Hyperthermic teratogenicity, thermal dose and diagnostic ultrasound during pregnancy: implications of new standards on tissue heating.

Hyperthermia is a recognized teratogen in mammalian laboratory animals and is a suspected teratogen for humans. The purpose of this synopsis is to reanalyse existing data on hyperthermia-induced teratogenic effects in experimental mammalian systems in terms of a thermal dose (temperature:time) concept, and then to illustrate the utility of this concept to human situations involving potential thermal increments to post-implantation embryos and foetuses. For example, the threshold temperature elevation for hyperthermia-induced teratogenic effects in experimental mammals is estimated (but not rigorously tested) to be approximately 1.5 degrees C above core values for exposures of long duration, possibly with a thermal dose of approximately 5 min duration or more at 4 degrees C. This level of tissue temperature increment is within the capability of some modern diagnostic ultrasound (DUS) devices sold within the USA and abroad. Epidemiological studies have not indicated any hazard from the use of DUS, but such studies are limited in sensitivity and were conducted with DUS devices whose acoustic outputs were relatively low compared to those presently available. After a regulatory change that allowed for substantially increased acoustic outputs, modern DUS devices were mandated to provide the user with on-screen information (the Thermal Index, or 'TI') about ultrasound-induced temperature increments in the target tissue. The TI is generally accurate to within a factor of 2, but the factor may be as high as 6 in certain obstetric settings. Thus, informed use of and attention to the TI is strongly advised, with this admonition gaining increased emphasis if the present regulations regarding allowable acoustic outputs of DUS devices were to be further relaxed or eliminated.

Safety of medical diagnostic ultrasound.

The exemplary safety record of diagnostic ultrasound (DUS) is probably an important reason that it has become so widely used. Advances in technology and procedures promise to make it even more valuable. At the same time, some of these advances bring with them new situations where harm can occur unless they are given appropriate attention. Maintaining patient safety along with increasing benefits requires (1) a vigorous continuing research program for determining optimum operating conditions and (2) effective means for communicating guidance to users. In this article, a standard developed in the USA for displaying safety information is discussed.

Biological effects of ultrasound: development of safety guidelines. Part II: general review.

In the 1920s, the availability of piezoelectric materials and electronic devices made it possible to produce ultrasound (US) in water at high amplitudes, so that it could be detected after propagation through large distances. Laboratory experiments with this new mechanical form of radiation showed that it was capable of producing an astonishing variety of physical, chemical and biologic effects. In this review, the early findings on bioeffects are discussed, especially those from experiments done in the first few decades, as well as the concepts employed in explaining them. Some recent findings are discussed also, noting how the old and the new are related. In the first few decades, bioeffects research was motivated partly by curiosity, and partly by the wish to increase the effectiveness and ensure the safety of therapeutic US. Beginning in the 1970s, the motivation has come also from the need for safety guidelines relevant to diagnostic US. Instrumentation was developed for measuring acoustic pressure in the fields of pulsed and focused US employed, and standards were established for specifying the fields of commercial equipment. Critical levels of US quantities were determined from laboratory experiments, together with biophysical analysis, for bioeffects produced by thermal and nonthermal mechanisms. These are the basis for safety advice and guidelines recommended or being considered by national, international, professional and governmental organizations.

Biological effects of ultrasound: development of safety guidelines. Part I: personal histories.

After the end of World War II, advances in ultrasound (US) technology brought improved possibilities for medical applications. The first major efforts in this direction were in the use of US to treat diseases. Medical studies were accompanied by experiments with laboratory animals and other model systems to investigate basic biological questions and to obtain better understanding of mechanisms. Also, improvements were made in methods for measuring and controlling acoustical quantities such as power, intensity and pressure. When diagnostic US became widely used, the scope of biological and physical studies was expanded to include conditions for addressing relevant safety matters. In this historical review, a major part of the story is told by 21 investigators who took part in it. Each was invited to prepare a brief personal account of his/her area(s) of research, emphasizing the "early days," but including later work, showing how late and early work are related, if possible, and including anecdotal material about mentors, colleagues, etc.

Current status of research on biophysical effects of ultrasound.

This overview of bioeffects of ultrasound presents some key aspects of selected papers dealing with biophysical end-points. Its purpose is to establish a basis for exposure and dosimetric standards for medical ultrasonic equipment. It is intended to provide essential background resource material for the medical/scientific community, and more specifically for scientific working groups. This document was prepared by members of the Safety Committee of the World Federation for Ultrasound in Medicine and Biology. It was produced as a resource document in response to a request for information by Working Group 12 (Ultrasound exposure parameters) of the International Electrotechnical Commission Technical Committee 87, Ultrasonics. IEC TC 87, WG12 is the working group responsible for generating international standards for the classification of equipment by its acoustic fields based on safety thresholds. Our paper is intended to update and supplement information on the thermal mechanism provided in the publication, "WFUMB Symposium on Safety and Standardisation in Medical Ultrasound: Issues and Recommendations Regarding Thermal Mechanisms for Biological Effects of Ultrasound" (WFUMB 1992). It also provides an overview of trends in research into nonthermal mechanisms as a preliminary to the next WFUMB Symposium on Safety of Medical Ultrasound when this subject will be examined in detail by a select group of international experts. The WFUMB-sponsored workshop will take place in Utsunomiya, Japan during 11-15th July, 1994. The purpose of the meeting is to evaluate the scientific literature and to formulate internationally accepted recommendations on the safe use of diagnostic ultrasound that may be endorsed as official policy of the WFUMB. It should be noted that the current publication is not intended for review or endorsement as an official WFUMB document. It is produced as a scientific paper by individuals who are members of the WFUMB Safety Committee, and it therefore represents the opinions of the authors. Nevertheless, during the preparation of this document, contributions were received from members of the International Electrotechnical Commission Technical Committee 87 as well as many other individual experts, and the authors sincerely acknowledge their support.

Scientifically based safety criteria for ultrasonography.

One of the major contributions of E. L. Carstensen to medical ultrasonography lies in the research studies by him and his colleagues on biophysical mechanisms for biological effects. These studies have done much to provide a basis for predicting conditions under which ultrasound will affect living systems. The scientific information that now exists makes possible an improved approach to decisions on safety for diagnostic ultrasonography. In particular, estimates of the maximum temperature produced in a sonographic examination provide an index that can be used to ensure safety from thermal hazards.

Temperature rise generated by a focussed Gaussian beam in a two-layer medium.

The temperature rise is calculated at points along the axis of a focussed Gaussian beam propagating through a two-layer medium; the first layer is non-attenuating and the second one consists of absorbing material simulating soft tissue. This two-layer medium is relevant to several situations encountered in medical applications of diagnostic ultrasound. These include fetal examinations via the abdominal wall, where the beam may travel a significant distance through urine or amniotic fluid before reaching the fetus.

A rotating ultrasonic waveguide for studying acoustic radiation forces on particles.

An apparatus was designed to allow a suspension of biological cells to be subjected to a well-defined, 160-kHz standing ultrasonic field while being viewed through a stereo microscope. Cell positions were recorded either photographically or by means of a video camera. The chamber cavity, which has a square cross section and pressure-release walls, acts as a single-mode acoustic waveguide. The well-defined single-mode field is achieved through use of a special design involving air-filled chamber windows. Aqueous metrizamide solution is used to fill the ultrasonic chamber because it has a unique combination of properties, including low viscosity, low osmolarity, and high density. The chamber rotates about its axis (whose inclination can be varied) producing the centripetal force necessary to contain the buoyant cells in the axial region. Observations were made on stroboscopically illuminated suspensions both of latex microspheres and of red blood cells. The particles formed groups at half-wavelength intervals along the rotation axis near positions of acoustic pressure-amplitude minima. The position and shape of these groupings are explained by a scalar-potential theory for noninteracting particles that considers gravitational, rotational, and acoustic radiation forces on the particles.

Measurements of frequency spectra of transmission coefficients to ultrasound through trapped microbubbles.

Techniques which use hydrophobic polycarbonate thin sheets containing randomly spaced, fairly uniform small pores immersed in water to trap air bubbles have been found to be useful in biophysical experiments. The utilization of broadband polyvinylidene fluoride transducers in this work made it possible to measure a continuous frequency spectrum of the transmission coefficient of the trapped bubbles. The results of the measurements show: (1) the frequency response curve of the bubble ensemble is much broader than that of a single bubble predicted by theory; and (2) as the incident sound pressure at a micropore membrane increases from 110 to 660 Pa the resonance frequency of bubbles shifts to lower values by as much as 7%.

Experimental frequency spectra of ultrasound transmission through two-dimensional ensembles of trapped microbubbles.

The frequency spectra of transmission coefficients for ultrasound passing through a sheet of gas-filled micropores have been measured using incident waves with amplitudes up to 2.4 x 10(4) Pa. It is found that as the amplitude of the incident wave is increased, the peak frequency of transmission loss through the two-dimensional trapped-bubble ensemble shifts to lower values by as much as 47%. The experiments indicate that the shifting is caused by the net displacements of air-water-membrane triple-phase lines and the air loss of the trapped bubble, which are due to the radiation force and microbubble production produced by the incident wave. Results of the experiments and possible theoretical explanations are discussed.

Theoretical criterion for acoustic aggregation.

Theory was given previously for the radiation force between two spherical particles immersed in a fluid and subjected to a sound field. From this theory an expression has been obtained for the effective energy of interaction. A minimum energy, defining a "binding energy" Wmin, occurs when the particles are in contact and aligned with their line of centers perpendicular to the oscillatory motion in the local sound field. When Wmin is large enough, dimers are formed which combine to build larger aggregates. A criterion for aggregation was obtained, similar to one arrived at by Schwan for aggregation produced by alternating electric fields, by setting Wmin equal to the thermal energy kT. Calculations suggest that aggregation of blood cells may occur during applications of medical ultrasound under some conditions. Experiments are needed to test possibilities.

Solutions of the bio-heat transfer equation.

A solution of the bio-heat transfer equation for a 'step-function point source' is presented and discussed. From this basic solution one can, in principle, obtain the temperature field resulting from a general heat source distribution by superposition. As an example, the method is used to calculate the temperature on the body surface at a point where therapeutic ultrasound is applied. Comparison is made with experimental results recently published by Williams and co-workers.

Sonically produced heat in a fluid with bulk viscosity and shear viscosity.

In a viscous fluid, sound produces heat in a spatial pattern which, in general, depends on the relative magnitudes of the shear viscosity coefficient eta and the bulk viscosity coefficient B'. It is well known that when the particle velocity components ui relative to Cartesian coordinates xi are given for an arbitrary sound field, or any field of flow, the volume rate of heat production qv can be determined from a dissipation function in the form B'T1 + eta T2. Here, T1 and T2 are quadratic functions involving derivatives of the type delta ui/delta xj. In this paper, examples are discussed for continuous monofrequency sound fields, including crossed plane waves, as well as focused and unfocused fields. In these examples, spatial distributions of the time-averaged quantity [qv] for media in which the loss mechanism is primarily bulk viscosity are compared to those for media in which shear viscosity dominates.

Ultrasonically induced intravascular streaming and thrombus formation adjacent to a micropipette.

Ultrasonically induced microstreaming around bubbles of gas have been shown to cause damage to biological materials in vitro at clinical exposure levels. The potential for ultrasonically induced cavitation and microstreaming in mammalian systems is of interest with respect to the safe application of clinical ultrasound. Ultrasonically induced intravascular microstreaming and formation of thrombi at 1 MHz is demonstrated adjacent the tip of a micropipette in contact with a mesenteric vessel of the mouse. These effects occur at or above therapeutic levels.

Nearfield of a piston source of ultrasound in an absorbing medium.

Approximate expressions are discussed which are applicable for acoustic quantities in the vicinity of a plane piston source of ultrasound which radiates into an absorbing medium. A particularly useful approach for nearfield calculations combines an expression valid near the axis with another, given by Pierce [Acoustics, An Introduction to Its Physical Principles and Applications (McGraw-Hill, New York, 1981), Chap. 5], which is valid elsewhere. This approach gives reasonable accuracy at relatively low computational cost. Computed plots are presented, showing spatial distributions of the square of the pressure amplitude. Most of the plots are for a source diameter of 1.2 cm, a frequency of 3 MHz, and an absorption coefficient of 0.15 Np/cm; these are representative of conditions for medical applications of ultrasound.

Optimization of exposure conditions for medical ultrasound.

Optimum exposure conditions are values of acoustic exposure parameters (e.g., intensity, pressure amplitude, time) which yield maximum net medical benefit in a therapeutic or diagnostic procedure. It is generally agreed that if the exposure values are too low, the procedures are ineffective, while if they are too high, harm will result. However, little quantitative information exists on what specific values the parameters should have to give greatest net benefit in various applications. The determination of optimum exposure conditions is an important goal, but the process is likely to be a long one, requiring efforts by many individuals and groups. In this review several approaches to the problem are discussed, and difficulties are pointed out.