Introduction to the Special Issue on COVID-19.

The COVID-19 pandemic has been a global event affecting all aspects of human life and society, including acoustic aspects. In this Special Issue on COVID-19 and acoustics, we present 48 papers discussing the acoustical impacts of the pandemic and how we deal with it. The papers are divided into seven categories which include: physical masking and speech production, speech perception, noise, the underwater soundscape, the urban soundscape, pathogen transmissibility, and medical diagnosis.

The Dependence of Glomerular Capillary Hemorrhage Induced by Contrast Enhanced Diagnostic Ultrasound on Microbubble Diameter.

A recently proposed two-criterion model for cavitational bioeffects in tissue with microbubbles (MBs) was tested. The glomerular capillary hemorrhage bioeffect was observed in rat kidney for contrast agent MB suspensions with mean diameters of 1.6, 3.1 and 5.5 µm. A diagnostic ultrasound machine was used at 3.6 MHz and 5.5 MHz for intermittent scans at power settings 2 dB apart. Petechial hemorrhage counts scored on the surface of the kidneys, and glomeruli were scored in histology. Thresholds for the petechial hemorrhage measurements were the same for the large and medium MB suspensions but substantially higher for the small MBs. For the histology, the medium MBs gave a higher threshold than the large MBs at 5.5 MHz. The pressure amplitude thresholds are in approximate agreement with theory, and the optimum MB size counterintuitively increased for increasing ultrasound frequency, as predicted. The two-criterion model of MB-associated capillary hemorrhage is supported.

A Two-Criterion Model for Microvascular Bio-Effects Induced In Vivo by Contrast Microbubbles Exposed to Medical Ultrasound.

The mechanical index (MI) is a theoretical exposure parameter for cavitational bio-effects of diagnostic ultrasound. The theory for the MI assumed that bubbles of all relevant sizes exist in tissue, a condition that is approximated for tissues that include a microbubble contrast agent. Therefore, the MI should allow science-based safety guidance for contrast-enhanced diagnostic ultrasound. However, theoretical predictions of bio-effects thresholds based on the MI typically do not concur with the frequency dependence of experimentally measured thresholds for bio-effects. For example, experimental thresholds for glomerular capillary hemorrhage in rats infused with contrast microbubbles increased approximately linearly with frequency, whereas the MI predicted a square root dependence. Here, cavitation thresholds were computed for linear versions of the acoustic pulses used in that study assuming bubbles containing either air, C3F8, or a 1:1 mixture of the two and surrounded by either blood or kidney tissue. Although no single threshold criterion was successful, combining results for one criterion that maximized circumferential stress in the capillary wall with another that ensured an inertial collapse produced thresholds that were consistent with experimental data. This suggests that a contrast-specific safety metric may be achieved following validation of this two-criterion model.

Comparison of Thermal Safety Practice Guidelines for Diagnostic Ultrasound Exposures.

This article examines the historical evolution of various practice guidelines designed to minimize the possibility of thermal injury during a diagnostic ultrasound examination, including those published by the American Institute of Ultrasound in Medicine, British Medical Ultrasound Society and Health Canada. The guidelines for prenatal/neonatal examinations are in general agreement, but significant differences were found for postnatal exposures. We propose sets of thermal index versus exposure time for these examination categories below which there is reasonable assurance that an examination can be conducted without risk of producing an adverse thermal effect under any scanning conditions. If it is necessary to exceed these guidelines, the occurrence of an adverse thermal event is still unlikely in most situations because of mitigating factors such as transducer movement and perfusion, but the general principle of "as low as reasonably achievable" should be followed. Some limitations of the biological effects studies underpinning the guidelines also are discussed briefly.

Conditionally Increased Acoustic Pressures in Nonfetal Diagnostic Ultrasound Examinations Without Contrast Agents: A Preliminary Assessment.

The mechanical index (MI) has been used by the US Food and Drug Administration (FDA) since 1992 for regulatory decisions regarding the acoustic output of diagnostic ultrasound equipment. Its formula is based on predictions of acoustic cavitation under specific conditions. Since its implementation over 2 decades ago, new imaging modes have been developed that employ unique beam sequences exploiting higher-order acoustic phenomena, and, concurrently, studies of the bioeffects of ultrasound under a range of imaging scenarios have been conducted. In 2012, the American Institute of Ultrasound in Medicine Technical Standards Committee convened a working group of its Output Standards Subcommittee to examine and report on the potential risks and benefits of the use of conditionally increased acoustic pressures (CIP) under specific diagnostic imaging scenarios. The term "conditionally" is included to indicate that CIP would be considered on a per-patient basis for the duration required to obtain the necessary diagnostic information. This document is a result of that effort. In summary, a fundamental assumption in the MI calculation is the presence of a preexisting gas body. For tissues not known to contain preexisting gas bodies, based on theoretical predications and experimentally reported cavitation thresholds, we find this assumption to be invalid. We thus conclude that exceeding the recommended maximum MI level given in the FDA guidance could be warranted without concern for increased risk of cavitation in these tissues. However, there is limited literature assessing the potential clinical benefit of exceeding the MI guidelines in these tissues. The report proposes a 3-tiered approach for CIP that follows the model for employing elevated output in magnetic resonance imaging and concludes with summary recommendations to facilitate Institutional Review Board (IRB)-monitored clinical studies investigating CIP in specific tissues.

A theoretical study of inertial cavitation from acoustic radiation force impulse imaging and implications for the mechanical index.

The mechanical index (MI) attempts to quantify the likelihood that exposure to diagnostic ultrasound will produce an adverse biological effect by a non-thermal mechanism. The current formulation of the MI implicitly assumes that the acoustic field is generated using the short pulse durations appropriate to B-mode imaging. However, acoustic radiation force impulse (ARFI) imaging employs high-intensity pulses up to several hundred acoustic periods long. The effect of increased pulse durations on the thresholds for inertial cavitation was studied computationally in water, urine, blood, cardiac and skeletal muscle, brain, kidney, liver and skin. The results indicate that, although the effect of pulse duration on cavitation thresholds in the three liquids can be considerable, reducing them by, for example, 6%-24% at 1 MHz, the effect on tissue is minor. More importantly, the frequency dependence of the MI appears to be unnecessarily conservative; that is, the magnitude of the exponent on frequency could be increased to 0.75. Comparison of these theoretical results with experimental measurements suggests that some tissues do not contain the pre-existing, optimally sized bubbles assumed for the MI. This means that in these tissues, the MI is not necessarily a strong predictor of the probability of an adverse biological effect.

Arrhenius thermodynamics and birth defects: chemical teratogen synergy. Untested, testable, and projected relevance.

This article addresses the issue of hyperthermia-induced birth defects with an accompanying additional teratogen, be it a chemical or a physical agent (i.e., a simultaneous "combinational" exposure to two teratogens, one of which is hyperthermia). Hyperthermia per se is a recognized human and animal teratogen. An excellent example of such combinational exposures is an epileptic woman who becomes pregnant while taking valproic acid (VPA) to control seizures. VPA is a recognized chemical teratogen, and fever (hyperthermia) is not an uncommon event during pregnancy. While VPA also may occasionally induce fever as a side effect, we are concerned here with fevers arising from other, unrelated causes. There is a small but internally consistent literature on these combinational-teratogen exposures involving hyperthermia plus a chemical teratogen; in each instance, the effect level has been observed to be synergistically elevated above levels induced by the separate teratogenic components. The data were empirical. The observed synergy is, however, consistent with Arrhenius thermodynamics, a well-known chemical rate equation. The need for information about combinational teratogen exposures is acute; fever is a common occurrence during pregnancy; and there are many instances whereby there is also the simultaneous presence of some other teratogen(s). Given that the rate of autism spectrum disorders in the United States was recently presented as 1 in 88 births, it seems reasonable to suspect that such combinational regimens are much more prevalent than previously thought. Our hypothesis is that synergistic birth defect levels from combinational regimens are consistent with Arrhenius thermodynamics.

The effect of static pressure on the strength of inertial cavitation events.

Recent investigations of cavitation in fluids pressurized up to 30 MPa found that the intensity of light emissions increased by 1000-fold over that measured for single bubble sonoluminescence. A series of measurements is reported here to extend this original work by resolving the static pressure dependence of the shock wave and light emissions from the first and the most energetic collapses, along with the total shock wave energy and light emissions for the event. Each of these parameters was found to increase with the static pressure of the fluid. Furthermore, the energy of these shock wave and light emissions was found to increase in proportion to the stored acoustic energy in the system. These findings were corroborated using the Gilmore equation to numerically compute the work done by the liquid during the bubble collapse. The overall findings suggest that the increased collapse strength at high static pressure is due to the increased tension required to generate inertial cavitation, and not an increased pressure gradient between the interior of the vaporous bubble and the surrounding liquid.

The effect of static pressure on the inertial cavitation threshold.

The amplitude of the acoustic pressure required to nucleate a gas or vapor bubble in a fluid, and to have that bubble undergo an inertial collapse, is termed the inertial cavitation threshold. The magnitude of the inertial cavitation threshold is typically limited by mechanisms other than homogeneous nucleation such that the theoretical maximum is never achieved. However, the onset of inertial cavitation can be suppressed by increasing the static pressure of the fluid. The inertial cavitation threshold was measured in ultrapure water at static pressures up to 30 MPa (300 bars) by exciting a radially symmetric standing wave field in a spherical resonator driven at a resonant frequency of 25.5 kHz. The threshold was found to increase linearly with the static pressure; an exponentially decaying temperature dependence was also found. The nature and properties of the nucleating mechanisms were investigated by comparing the measured thresholds to an independent analysis of the particulate content and available models for nucleation.

Should the mechanical index be revised for ARFI imaging?

The mechanical index (MI) quantifies the likelihood that exposure to diagnostic ultrasound will produce an adverse biological effect by a nonthermal mechanism. The current formulation of the MI is based on inertial cavitation thresholds in two liquids, water and blood, as calculated by a formalism assuming very short pulse durations. Although tissue contains a high proportion of water, it is not a liquid but a viscoelastic solid. Further, acoustic radiation force impulse imaging employs high-intensity pulses up to several hundred acoustic periods long. The effect of these differences was studied in water, blood and five representative tissues.

The thermal index: its strengths, weaknesses, and proposed improvements.

The thermal index (TI) has been used as a relative indicator of thermal risk during diagnostic ultrasound examinations for many years. It is useful in providing feedback to the clinician or sonographer, allowing assessment of relative, potential risks to the patient of an adverse effect due to a thermal mechanism. Recently, several shortcomings of the TI formulations in quantifying the risk to the patient have been identified by members of the basic scientific community, and possible improvements to address these shortcomings have been proposed. For this reason, the Output Standards Subcommittee of the American Institute of Ultrasound in Medicine convened a subcommittee to review the strengths of the TI formulations as well as their weaknesses and proposed improvements. This article summarizes the findings of this subcommittee. After a careful review of the literature and an assessment of the cost of updating the TI formulations while maximizing the quality of patient care, the Output Standards Subcommittee makes the following recommendations: (1) some inconsistencies in the current TI formulations should be resolved, and the break point distance should be redefined to take focusing into consideration; (2) an entirely new indicator of thermal risk that incorporates the time dependence not be implemented at this time but be included in continuing efforts toward standards or consensus documents; (3) the exponential dependence of risk on temperature not be incorporated into a new definition of the TI formulations at this time but be included in continuing efforts toward standards or consensus documents; (4) the TI formulations not be altered to include nonlinear propagation at this time but be included in continuing efforts toward standards or consensus documents; and (5) a new indicator for risk from thermal mechanisms should be developed, distinct from the traditional TI formulations, for new imaging modalities such as acoustic radiation force impulse imaging, which have more complicated pulsing sequences than traditional imaging.

Augmentation of HIFU-induced heating with fibers embedded in a phantom.

The effect of fibers on the rate of heat deposition in the focal region of high-intensity focused ultrasound (HIFU) beams was investigated. Nylon, stainless steel and copper fibers of diameters 0.23-0.25, 0.33 and 0.51-0.53 mm embedded in a phantom were exposed to HIFU. The total energy deposited was quantified by measuring the volumes of the lesions formed. The average volumes of the lesions normalized to the average volume of control lesions were 1.19±0.19, 1.43±0.19 and 2.67±0.21 for increasing nylon fiber diameter, indicating an augmented rate of heating. The maximum normalized volume of lesions at the metal fibers was 0.655. These results are consistent with the material properties, which suggest that the mechanism is increased acoustic absorption along with reduction of heat loss by the nylon fiber. The study supports the possibility of improving the efficacy of HIFU-induced hemostasis in vivo by use of a specially designed, nylon fiber-based medical appliance.

Transient cavitation in high-quality-factor resonators at high static pressures.

It is well known that cavitation collapse can generate intense concentrations of mechanical energy, sufficient to erode even the hardest metals and to generate light emissions visible to the naked eye [sonoluminescence (SL)]. Considerable attention has been devoted to the phenomenon of "single bubble sonoluminescence" (SBSL) in which a single stable cavitation bubble radiates light flashes each and every acoustic cycle. Most of these studies involve acoustic resonators in which the ambient pressure is near 0.1 MPa (1 bar), and with acoustic driving pressures on the order of 0.1 MPa. This study describes a high-quality factor, spherical resonator capable of achieving acoustic cavitation at ambient pressures in excess of 30 MPa (300 bars). This system generates bursts of violent inertial cavitation events lasting only a few milliseconds (hundreds of acoustic cycles), in contrast with the repetitive cavitation events (lasting several minutes) observed in SBSL; accordingly, these events are described as "inertial transient cavitation." Cavitation observed in this high pressure resonator is characterized by flashes of light with intensities up to 1000 times brighter than SBSL flashes, as well as spherical shock waves with amplitudes exceeding 30 MPa at the resonator wall. Both SL and shock amplitudes increase with static pressure.

Ultrasound biosafety considerations for the practicing sonographer and sonologist.

The purpose of this article is to present the practicing sonographer and sonologist with an overview of the biohazards of ultrasound and guidelines for safe use.

The risk of exposure to diagnostic ultrasound in postnatal subjects: nonthermal mechanisms.

This review examines the nonthermal physical mechanisms by which ultrasound can harm tissue in postnatal patients. First the physical nature of the more significant interactions between ultrasound and tissue is described, followed by an examination of the existing literature with particular emphasis on the pressure thresholds for potential adverse effects. The interaction of ultrasonic fields with tissue depends in a fundamental way on whether the tissue naturally contains undissolved gas under normal physiologic conditions. Examples of gas-containing tissues are lung and intestine. Considerable effort has been devoted to investigating the acoustic parameters relevant to the threshold and extent of lung hemorrhage. Thresholds as low as 0.4 MPa at 1 MHz have been reported. The situation for intestinal damage is similar, although the threshold appears to be somewhat higher. For other tissues, auditory stimulation or tactile perception may occur, if rarely, during exposure to diagnostic ultrasound; ultrasound at similar or lower intensities is used therapeutically to accelerate the healing of bone fractures. At the exposure levels used in diagnostic ultrasound, there is no consistent evidence for adverse effects in tissues that are not known to contain stabilized gas bodies. Although modest tissue damage may occur in certain identifiable applications, the risk for induction of an adverse biological effect by a nonthermal mechanism due to exposure to diagnostic ultrasound is extremely small.

Fetal thermal dose considerations during the obstetrician's watch: Implications for the pediatrician's observations.

There are a number of seemingly "usual" thermal episodes during pregnancy for which it is relatively easy to determine a rudimentary aspect of thermal dose; these episodes include fever, labor, labor plus epidural, and the normally-occurring 0.5 degrees C temperature elevation above maternal core temperature of the fetus during the entirety of the third trimester. Complications can involve, for instance, fever during the third trimester. We consider the thermal doses of five different but "usual" or "normal" hyperthermic episodes during human pregnancy and compare those doses with the thermal doses involved with both single and cohort exposures of pregnant guinea pigs throughout their gestational period. The end-point studied in the guinea pigs was microencephaly. In nine of the 10 comparisons (human fetal thermal dose vs. guinea pig fetal thermal dose) the human dose is substantially larger than that of the guinea pig thermal dose, which was substantially teratogenic. This situation is essentially the inverse of the type of information contained in the Physician's Desk Reference (PDR) on drugs, in which it is not unusual to discern that at high drug levels there may be teratogenic effects in laboratory animals, but such effects were not observed at "clinical" drug levels in animals or subsequent clinical trials. With hyperthermic events, however, it appears that the teratogenically-effective thermal dose levels associated with animal testing are quite low relative to those thermal doses associated with relatively "normal" obstetric observations during a pregnancy.

A proposal to clarify the relationship between the thermal index and the corresponding risk to the patient.

The thermal index (TI) displayed on the screens of most modern diagnostic ultrasound machines is linearly proportional to the absorbed power or, equivalently, to the in-situ intensity or temperature rise. Users are instructed to interpret the TI as a "relative indication of bioeffect risk." The thermal dose is a well-known empirical relationship between the temperature T of a biological system and the time t needed for that temperature to induce a deleterious effect. For any two temperatures, T1 and T2, and the corresponding times t1 and t2, required to produce the same level of effect, this general relation holds: t1/t2=RT2-T1, where R is the thermal normalization constant. Hence, it is experimentally determined that the rate of induction, or risk, of a thermal effect increases exponentially with temperature. Because exponential relationships are not intuitive to many users, there is a significant potential for underestimation of the thermal risk associated with exposure to diagnostic ultrasound. To better quantify this risk and thereby make the displayed information more useful, the current linear display of the calculated value of the thermal index, i.e., of TIcur, should be altered to an exponential form based on the thermal dose and representing the excess risk associated with the exposure: TInew=(RTIcur-1)/(R-1). This expression has the advantage that for the usual choice of R=4 for T3.5, the displayed TInew>>TIcur, consistent with empirical observations of the likelihood of harm. Additional advantages also obtain.

Evaluation of the threshold for lung hemorrhage by diagnostic ultrasound and a proposed new safety index.

In a recent report (O'Brien et al. (2006b), it was suggested that the current expression for the mechanical index (MI) was not well suited to its function of quantifying the likelihood of an adverse biological effect after exposure of the gas-filled lung to diagnostic ultrasound. The purpose of this study was to analyze the relatively large database of experimental thresholds for the induction of lung hemorrhage to: (i) determine which variable(s) best describe the data and (ii) use the resulting equation to obtain a new formulation for the MI for lung exposures. Data from 14 studies of lung hemorrhage in four common laboratory animals (mouse, rat, rabbit and pig) were tabulated with regard to five common acoustic variables: center frequency (f(c)), pulse repetition frequency (PRF), pulse duration (PD), exposure duration (ED) and the threshold in situ peak rarefactional pressure (p(r)). The 34 threshold data points were fit by linear regression to: (i) a multiplicative model of the other variables, p(r) = Af(c)(B)PRF(C)PD(D)ED(E), where A is a constant; (ii) 14 "reduced" models in which one or more variables were not included in the analysis; (iii) four models in which a multiplicative combination of variables has a common name e.g., duty factor; and (iv) the general form of the current expression for the MI. The MI was shown to provide a poor fit to the threshold data (r(2) = 0.382), as were three of the four named models. The best fits were found for the complete model and for three reduced models, all of which contain the exposure duration. Because the implementation of a time-dependent safety parameter would present significant practical difficulties, a different model, p(r) = Af(c)(B)PRF(C)PD(D), was chosen as the basis for the new MI. Thus, the expression for the lung-specific mechanical index, MI(Lung), includes several, rather than only one, of the relevant acoustic variables. This is the first potential safety index developed as a direct result of experimental measurements rather than theoretical analysis.

Quantification of risk from fetal exposure to diagnostic ultrasound.

Biomedical ultrasound may induce adverse effects in patients by either thermal or non-thermal means. Temperatures above normal can adversely affect biological systems, but effects also may be produced without significant heating. Thermally induced teratogenesis has been demonstrated in many animal species as well as in a few controlled studies in humans. Various maximum 'safe' temperature elevations have been proposed, although the suggested values range from 0.0 to 2.5 degrees C. Factors relevant to thermal effects are considered, including the nature of the acoustic field in situ, the state of perfusion of the embryo/fetus, and the variation of sensitivity to thermal insult with gestational stage of development. Non-thermal mechanisms of action considered include acoustic cavitation, radiation force, and acoustic streaming. While cavitation can be quite destructive, it is extremely unlikely in the absence of stabilized gas bodies, and although the remaining mechanisms may occur in utero, they have not been shown to induce adverse effects. For example, pulsed, diagnostic ultrasound can increase fetal activity during exposure, apparently due to stimulation of auditory perception by radiation forces on the fetal head or auditory structures. In contrast, pulsed ultrasound also produces vascular damage near developing bone in the late-gestation mouse, but by a unknown mechanism and at levels above current US FDA output limits. It is concluded that: (1) thermal rather than nonthermal mechanisms are more likely to induce adverse effects in utero, and (2) while the probability of an adverse thermal event is usually small, under some conditions it can be disturbingly high.