Ocular Ultrasound: Review of Bioeffects and Safety, Including Fetal and Point of Care Perspective: Review of Bioeffects and Safety, Including Fetal and Point-of-Care Perspective.

Ocular ultrasound is an invaluable tool for the evaluation of the eye and orbit. However, the eye and orbit are potentially sensitive to the thermal and mechanical effects of ultrasound. When performing B-mode imaging, dedicated ocular settings should be used. If these settings are not available, limiting the acoustic output to Food and Drug Administration (FDA) recommended maximum levels is strongly advised. Especially important is the acoustic output in spectral (pulsed) and color Doppler modes, which can exceed the FDA's maximum recommended levels for the eye. Adjusting settings to decrease acoustic output and limiting the time of the examination should be done when performing a Doppler examination. The acoustic output of shear wave elastography is significantly higher than FDA guidelines for the eye and should be considered experimental.

Comparison between experimental and computational methods for the acoustic and thermal characterization of therapeutic ultrasound fields.

For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue-mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively).

Trends in diagnostic ultrasound acoustic output from data reported to the US Food and Drug Administration for device indications that include fetal applications.

OBJECTIVES: A survey was conducted of acoustic output data received by the US Food and Drug Administration for diagnostic ultrasound devices whose indications for use include fetal applications to assess trends in maximum available acoustic output over time. METHODS: Data were collected from 124 regulatory submissions received between 1984 and 2010. Data collection excluded transducers not indicated for diagnostic fetal imaging. The output parameters of ultrasonic power, mean center frequency, and bone thermal index (TIB) were extracted or computed from the submissions for 3 periods: 1984-1989, 1992-1997, and 2005-2010. The data were stratified according to the following imaging modes: M-mode, B/M-mode, pulsed wave Doppler, color flow Doppler, and continuous wave Doppler. RESULTS: Ultrasonic power and maximum TIB values have increased roughly an order of magnitude from pre-1991 to post-1991 periods; the center frequency has decreased somewhat (4.2 to 3.4 MHz). The percentage of Doppler-mode transducers has increased substantially over time, with the majority of the diagnostic fetal imaging transducers currently designed to operate in Doppler modes; this increase is particularly important, since Doppler modes generate much higher TIB levels than B/M-modes. Color flow Doppler ultrasound currently operates at the highest mean ultrasonic power level (with a 14-fold increase over time). CONCLUSIONS: The observed trends in increased acoustic output for both Doppler and non-Doppler modes underscore the widely recognized importance of adherence to the ALARA (as low as reasonably achievable) principle and prudent use in fetal ultrasound imaging.

Challenges and regulatory considerations in the acoustic measurement of high-frequency (>20 MHz) ultrasound.

This article examines the challenges associated with making acoustic output measurements at high ultrasound frequencies (>20 MHz) in the context of regulatory considerations contained in the US Food and Drug Administration industry guidance document for diagnostic ultrasound devices. Error sources in the acoustic measurement, including hydrophone calibration and spatial averaging, nonlinear distortion, and mechanical alignment, are evaluated, and the limitations of currently available acoustic measurement instruments are discussed. An uncertainty analysis of acoustic intensity and power measurements is presented, and an example uncertainty calculation is done on a hypothetical 30-MHz high-frequency ultrasound system. This analysis concludes that the estimated measurement uncertainty of the acoustic intensity is +73%/-86%, and the uncertainty in the mechanical index is +37%/-43%. These values exceed the respective levels in the Food and Drug Administration guidance document of 30% and 15%, respectively, which are more representative of the measurement uncertainty associated with characterizing lower-frequency ultrasound systems. Recommendations made for minimizing the measurement uncertainty include implementing a mechanical positioning system that has sufficient repeatability and precision, reconstructing the time-pressure waveform via deconvolution using the hydrophone frequency response, and correcting for hydrophone spatial averaging.

Hydrophone Measurements for Biomedical Ultrasound Applications: A Review.

This article presents basic principles of hydrophone measurements, including mechanisms of action for various hydrophone designs, sensitivity and directivity calibration procedures, practical considerations for performing measurements, signal processing methods to correct for both frequency-dependent sensitivity and spatial averaging across the hydrophone sensitive element, uncertainty in hydrophone measurements, special considerations for high-intensity therapeutic ultrasound, and advice for choosing an appropriate hydrophone for a particular measurement task. Recommendations are made for information to be included in hydrophone measurement reporting.

Effects of ultrasound and ultrasound contrast agent on vascular tissue.

BACKGROUND: Ultrasound (US) imaging can be enhanced using gas-filled microbubble contrast agents. Strong echo signals are induced at the tissue-gas interface following microbubble collapse. Applications include assessment of ventricular function and virtual histology. AIM: While ultrasound and US contrast agents are widely used, their impact on the physiological response of vascular tissue to vasoactive agents has not been investigated in detail. METHODS AND RESULTS: In the present study, rat dorsal aortas were treated with US via a clinical imaging transducer in the presence or absence of the US contrast agent, Optison. Aortas treated with both US and Optison were unable to contract in response to phenylephrine or to relax in the presence of acetylcholine. Histology of the arteries was unremarkable. When the treated aortas were stained for endothelial markers, a distinct loss of endothelium was observed. Importantly, terminal deoxynucleotidyl transferase mediated dUTP nick-end-labeling (TUNEL) staining of treated aortas demonstrated incipient apoptosis in the endothelium. CONCLUSIONS: Taken together, these ex vivo results suggest that the combination of US and Optison may alter arterial integrity and promote vascular injury; however, the in vivo interaction of Optison and ultrasound remains an open question.

Egg white as a blood coagulation surrogate.

Egg white, a protein-containing solution, is characterized as a blood coagulation surrogate for the acoustical and thermal evaluation of therapeutic ultrasound, especially high intensity focused ultrasound (HIFU) devices. Physical properties, including coagulation temperature, frequency dependent attenuation, sound speed, viscosity, and thermal properties, were measured as a function of temperature (20-95 degrees C). Thermal coagulation and attenuation (5-12 and 1 MHz) of cow blood, pig blood, and human blood also were assessed and compared with egg white. For a 30 s thermal exposure, both egg white and blood samples (3 mm thickness) started to denature at 65 degrees C and coagulate into an elastic gel at 85 degrees C. The attenuation of egg white was found to be similar to that of the blood samples, having values of 0.23f(1.09), 1.58f(0.61), and 2.7f(0.5) dB/cm at 20, 75, and 95 degrees C, respectively. This significant attenuation increase with temperature was determined to be caused mainly by bubble cavity formation. The other temperature-dependent parameters are also similar to the reported values for blood. These properties make egg white a potentially useful bench testing tool for the safety and efficacy evaluation of therapeutic ultrasound devices.

Frequency dependence of backscatter from thin, oblique, finite-length cylinders measured with a focused transducer-with applications in cancellous bone.

A model is presented for the echo from a thin, oblique, finite-length cylinder. The echo is calculated from the line integral of the transducer directivity pattern along the cylinder axis. The model was validated with broadband pulse-echo measurements from (1) a perpendicular (to the ultrasound beam) nylon wire as a function of lateral displacement from the beam center, (2) a tilted nylon wire as a function of the angle of inclination relative to the ultrasound beam, and (3) a quasi-parallel-nylon-wire phantom, which mimicked the scattering properties of cancellous bone. The transducer directivity pattern (as a function of position and frequency) was measured with a membrane hydrophone. The model predicts an approximately cubic frequency dependence of backscatter coefficient from the phantom, as has been observed experimentally in cancellous bone. The model also predicts the relationship between the cylinder length and the exponent of a power law fit to backscatter coefficient versus frequency, which is 4 for very short (compared to a wavelength) cylinders and asymptotically approaches 3 for very long cylinders.

Pressure Pulse Distortion by Needle and Fiber-Optic Hydrophones due to Nonuniform Sensitivity.

Needle and fiber-optic hydrophones have frequency-dependent sensitivity, which can result in substantial distortion of nonlinear or broadband pressure pulses. A rigid cylinder model for needle and fiber-optic hydrophones was used to predict this distortion. The model was compared with measurements of complex sensitivity for a fiber-optic hydrophone and three needle hydrophones with sensitive element sizes ( ) of 100, 200, 400, and . Theoretical and experimental sensitivities agreed to within 12 ± 3% [root-mean-square (RMS) normalized magnitude ratio] and 8° ± 3° (RMS phase difference) for the four hydrophones over the range from 1 to 10 MHz. The model predicts that distortions in peak positive pressure can exceed 20% when and spectral index (SI) >7% and can exceed 40% when and SI >14%, where is the wavelength of the fundamental component and SI is the fraction of power spectral density contained in harmonics. The model predicts that distortions in peak negative pressure can exceed 15% when . Measurements of pulse distortion using a 2.25 MHz source and needle hydrophones with , 400, and agreed with the model to within a few percent on the average for SI values up to 14%. This paper 1) identifies conditions for which needle and fiber-optic hydrophones produce substantial distortions in acoustic pressure pulse measurements and 2) offers a practical deconvolution method to suppress these distortions.

A closer look at ultrasonic attenuation and heating in a tissue-mimicking material.

A well-characterized ultrasound tissue-mimicking material (TMM) can be important in determining the acoustic output and temperature rise from high intensity therapeutic ultrasound (HITU) devices and also in validating computer simulation models. A HITU TMM previously developed and characterized in our laboratory has been used in our acoustic and temperature measurements as well as modeled in our HITU simulation program. A discrepancy between thermal measurement and simulation, though, led us to further investigate the TMM properties. We found that the 2-parameter analytic fit commonly used to represent the attenuation of the TMM in the computer modeling was not adequate over the entire frequency range of interest, 1 MHz to 8 MHz in this study, indicating that we and others may have not been characterizing TMMs, and possibly tissue, optimally. By comparing measurements and simulations, we found that a 3-parameter analytic fit for attenuation gave a more accurate value for attenuation at 1 MHz and 2 MHz, and using that fit the temperature rise measurements in the TMM that agreed more closely with the simulation results.

An ultrasonic time-delay spectrometry system employing digital processing.

Time-delay spectrometry (TDS) is a swept-frequency technique that has proven useful in several ultrasonic applications. Commercial TDS systems are available, but only in the audio frequency range. Several ultrasonic research TDS systems have been constructed, and they have been used effectively for substitution calibration of hydrophones and for measurement of attenuation and sound velocity in materials. Unfortunately these systems depend on features of commercial equipment no longer manufactured, so a new system has been designed using modern equipment and straightforward signal processing. This system requires a frequency source with a reasonably linear sweep of frequency versus time, audio frequency filters, a standard double-balanced mixer, a power splitter, a waveform digitizer capable of handling audio frequency signals, and a personal computer. An optional implementation that shifts the signal to a lower frequency for more convenient digitization and easier velocity measurements additionally requires an audio frequency oscillator and an audio-range analog multiplier. The processing steps are performed with standard signal processing software. To demonstrate the operation of the system, substitution calibration measurements of hydrophones as well as attenuation measurements on a tissue mimicking material were obtained and compared to a custom TDS system previously described by the authors. The data from these two TDS systems agree to within +/- 0.5 dB in the 1-10 MHz frequency range used. Higher frequency source transducers could be used to extend this range.

Variation of High-Intensity Therapeutic Ultrasound (HITU) Pressure Field Characterization: Effects of Hydrophone Choice, Nonlinearity, Spatial Averaging and Complex Deconvolution.

Reliable acoustic characterization is fundamental for patient safety and clinical efficacy during high-intensity therapeutic ultrasound (HITU) treatment. Technical challenges, such as measurement variation and signal analysis, still exist for HITU exposimetry using ultrasound hydrophones. In this work, four hydrophones were compared for pressure measurement: a robust needle hydrophone, a small polyvinylidene fluoride capsule hydrophone and two fiberoptic hydrophones. The focal waveform and beam distribution of a single-element HITU transducer (1.05 MHz and 3.3 MHz) were evaluated. Complex deconvolution between the hydrophone voltage signal and frequency-dependent complex sensitivity was performed to obtain pressure waveforms. Compressional pressure (p+), rarefactional pressure (p-) and focal beam distribution were compared up to 10.6/-6.0 MPa (p+/p-) (1.05 MHz) and 20.65/-7.20 MPa (3.3 MHz). The effects of spatial averaging, local non-linear distortion, complex deconvolution and hydrophone damage thresholds were investigated. This study showed a variation of no better than 10%-15% among hydrophones during HITU pressure characterization.

Quantification of Temperature Rise within the Lens of the Porcine Eye Caused by Ultrasound Insonation.

The soft tissue thermal index defined in the Output Display Standard is not applicable to eye exposures because of unique eye properties such as high ultrasound absorption in the lens and orbital fat. To address this potential safety issue, the U.S. Food and Drug Administration has recommended a maximum exposure level for ophthalmic exams of 50 mW/cm2 (derated spatial-peak temporal-average intensity, ISPTA.3) based on a model of ultrasound propagation in the eye. To gain a better understanding of actual temperature rise as a function of ISPTA.3, an ex vivo experimental study within the porcine lens was performed. Both temperature and acoustic pressure were measured simultaneously in the lens using a fiberoptic probe. At ISPTA.3 = 50 mW/cm2, the maximum and average temperature rises over 133 measurements were 0.23°C and 0.09°C, respectively. A 1.5°C temperature rise was not obtained until ISPTA.3 ≈ 435 mW/cm2. The data indicate that operating below the Food and Drug Administration guidance level should result in relatively low heating in ophthalmic exposures.

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.

Progress in medical ultrasound exposimetry.

Biomedical applications of ultrasound have experienced tremendous growth over the past 50 years. Early work in thermal therapy and surgery soon was followed by diagnostic imaging and Doppler. Because patient safety was an important issue from the beginning, the study of methods for measuring exposure levels, and their relationship to possible biological effects, paralleled the growth of the various therapeutic and diagnostic techniques. The diverse conditions of use have presented a range of exposure measurement challenges, and the sensors and techniques used to evaluate ultrasound fields have had to evolve as new or expanded clinical applications have emerged. In this paper some of the more notable of these developments are presented and discussed. Topics covered include devices and techniques, methods of calibration, progress in standardization, and current problem areas, including the effects of nonlinear propagation. Some early methods are described, but emphasis is given to more recent work applicable to present and future uses of ultrasound in medicine and biology.

Correction for frequency-dependent hydrophone response to nonlinear pressure waves using complex deconvolution and rarefactional filtering: application with fiber optic hydrophones.

Nonlinear acoustic signals contain significant energy at many harmonic frequencies. For many applications, the sensitivity (frequency response) of a hydrophone will not be uniform over such a broad spectrum. In a continuation of a previous investigation involving deconvolution methodology, deconvolution (implemented in the frequency domain as an inverse filter computed from frequency-dependent hydrophone sensitivity) was investigated for improvement of accuracy and precision of nonlinear acoustic output measurements. Timedelay spectrometry was used to measure complex sensitivities for 6 fiber-optic hydrophones. The hydrophones were then used to measure a pressure wave with rich harmonic content. Spectral asymmetry between compressional and rarefactional segments was exploited to design filters used in conjunction with deconvolution. Complex deconvolution reduced mean bias (for 6 fiber-optic hydrophones) from 163% to 24% for peak compressional pressure (p+), from 113% to 15% for peak rarefactional pressure (p-), and from 126% to 29% for pulse intensity integral (PII). Complex deconvolution reduced mean coefficient of variation (COV) (for 6 fiber optic hydrophones) from 18% to 11% (p+), 53% to 11% (p-), and 20% to 16% (PII). Deconvolution based on sensitivity magnitude or the minimum phase model also resulted in significant reductions in mean bias and COV of acoustic output parameters but was less effective than direct complex deconvolution for p+ and p-. Therefore, deconvolution with appropriate filtering facilitates reliable nonlinear acoustic output measurements using hydrophones with frequency-dependent sensitivity.

Models and regulatory considerations for transient temperature rise during diagnostic ultrasound pulses.

A new diagnostic ultrasound (US) technique, sometimes called radiation force imaging, produces and detects motion in solid tissue or acoustic streaming in fluids via a high-intensity beam. Current models for estimating temperature rise during US exposure calculate the steady-state rise, using time-averaged acoustic output, as the worst case for safety consideration. Although valid for very short pulses, this analysis might not correspond to a worst-case scenario for the longer pulses or pulse bursts, up to hundreds of ms, used by this newer method. Models are presented to calculate the transient temperature rise from these pulse bursts for both the bone at focus and soft tissue situation. It is shown, based on accepted time-temperature dose criteria, that, for the bone at focus case and pulse lengths and intensities utilized by these methods, temperature may increase to levels that raise safety concerns. Also, regulatory aspects of this modality are analyzed in terms of the current FDA acoustic output limits for diagnostic US devices.

IGBT-based kilovoltage pulsers for ultrasound measurement applications.

Two high-voltage pulser designs are presented that offer advantages in some ultrasound measurement applications, such as driving thick ultrasonic source transducers used for broadband measurements of attenuation or hydrophone frequency response and directivity. The pulsers use integrated gate bipolar transistors (IGBTs) as the switching devices, and in one design an output voltage pulse is produced that has a peak amplitude nearly twice that of the supply voltage. The pulsers are inexpensive and relatively easy to construct. The power supply need only provide the average current to charge the capacitors, as opposed to the much higher peak pulse current. With a 1200 V supply and a pulse repetition frequency of 200 Hz, the nondoubling and doubling pulsers provided peak voltages of greater than 1100 V and 2200 V, respectively, into loads ranging from 50 omega to 500 omega. For a 50 omega load, slewing rates of 38 V/ns and 23 V/ns were measured for the nondoubling and doubling pulsers, respectively. For a 500 omega load these values were 56 V/ns and 36 V/ns.

Interlaboratory evaluation of hydrophone sensitivity calibration from 0.1 to 2 MHz via time delay spectrometry.

Knowing the low-frequency response of hydrophones, down to 100 kHz at least, is important for accurate biomedical ultrasound measurements. However, current international standards do not extend below 500 kHz. Furthermore, commercial hydrophone sources typically do not supply sensitivity data below 1-2 MHz. Therefore, to help identify and validate practical calibration methods below 2 MHz, the authors have extended their previous individual efforts in an interlaboratory evaluation of sensitivity calibration using the swept-frequency technique, time delay spectrometry (TDS). Calibrations were performed for needle and membrane PVDF hydrophones using each laboratory's TDS system. Each site employed the same purpose-built broadband source transducers, comprising both plano-concave and biconcave 1-3 piezocomposite elements 4 cm in diameter, with maximum and minimum thicknesses of approximately 1.5 and 0.1 cm. Agreement between laboratories was within the estimated measurement precision of +/-0.6 dB. The results demonstrated that a TDS system employing such transducers constitutes a viable method for hydrophone calibrations in this frequency range.