the interaction between different physical mechanisms involved in hemostasis a mathematical model for acoustic hemostasis is developed. This model comprises the nonlinear Westervelt equation and the bioheat equations in tissue and blood vessel. In a three dimensional domain, the nonlinear hemodynamic equations are coupled with the acoustic and thermal equations. Convective cooling and acoustic streaming effects are incorporated in the modeling study. Effect of acoustic streaming on the blood flow out of the wound has been studied for two wound shapes and different sonication angles. It was theoretically shown that if focused ultrasound beam is applied directly to the bleeding site, the flow out of the wound can be reduced due to the acoustic streaming effect. Bleeding can be completely stopped even for a big wound, if the focal point location, ultrasound power and sonication angle are appropriately chosen. The sonication angles should be chosen in the range between 45° and 90°. The temperature around 70°C can be achieved within a second on the blood vessel wall, thus showing the theoretical possibility of sealing the bleeding site by focused ultrasound.

Laparoscopic high intensity focused ultrasound for the treatment of soft tissue

There is a growing demand to perform focal surgery, particularly for prostate and kidney tumors. RF and Cryo ablation are used for treatment of tumors; however, there are reported complications mainly skipping of cancer cells and bleeding. It has been shown that HIFU can provide acoustic hemostasis to overcome such complications. However, HIFU must compete with these modalities with improved treatment efficiency and the size of the applicator must fit in a 12 mm trocar/port used during the laparoscopic surgery. We modified the Sonatherm-600i applicator and transducer that generates a split beam HIFU at 4 MHz with a center element for imaging operating at 6.5 MHz. The transducer is integrated in a robotic probe that renders bi-plane images for tissue localization and ablation. Based on selected tissue ablation volume, treatment trajectory is generated by the computer to provide optimum thermal dose to result in complete coagulative necrosis. The treatment is conducted using continuous HIFU with an interlaced imaging for tissue change monitoring. The ablation efficiency of this device is @ 1 cc/min that is better than Cryo and RF ablation. Results will be presented from recent animal studies.

High intensity focused ultrasound characterization of deep bleeder acoustic coagulation cuffs.

Research prototype therapeutic ultrasound “cuffs” have been recently constructed to demonstrate the feasibility of cauterizing bleeding (acoustic hemostasis) of deep limb wounds, such as those from military combat or other penetrating trauma. The deep bleeder acoustic coagulation (DBAC) cuffs required a variety of HIFU power and acoustic beam assessments to assure safety and efficacy. The cuff, capable of > 1000 W acoustic power, comprised multiple two‐dimensional (2‐D) HIFU arrays that surrounded the limb and could dose with multiple arrays simultaneously. Each array was capable of high power (>170 W), significant electronic steering (solid angle = 57×34 deg), and depth focusing (5–20 cm). Device characterization required both individual array power measurements, and “integrated” whole cuff multiarray dosing assessment. The single array characterizations included (a) low‐power beam plots, (b) high power focused power assessment in “apertured” radiation force balance tests, and (c) Schlieren beam pattern assessment. The integrated (whole cuff) behavior was evaluated using (1) integrated tissue mimicking material (TMM) phantoms replicating limbs, which included soft tissues, blood vessels, pulsatile arterial and “bleeder” blood flows, and were able to measure HIFU closed‐loop targeting accuracy; and (2) TMM HIFU phantoms (measuring full power heating to 100 °C). [This research was sponsored by U.S. DARPA Contract No. HR0011‐08‐3‐0004].

Therapeutic ultrasound: Recent trends and future perspectives

Before ultrasound-imaging systems became widely available, ultrasound therapy devices showed great promise for general use in medicine. However, it is only in the last decade that ultrasound therapy has begun to obtain clinical acceptance. Recently, a variety of novel applications of therapeutic ultrasound have been developed that include sonothrombolysis, site-specific and ultrasound-mediated drug delivery, shock wave therapy, lithotripsy, tumor ablation, acoustic hemostasis and several others. This paper reviews a few selected applications of therapeutic ultrasound. It will address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. As a plenary presentation, its audience is intended for the ultrasound scientist or engineer, and thus is not presented at the level of the experienced medical ultrasound professional.

High intensity ultrasound activation of coagulation factors

Although it has been demonstrated that High Intensity Focused Ultrasound (HIFU) can induce vascular cauterization, acoustic hemostasis technology has not been successful in making the transition from proof-of-concept to clinical settings. One reason for this lack of acceptance is the limited understanding of the fundamental mechanisms involved in ultrasound-vessel and ultrasound-blood interactions. The aim of this research was to investigate the hematological and biochemical mechanisms which are influenced by HIFU induced coagulation. HIFU was used to induce coagulation in an in vitro hematological flow system and in animal models. The flow circuit and in vivo arteries were instrumented with flow probes and thermocouples in the treatment region. Physiological parameters were recorded throughout the in vivo experiments. Blood samples were drawn for analysis prior to, during, and immediately following each HIFU treatment. Clotting time, complete blood count, and biochemical analysis were performed immediately and citrated samples were immediately centrifuged and frozen for future analysis. Results indicate that HIFU can change local and systemic levels of thombin/anti-thrombin complex (TAT) and tissue plasminogen activator (tPA), as well as induce changes in activated clotting time (ACT). These results indicate that HIFU can induce coagulation via the coagulation cascades (TAT) and that normal hematological response to thrombus formation is unaffected.

Hemorrhage control using high intensity focused ultrasound

Hemorrhage control is a high priority task in advanced trauma care, because hemorrhagic shock can result in less than a minute in cases of severe injuries. Hemorrhage was found to be solely responsible for 40–50% of traumatic civilian and battlefield deaths in recent years. The majority of these deaths were due to abdominal and pelvic injuries with hidden and inaccessible bleeding of solid organs such as liver, spleen, and kidneys, as well as major blood vessels. High intensity focused ultrasound (HIFU) offers a promising method for hemorrhage control. An important advantage of HIFU is that it can deliver energy to deep regions of tissue where hemorrhage is occurring, allowing cauterization at depth of parenchymal tissues, or in difficult-to-access anatomical regions, while causing no or minimal biological effects in the intervening and surrounding tissues. Moreover, HIFU can cause both thermal and mechanical effects that are shown to work synergistically for rapid hemorrhage control. The major challenges of this method are in development of bleeding detection techniques for accurate localization of the injury sites, delivery of large HIFU doses for profuse bleeding cases, and ensuring safety when critical structures are in the vicinity of the injury. Future developments of acoustic hemostasis technology are anticipated to be for applications in peripheral vascular injuries where an acoustic window is usually available, and for applications in the operating room on exposed organs.

Acoustic virtual laboratory: A modeling tool for high‐intensity focused ultrasound applications

The field of high‐intensity focused ultrasound (HIFU) is emerging with strong potential and broad medical applications. Characterized by its ability to penetrate at depth inside the body without harming intervening tissue, therapeutic ultrasound has posed the basis for a new array of noninvasive therapies. However, the inherent complexity of biological media and the nonlinear nature of ultrasound propagation at HIFU regimes make optimization and control of the therapy still a challenging task. In this respect, an accurate modeling tool, the Acoustic Virtual Laboratory (AVL), will be presented for solving multidimensional HIFU problems in complex geometries that can greatly assists in predicting HIFU applications effects and, therefore, help in the optimization and control of the treatment. AVL consists of 2‐D, 2.5‐D (cylindrical symmetry), and 3‐D coupled solutions for acoustic and elastic wave propagation in heterogeneous, lossy, bubbly, and porous media with the bioheat equation for temperature estimation. It includes linear and nonlinear wave propagation, arbitrary frequency power law for attenuation, and can account for multiple reflections and backscattered fields. Sample results for tumor ablation, acoustic hemostasis, and propagation through porous bones will be illustrated. [Work supported by US Army Medical Research Acquisition Activity and NIH NCRR Grant R21 RR 21472.]

Therapeutic ultrasound

The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable, and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. Among these applications are tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally noninvasive, image-guided, bloodless surgery. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of high-intensity focused ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the induction of acoustic hemostasis, especially in organs that are difficult to treat using conventional medical and surgical techniques. [Work supported in part by the NIH, NSBRI, ONR, and DARPA.]

TU-B-I-609-01: Therapeutic Ultrasound

The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. These applications broadly include: Tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally non-invasive, image-guided therapy. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the introduction of acoustic hemostasis, especially in organs which are difficult to treat using conventional medical and surgical techniques. [Supported in part by the NIH and the US Army]

A pulsatile flow phantom for image-guided high-intensity focused ultrasound studies on blood vessels

A pulsatile flow phantom has been developed for controlled studies of acoustic hemostasis and high intensity focused ultrasound (HIFU) effects on blood vessels. The flow phantom consists of an excised carotid artery attached to a pulsatile pump and embedded in an optically and acoustically transparent gel to create an ex vivo model of a human artery. The artery was punctured with a needle to simulate percutaneous vascular injury. A HIFU transducer with a focal distance of 6 cm and a frequency of 3.33 MHz was used to treat the puncture. B-mode and power-Doppler ultrasound were used to locate the site of the puncture, target the HIFU focus, and monitor treatment. Also, the effects of vascular flow on HIFU lesions were studied by treating vessels in the phantom for different times at a variety of flows. In both studies, histology was done on the artery. In nine trials, HIFU was able to provide complete hemostasis in 55 ± 31 s. It is feasible to use the flow phantom to study acoustic hemostasis of blood vessels. Histology shows that the flow in the phantom appears to diminish the vascular damage from HIFU.

Dual frequency high intensity focused ultrasound to accelerate hemostasis

In acoustic hemostasis, cavitation appears to help emulsify and heat tissue to form a paste which seals lacerations. Our objective was to mix two frequencies to enhance cavitation, increase heat deposition, and accelerate hemostasis. A focused transducer (curvature 5 cm) with a 4.3-MHz center element (diameter 2 cm) and a 125-kHz outer annular element (inner and outer diameters, 3 and 5 cm) was engineered. This dual frequency transducer was used to create lesions in a transparent gel phantom and to induce hemostasis in five rabbits. Hemostasis time was determined with both frequencies (4.3 MHz at 620 W/cm2, 125 kHz at 4 W/cm2) and with the high frequency only (4.3 MHz at 620 and 780 W/cm2). In gels, dual frequency HIFU created larger, broader lesions than 4.3-MHz HIFU alone. Bubbles created by just low frequency could be seen and, with sufficient time, created small local lesions. In rabbits, hemostasis times (∼1 min for 25-ml/min bleeds) were decreased 20% with dual frequency compared to the 4.3-MHz wave alone at the same intensity or same total electrical power. Dual frequency mixing can enhance heat deposition and accelerate hemostasis by HIFU. [Work supported by NSBRI SMS00203, NIH Fogarty, ONRIFO, and NSF BES0002932.]

Intra-operative acoustic hemostasis of liver: production of a homogenate for effective treatment

Objective: We have shown that High-Intensity Focused Ultrasound (HIFU) can effectively control bleeding from injuries to solid organs such as liver, spleen, and lung. Achievement of hemostasis was augmented when a homogenate of tissue and blood was formed. The objective of this study was to investigate quantitatively the effect of homogenate production on HIFU application time for hemostasis. Possible mechanisms involved in homogenate production were also studied. Methods: Ten anesthetized rabbits had laparotomy and liver exposure. Liver incisions, 15–25 mm long and 3–4 mm deep, were made followed immediately by HIFU application. Two electrical powers of 80 and 100 W corresponding to focal acoustic intensities of 2264 and 2829 W/cm 2, respectively were used. Tissue and homogenate temperatures were measured. Smear and histological tissue sample analysis using light microscopy were performed. Results: In treatments with homogenate formation, hemostasis was achieved in 76 ± 1.3 s (Mean ± Standard Error Mean: SEM) at 80 W. In treatments without homogenate formation (at 80 W), hemostasis was achieved in 106 ± 0.87 s. At 100 W, hemostasis was achieved in 46 ± 0.3 s. The time required for homogenate formation, at 80 and 100 W were 60 ± 2.5 and 23 ± 0.3 s, respectively. The homogenate temperature was 83 °C (SEM 0.6 °C), and the non-homogenate tissue temperature at the treatment site was 60 °C (SEM 0.4 °C). The smear and histological analysis showed significant blood components and cellular debris in the homogenate, with some intact cells. Conclusion: The HIFU-induced homogenate of blood and tissue resulted in a statistically significant shorter HIFU application time for hemostasis. The incisions with homogenate had higher temperatures as compared to incisions without homogenate. Further studies of the correlation between homogenate formation and temperature must be done, as well as studies on the long-term effects of homogenate in achieving hemostasis.

The relation between cavitation and platelet aggregation during exposure to high-intensity focused ultrasound

Our previous study showed that high-intensity focused ultrasound (HIFU) is capable of producing “primary acoustic hemostasis” in the form of ultrasound (US)-induced platelet activation, aggregation and adhesion to a collagen-coated surface. In the current study, 1.1 MHz continuous-wave HIFU was used to investigate the role of cavitation as a mechanism for platelet aggregation in samples of platelet-rich plasma. A 5 MHz passive cavitation detector was used to monitor cavitation activity and laser aggregometry was used to measure platelet aggregation. Using spatial average intensities from 0 to 3350 W/cm 2, the effects of HIFU-induced cavitation on platelet aggregation were investigated by enhancing cavitation activity through use of US contrast agents and by limiting cavitation activity through use of an overpressure system. Our results show that increased cavitation activity lowers the intensity threshold to produce platelet aggregation and decreased cavitation activity in the overpressure system raises the intensity threshold for platelet aggregation. (E-mail: poliachi@u.washington.edu)

Therapeutic ultrasound

The use of ultrasound in medicine is now quite commonplace, especially with the recentintroduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices.Moreover, ultrasound has expanded beyond the imaging realm, with methods and applicationsextending to novel therapeutic and surgical uses. These applications broadly include: tissueablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity,extracorporeal lithotripsy, and the enhancement of natural physiological functions such aswound healing and tissue regeneration. A particularly attractive aspect of this technology is thatdiagnostic and therapeutic systems can be combined to produce totally non-invasive, imageguidedtherapy. This general lecture will review a number of these exciting new applications ofultrasound and address some of the basic scientific questions and future challenges in developingthese methods and technologies for general use in our society. We shall particularly emphasizethe use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignanttumors as well as the introduction of acoustic hemostasis, especially in organs which are difficultto treat using conventional medical and surgical techniques.

A theoretical model for bubble enhanced ultrasound heating due to time-dependent bubble size distributions

Substantial in vitro and in vivo evidence shows that cavitation activity can affect tissue heating in focused ultrasound surgery and acoustic hemostasis applications. In particular, the heating rate in tissue increases significantly after cavitation sets in. Exploitation of this phenomenon for clinical use requires knowledge of, among other parameters, the time-dependent bubble size distribution sustained during insonation. Difficulties associated with the measurement of bubble sizes during in vitro or in vivo experiments call for a theoretical approach to the problem. We will present a theoretical model that estimates the time-dependent distribution of bubble equilibrium radii. Shape instability thresholds and rectified diffusion thresholds bound asymptotic bubble size distributions, and the instantaneous size distributions are governed by growth rates. The temperature rise caused by such bubble activity is calculated and compared with experimental data. [Work supported by DARPA and the U.S. Army.]

High intensity focused ultrasound for arrest of bleeding

High Intensity Focused Ultrasound (HIFU) has been shown to provide an effective method of hemostasis, in animal studies, for both solid organs and blood vessels (acoustic hemostasis). Moderate to profuse bleeding from major blood vessels, liver, and spleen, can be stopped within 1–2 min of HIFU application. The efficacy of acoustic hemostasis has been demonstrated using HIFU frequencies of 1–10 MHz, and acoustic intensities of 1000–5000 W/cm2. Conventional B-mode ultrasound imaging and Doppler appear to provide a effective visualization, targeting, and monitoring methods when extracorporeal application, in case of internal bleeding, is desired. Both thermal and mechanical mechanisms of HIFU appear to be responsible for achieving hemostasis. The thermal mechanism, due to ultrasound absorption, raises the tissue temperature in excess of 70<th>°C in less than a second, leading to shrinkage of the tissue and collapse of small blood vessels. The mechanical mechanism, due to cavitation activity, disrupts the tissue structure, leading to the occlusion of large blood vessels. Both mechanisms result in coagulative necrosis of tissue, and arrest of bleeding. Acoustic hemostasis may provide an effective method in surgery and prehospital settings for treating bleeding in trauma and elective surgery patients.

High intensity focused ultrasound: a method of hemostasis.

Acoustic hemostasis is a new field of ultrasound research in which high intensity focused ultrasound (HIFU) is used to induce hemostasis in actively bleeding, injured solid organs and blood vessels. In animal studies, moderate to profuse bleeding from parenchymal and vascular injuries has been arrested within approximately 1 minute of HIFU application, even when a large dose of heparin was administered. Moreover, acoustic hemostasis has shown promise in cauterizing large regions of liver, providing a method for bloodless resectioning of abnormal tissue. Two distinct physical mechanisms of HIFU appear to contribute to hemostasis: (1) a thermal mechanism in which absorption of sound leads to temperature elevations, and (2) mechanical mechanisms (acoustic cavitation) in which gas and vapor-filled voids oscillate with large displacement amplitudes. While the thermal mechanism results in a temperature increase in excess of 70 degrees C in about 1 second, the mechanical mechanism appears to result in structural disruption of tissue and possible release of coagulation-inducing tissue factors. Of utmost importance in further development of HIFU as a clinical tool is targeting and monitoring of the HIFU treatment. We have obtained initial success in integrating HIFU with ultrasound imaging so as to develop an image-guided therapy system. Image-guided acoustic hemostasis may provide a valuable method of hemostasis in surgical and prehospital settings with applications in trauma and elective surgery.

Role of high intensity focused ultrasound induced cavitation on platelet aggregation

Our previous studies showed that high-intensity focused ultrasound (HIFU) is capable of producing ‘‘primary acoustic hemostasis’’ in the form of platelet activation, aggregation, and adhesion to a collagen-coated surface. In current studies, 1.1 MHz CW HIFU was used to investigate the role of cavitation as a mechanism for platelet aggregation in samples of platelet rich plasma. A 5 MHz passive cavitation detector was used to monitor cavitation activity, and laser aggregometry was used to measure platelet aggregation. Using spatial average intensities from 0 to 4000 W/cm2, the effects of HIFU induced cavitation on platelet aggregation were investigated by enhancing cavitation activity through use of ultrasound contrast agents, and by limiting cavitation activity through use of an overpressure system. Our results show that increased cavitation activity lowers the intensity threshold to produce platelet aggregation, and decreased cavitation activity in the overpressure system raises the intensity threshold for platelet aggregation. [Research supported by DARPA.]

Effect of high-intensity focused ultrasound on platelet activation, aggregation, and adhesion

High-intensity focused ultrasound (HIFU) has been examined as a noninvasive means for achieving acoustic hemostasis [Delon-Martin et al., UMB 21, 113–119 (1995); Hynynen et al., UMB 22, 193–201 (1996); Vaezy et al., UMB 24, 903–910 (1998)]. Our own efforts in acoustic hemostasis are directed toward using diagnostic ultrasound to locate a hemorrhage and HIFU to halt the bleeding. To enhance the imaging of blood, the use of ultrasound contrast agents (UCAs; gas-filled microbubbles that increase the echogenicity of fluids) has been proposed as a means to locate internal bleeding; however, the combination of UCAs and ultrasound has been found to cause bioeffects in whole blood [Miller et al., UMB 23, 625–633 (1997); Poliachik et al., UMB 25, 991–998 (1999)]. Our results have shown that HIFU can cause platelets in a platelet rich plasma (PRP) sample to activate, aggregate, and adhere to a collagen-coated surface. Furthermore, UCAs can increase the amount of cavitation induced by HIFU, and thus lead to an increase in platelet activity. Although HIFU exposure alone can induce platelet activity, the addition of UCAs increases the amount and the rate of cavitation (cavitation dose); therefore, cavitation is the likely mechanism of HIFU-induced platelet activity. [Research supported by DARPA.]