Statement on Biological Effects of Ultrasound in Vivo

Investigations involving laboratory mammals have contributed significantly to our understanding of ultrasonically induced biological effects in humans and the mechanisms that are most likely responsible.  Adverse biological effects have been observed in some mammalian studies under conditions that may occur with diagnostic scanners. The following statement summarizes observations relative to diagnostic ultrasound parameters and indices.

Ultrasound systems may induce biological effects with likelihoods that depend on parameters of the ultrasound source and the tissue exposed. The relevant ultrasound source factors may include acoustic intensity, output power, acoustic source dimensions, beam focusing properties, frequency, peak rarefactional pressure, scan rate, pulse repetition frequency, pulse duration, transducer self-heating, dwell time, and exposure duration. The tissue factors may include type of tissue exposed, the presence of gas bodies, intervening attenuation, tissue absorption, speed of sound, nonlinearity parameter, perfusion, thermal conductivity, thermal diffusivity, anatomic structure, cellular proliferation rate, and potential for regeneration. Age and stage of development are important factors when considering fetal and neonatal safety.

This statement is organized into three parts:

Biological Effects in Tissues Without Naturally Occurring Gas Bodies or Contrast Agents: This section describes nonthermal biological effects due to the oscillation of gas bodies that are formed as a result of ultrasound exposure. The term “gas bubble” is used to describe a gas body being surrounded by a fluid, tissue, or both and that it is small compared to the acoustic wavelength.

Biological Effects in Tissues with Naturally Occurring Gas Bodies: This section describes nonthermal biological effects due to the interaction of ultrasound with naturally occurring gas bodies, such as may be found in the postnatal lung or bowels.

Biological Effects of Heat: This section describes potential thermal biological effects due to tissue absorption of ultrasound. 

Biological Effects in Tissues Without Naturally Occurring Gas Bodies or Contrast Agents

Biologically significant adverse nonthermal effects have been observed in tissues not known to contain stabilized gas bodies (as opposed to lungs and intestines, which are discussed in the next section) when exposed to pulsed ultrasound. This section concerns the conditions under which microscopic gas bodies, ie, bubbles, may be formed and driven by an ultrasound beam into oscillations that could result in tissue damage.  The mechanical index (MI) has been formulated to assist users in evaluating the likelihood of adverse nonthermal biological effects for diagnostically relevant exposures.  The MI is equal to the peak rarefactional pressure (in megapascals) measured in water (derated assuming tissue attenuation of 0.3 dB/cm/MHz) divided by the square root of the ultrasonic center frequency (in megahertz).¹

1. Most scanners display MI on screen according to the Output Display Standard (ODS).  Most scanners follow the Food and Drug Administration (FDA) guidance² on output, which recommends that MI not exceed 1.9.  No adverse nonthermal bioeffects have been observed in tissues without gas bodies for MI values below 1.9.  AIUM recommends that MI not exceed 1.9.

2. Experimental values for the inertial cavitation threshold in vivo lie at or above approximately 3.6 MPa for frequencies of 0.5 MHz or greater. Such a level would not be attainable if MI does not exceed 1.9. ^3,4

3. The lowest empirical thresholds for induction of adverse nonthermal effects in tissues correspond to MI > 4 for extravasation of blood cells in mouse kidneys, and MI > 5 for hind limb paralysis in the mouse neonate.⁵

4. For mammalian biological effects research relating to diagnostic ultrasound, including experiments with pulsed ultrasound,^6-8 no adverse nonthermal bioeffects have been observed for MI values less than the FDA maximum recommended level for diagnostic ultrasound, MI = 1.9, in tissues without gas bodies.

Biological Effects in Tissues with Naturally Occurring Gas Bodies

Biologically significant adverse nonthermal effects have been identified in organs containing stable bodies of gas for diagnostically relevant exposure conditions. Gas bodies occur naturally in postnatal lungs and in the folds of the intestinal mucosa. This section concerns naturally occurring gas bodies encountered in pulmonary and abdominal ultrasound, whereas a separate statement deals with the use of gas body contrast agents as would be used for contrast-enhanced diagnostic ultrasound.  (see AIUM “Statement on Biological Effects in Tissues with Ultrasound Contrast Agents").

1.  Currently available diagnostic ultrasound devices have been shown to produce capillary hemorrhage in the lungs^9-10 and intestines⁵ of some mammals under certain experimental conditions. 

2. The minimum threshold value of the MI for pulmonary capillary hemorrhage in laboratory mammals is approximately 0.4.¹¹ The corresponding threshold for intestines is 1.4.  No adverse nonthermal effects have been observed in these organs below these levels.  For pulmonary and intestinal imaging, the ALARA (As Low As Reasonably Achievable) principle should be practiced.

3.  The mechanism for pulmonary capillary hemorrhage by ultrasound is presently uncertain.¹²

4. In experimental mammalian models of ultrasound, induced pulmonary hemorrhage was shown by the presence of B-Lines (comet tails artifacts).⁹

5. The translation of laboratory bioeffects findings to human clinical conditions is problematic, but the risk to human patients should be less than that for laboratory animal studies due to differences in body size and biophysical conditions.  The health implications of these bioeffects observations for humans, should they occur during thoracic or abdominal ultrasound examinations, are yet to be determined.

Biological Effects of Heat

Diagnostic ultrasound scanners can produce significant thermal effects under certain conditions. This section concerns the conditions under which significant thermal effects can occur when using diagnostic ultrasound parameters.

1. An excessive temperature increase can produce adverse effects in mammals. Temperature increases of several degrees Celsius above the normal core range can occur naturally (i.e., even in the absence of ultrasound). The probability of an adverse biological effect increases with both the magnitude and the duration of the temperature rise. 

2. Calculations are used to obtain safety indices for clinical exposures in which direct temperature measurements are not feasible.  Experimental evidence shows that thermal index (TI) resulting from ultrasound exposure is generally capable of predicting measured values of maximum temperature increase (ΔT_max in ºC) within a factor of 2.¹³ (For instance, a TI value of 2 could correspond to a ΔT_max between 1 and 4ºC.)  Temperature increases also depend on dwell time.  These thermal indices provide a real-time display of the relative probability that a diagnostic system could induce thermal injury in the exposed subject. Under most clinically relevant conditions, the soft tissue thermal index (TIS) either overestimates or closely approximates the maximum temperature increase (ΔT_max).  However, in some applications, such as fetal examinations in which the ultrasound beam passes through a layer of relatively low attenuating liquid (e.g.,urine or amniotic fluid) the TI can underestimate ΔT_max by up to a factor of 2.^13,14

3. Maximum combinations of temperature rise and exposure duration without adverse effects based on empirical evidence^14-16 are shown in Table 1.  For guidance on limiting TI values in clinical applications, see AIUM official Statement on Recommended Maximum Scanning Times for Displayed Thermal Index (TI) . In that statement, recommended TI values are lower than ΔT values because a safety margin is included. 

Table 1.  Maximum combinations of temperature rise and exposure duration without adverse effects.

Values (except postnatal case for 1.5ºC) are derived from empirical relations ΔT = A – (log₁₀ t)/B, or, equivalently, t = 10.0^[B*(A – ΔT)], where ΔT is temperature rise (ºC), t is time (minutes).  For fetal applications, A = 4.5ºC and B = 0.6 ^16,17.  For postnatal applications, A = 6ºC (ΔT <9.6ºC) or 9ºC (ΔT>9.6ºC ) and B = 0.6 (ΔT <6ºC) or 0.3 (ΔT >6ºC)).^15-17

4. In general, adult tissues are more tolerant of temperature increases than fetal and neonatal tissues. Therefore, higher temperatures and/or longer exposure durations would be required for thermal damage.  General considerations applicable to fetal and postnatal subjects are as follows:

a. A diagnostic exposure that produces a maximum in situ temperature rise of no more than 1.5°C above normal physiological levels (37°C) may be used clinically without reservation on thermal grounds.¹⁸

b.  In general, temperature elevations become progressively greater from B-mode to color Doppler to M-mode to spectral Doppler / Acoustic Radiation Force Impulse (ARFI) applications due to differences in the temporal average ultrasound intensity.

c. Transducer self-heating can be a significant component of the temperature rise of tissues close to the transducer. This may be of significance in transvaginal scanning, but no data for the fetal temperature rise are available. 

5. Although less data are available for fetal tissues than for adult tissues, the following conclusions are justified^{16, 18, 19}:

a.  Current FDA-cleared ultrasound scanners may be capable of increasing the temperature of the conceptus by more than 1.5ºC.

b.  For identical exposure conditions, the temperature rise near bone is significantly greater than in soft tissues, and it increases with ossification development throughout gestation. For this reason, conditions in which an acoustic beam impinges on ossifying fetal bone deserve special attention due to its proximity to other developing tissues.  For obstetric exams, monitoring the TIS is recommended up to 10 weeks from the last menstrual period and TIB (TI with bone near focus) thereafter.

c.  Although an adverse fetal outcome is possible at any time during gestation, most severe and detectable effects of thermal exposure in mammals have been observed during the period of organogenesis. For this reason, exposures during the first trimester should be restricted to the lowest outputs and dwell times consistent with the ALARA principle to obtain the necessary diagnostic information.  This is particularly relevant for spectral Doppler exposure.

d. Ultrasound exposures that elevate fetal temperature by 4°C above normal for 5 minutes or more have the potential to induce severe developmental defects. Thermally induced congenital anomalies have been observed in a large variety of animal species. In current clinical practice, using commercially available equipment, it is unlikely that such thermal exposure would occur at a specific fetal anatomic site provided that the thermal index (TI) is at or below 2.5 and the dwell time on that site does not exceed 4 minutes.  There is no time limit for scans in which TI always remains below 0.7.

References

1.  International Electrotechnical Commission. IEC 60601-2-37.  Medical Electrical Equipment, Part 2-37: Particular Requirements for the Basic Safety and Essential Performance of Ultrasonic Medical Diagnostic and Monitoring Equipment. 2nd ed. Geneva, Switzerland: International Electrotechnical Commission; 2007.

2.  US Food and Drug Administration.  Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers . Rockville, MD: US Food and Drug Administration, Center for Devices and Radiological Health;  2019.

3.  Church CC, Nightingale K, Labuda C. A theoretical study of inertial cavitation from acoustic radiation force impulse (ARFI) imaging and implications for the mechanical index.  Ultrasound Med Biol 2015; 41:472–485.

4 Nightingale, K et al. Conditionally increased acoustic pressures in nonfetal diagnostic ultrasound examinations without contrast agents: a preliminary assessment. J Ultrasound Med. 2015; 34, doi:10.7863/ultra.34.7.15.13.0001

5.  Church CC, Carstensen EL, Nyborg WL, Carson PL, Frizzell LA, Bailey MR. The risk of exposure to diagnostic ultrasound in postnatal subjects: nonthermal mechanisms.  J Ultrasound Med  2008; 27:565–592.

6.  Carstensen EL, Gracewski S, Dalecki D. The search for cavitation in vivo.  Ultrasound Med Biol 2000; 26:1377–1385 .

7.  American Institute of Ultrasound in Medicine. Nonthermal bioeffects in the absence of well-defined gas bodies.  J Ultrasound Med  2000; 19:109–119, 154–168.

8.  Miller DL, Averkiou MA, Brayman AA, et al. Bioeffects considerations for diagnostic ultrasound contrast agents.  J Ultrasound Med  2008; 27:611–632.

9.  Miller DL. Induction of pulmonary hemorrhage in rats during diagnostic ultrasound. Ultrasound Med Biol 2012; 38:1476–1482.

10.  Miller DL, Dou C, Raghavendran K. Anesthetic techniques influence the induction of pulmonary capillary hemorrhage during diagnostic ultrasound scanning in rats. J Ultrasound Med 2015; 34:289–297.

11. Miller DL, Abo A, Abramowicz JS, Bigelow TA, Dalecki D, Dickman E, Donlon J, Harris G, Nomura J. Diagnostic Ultrasound Safety Review for Point-of-Care Ultrasound Practitioners. J Ultrasound Med, 2020;39:1069–1084.

12. Miller DL. Mechanisms for induction of pulmonary capillary hemorrhage by diagnostic ultrasound: review and consideration of acoustical radiation surface pressure. Ultrasound Med Biol. 2016;42:2743-2757.

13. Shaw A, Pay NM, Preston RC. Assessment of the Likely Thermal Index Values for Pulsed Doppler Ultrasonic Equipment—Stages II and III:  Experimental Assessment of Scanner/Transducer Combinations. NPL Report CMAM 12. Teddington, England: National Physical Laboratory; 1998.

14. Jago JR, Henderson J, Whittingham TA, Mitchell G. A comparison of AIUM/NEMA thermal indices with calculated temperature rises for a simple third trimester pregnancy tissue model.  Ultrasound Med Biol 1999; 25:623–628.

15. O’Brien WD Jr, Deng CX, Harris GR, et al. The risk of exposure to diagnostic ultrasound in postnatal subjects: thermal effects.  J Ultrasound Med 2008; 27:517–535.

16. Miller MW, Nyborg WL, Dewey WC, Edwards MJ, Abramowicz JS, Brayman AA.  Hyperthermic teratogenicity, thermal dose and diagnostic ultrasound during pregnancy:  Implications of new standards on tissue heating.  Int J Hyperthermial 2002; 18:361-384.

17. Harris GR, Church CC, Dalecki D, Ziskin MC, Bagley JE, Comparison of thermal safety practice guidelines for diagnostic ultrasound exposures.  Ultrasound in Med. & Biol., 2016; 42:345-357

18. WFUMB Symposium on Safety of Ultrasound in Medicine Recommendations on the Safe Use of Ultrasound. Ultrasound in Med. & Biol., Vol. 24, Supplement 1, pp. xv–xvi, 1998

19. Church CC, Barnett SB. Ultrasound-induced heating and its biological consequences. In: ter Haar G (ed).  The Safe Use of Ultrasound in Medical Diagnosis. London, England: British Institute of Radiology; 2012:46–68.