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.

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.

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.

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.

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.

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.

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 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.

Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: 5. Temperature.

This research project tested the hypothesis that cold-equilibrated (approximately 0 degrees C) human erythrocytes in vitro in the presence of an ultrasound contrast agent (Albunex) will undergo greater ultrasound-induced hemolysis than physiologically equilibrated (37 degrees C) human erythrocytes in vitro because of a temperature-related transition in membrane fluidity leading to increased fragility. First, it was shown that cold-equilibrated erythrocytes are more susceptible to mechanically induced hemolysis than physiologically equilibrated erythrocytes. Second, when adjustments were made for (1) temperature-dependent efficiencies of a 1-MHz transducer (200 micros pulse length, 20 ms interpulse interval, 30 s exposure duration) such that when cold or physiological temperatures were employed, there were equivalent acoustic outputs in terms of peak negative pressure (MPa P-) and (2) comparable viscosities of the 0 and 37 degrees C blood plasmas, the cold (approximately 0 degrees C) erythrocytes displayed substantially greater amounts of ultrasound-induced hemolysis than the physiological (37 degrees C) erythrocytes. The data supported the hypothesis.

A simple viscoelastic model for soft tissues in the frequency range 6-20 MHz.

In this paper, we present measurements of the shear properties of porcine skeletal muscle, liver, and kidney and a novel model describing them. Following a previously used method, shear mechanical impedances are measured, and complex shear moduli are obtained in the frequency range 6-20 MHz. As indicated in previous results, negative storage moduli are obtained in some measurements, which yield negative shear moduli in traditional linear viscoelastic models such as the Maxwell model, the Voigt model, and the Kelvin model. To resolve this problem, we propose a simple extension of the Voigt model. A mass is introduced into the model to account for the extra phase shift that apparently produces the negative moduli, and the shear stress thereby is related to the inertia of the material. The observed negative storage moduli are predicted by the new model when the relaxation time of the material is large and the working frequency is high. The model is fitted to experimental data to obtain values for material constants.

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.

Porous PLGA microparticles: AI-700, an intravenously administered ultrasound contrast agent for use in echocardiography.

The production and characterization of AI-700, an intravenously administered ultrasound contrast agent under investigation for myocardial perfusion echocardiography, are described. The product consists of small, porous microparticles filled with decafluorobutane gas, and formulated as a dry powder. Small scale spray drying studies demonstrated that porous PLGA microparticles could be produced with varying porosity using ammonium bicarbonate as a volatile pore-forming agent. The porous microparticles of AI-700 were created aseptically by spray drying a water-in-oil emulsion containing poly-d,l-lactide-co-glycolide, 1,2-diarachidoyl-sn-glycero-3-phosphocholine, and ammonium bicarbonate using a two-chamber spray dryer. The porous microparticles were further formulated into a dry powder drug product (AI-700) containing decafluorobutane gas and excipients. The dry powder was reconstituted with sterile water prior to evaluation. Microscopy demonstrated that the microparticles were sphere-shaped and internally porous. The microparticles were appropriately sized for intravenous administration, having an average diameter of 2.3 mum. Zeta-potential analysis demonstrated that the microparticles would be expected to be stable post-reconstitution. The microparticles retained encapsulated gas post-reconstitution, had high acoustic potency that was stable over time and were physically stable upon exposure to high-power ultrasound, as used clinically. AI-700 has the characteristics desirable for an intravenously administered ultrasound contrast agent for myocardial perfusion echocardiography.

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.

Evaluation of a new ultrasound contrast agent (AI-700) using two-dimensional and three-dimensional imaging during acute ischemia.

BACKGROUND: A new intravenous contrast agent, AI-700, was evaluated to determine whether a bolus injection could be used to detect myocardial perfusion abnormalities during acute ischemia by using 2-dimensional (2D) and 3-dimensional (3D) myocardial contrast echocardiography. METHODS: 2D MCE was performed in 14 closed-chest dogs during coronary occlusion by using both continuous and triggered gray scale harmonic imaging and triggered power Doppler imaging. 3D MCE (open-chest) and nuclear perfusion imaging were performed in 10 of the 14 dogs. Postmortem triphenyl tetrazolium chloride (TTC) staining was performed to verify infarction. RESULTS: Thirteen of the 14 dogs had infarct by TTC; all 10 that had nuclear imaging showed a perfusion defect. Of the 13 dogs that had infarction, perfusion defects were detected in all (13 of 13) by gray scale harmonic imaging (sensitivity = 100%), and in 11 of 13 by power Doppler imaging (sensitivity = 85%). All 10 dogs that had nuclear imaging showed perfusion defects by gray scale harmonic imaging (sensitivity = 100%) and 8 of 10 by power Doppler imaging (sensitivity = 80%). The perfusion defect size, derived from 3D imaging (25% +/- 12%) correlated well with that from nuclear imaging (24% +/- 12%) (y = 0.9x + 3.8, r = 0.96, mean difference = 1.3% +/- 2.6%). The perfusion defect mass by 3D (22 +/- 14 g) also correlated well with the infarct mass by TTC staining (24 +/- 16 g) (y = 0.8x + 2.9, r = 0.89, P <.001, mean difference = -2.8 +/- 7.6 g). CONCLUSION: After a single bolus of AI-700, both 2D and 3D MCE could accurately detect perfusion defects representing the area at risk of infarction during acute ischemia compared with nuclear imaging and predicted the size of infarction as verified by TTC staining.