Comparison of Thermal Safety Practice Guidelines for Diagnostic Ultrasound Exposures

Ultrasound in Med. & Biol., Vol. 42, No. 2, pp. 345–357, 2016 Copyright Ó 2016 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter

http://dx.doi.org/10.1016/j.ultrasmedbio.2015.09.016

Review

d

COMPARISON OF THERMAL SAFETY PRACTICE GUIDELINES FOR DIAGNOSTIC ULTRASOUND EXPOSURES GERALD R. HARRIS,* CHARLES C. CHURCH,y DIANE DALECKI,z MARVIN C. ZISKIN,x and JENNIFER E. BAGLEY{ * Center for Devices and Radiological Health, U.S. Food and Drug Administration (Retired), Silver Spring, Maryland, USA; National Center for Physical Acoustics, University of Mississippi, University, Mississippi, USA; z Department of Biomedical Engineering, University of Rochester, Rochester, New York, USA; x Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and { Department of Medical Imaging and Radiation Sciences, University of Oklahoma Health Sciences Center, Tulsa, Oklahoma, USA y

(Received 13 January 2015; revised 8 September 2015; in final form 16 September 2015)

Abstract—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. (E-mail: gerald.harris13@ gmail.com) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Bio-effects, Fetal, Output display standard, Thermal index, Ultrasound.

AIUM (2008a), British Medical Ultrasound Society (BMUS) (2010), Health Canada (2001), Miller and Ziskin (1989) and Nelson et al. (2009). The second goal is to propose sets of guidelines for clinical examinations in terms of combinations of thermal index (TI) and exposure time that minimize the risk of producing an adverse thermal effect under any scanning conditions. It is noted that some of these safety guidelines are acknowledged by other organizations. For example, the World Federation for Ultrasound in Medicine and Biology (WFUMB), with affiliated organizations representing Europe, Asia, North and Latin America, Australia, New Zealand and African and Mediterranean countries, has a Clinical Safety Statement for Diagnostic Ultrasound (WFUMB 2012) that references the BMUS guidelines. First, a brief review of the thermal index is given. Then, because all of the guidelines are based on the thermal dose concept (Sapareto and Dewey 1984), a brief summary of thermal dose is presented. Next the various guidelines are described under two categories, prenatal/ neonatal and postnatal. They are compared using plots

INTRODUCTION Over the years, a number of safety statements and recommendations dealing with the potential for ultrasoundinduced thermal bio-effects during a diagnostic examination have been published. Initially these practice guidelines took the form of recommending safety boundaries that defined maximum scanning or exposure times for a given temperature or temperature rise. Then, the advent of the output display standard (ODS) (American Institute of Ultrasound in Medicine [AIUM] 1993, 2004, 2014; International Electrotechnical Commission [IEC] 2007) made implementation more practical and convenient for the clinical user. However, differences among the various guidelines have led to uncertainty as to how they should be applied. Therefore, the first goal of this article is to review and compare guidelines that have been published by five sources: Address correspondence to: Gerald R. Harris, 132 South Van Buren Street, Rockville, MD 20850-2801, USA. E-mail: gerald. [email protected] 345

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of temperature rise or TI versus exposure time. Finally, based on an analysis of these guidelines, some simplified recommendations are made. THERMAL INDEX The thermal index (TI) was created to provide sonographers and physicians with a relatively simple guide to know how any change in scanner settings affects the risk of an adverse bio-effect of a thermal mechanism. There are currently three forms of the TI, one for soft tissue (TIS) and two for bone (bone thermal index [TIB] and cranial thermal index [TIC]). For examinations that expose only soft tissue, the TIS should be selected. When bone is in the beam, the TIB should be displayed unless the bone is close to the transducer, in which case the TIC would be the relevant bone index. For example, in early pregnancy, when no significant bone is present in the fetus, the TIS should be used; later in pregnancy (e.g., more than 10 wk after the last menstrual period), the TIB should be used. However, for a neonatal cephalic examination, the TIC is the relevant index. The TI is a unitless quantity related to temperature rise through its definition as the ‘‘ratio of attenuated acoustic power at a specified point to the attenuated acoustic power required to raise the temperature at that point in a specific tissue model by 1 C’’ (IEC 2007). For practical reasons, the specific tissue models used for the thermal indexes were simplified and based on average conditions (Abbott 1999), so the TI should not be interpreted as representing an actual temperature rise in degrees Centigrade in a given examination; however, for an individual transducer/scanner combination, it is useful as a relative indication of the maximum temperature rise in scanned and unscanned fields (AIUM 2008b). This difference between the TI and the actual tissue temperature rise has led developers of practice guidelines to introduce safety factors when making recommendations about TI settings, as will be described subsequently.

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Here, CT 5 1 C, a constant to render the exponent dimensionless, R 5 4 for T(t) # 43 C and R 5 2 for T(t) . 43 C (Sapareto and Dewey 1984). This expression defines an ‘‘iso-effect relationship’’ between two different thermal exposure conditions by asserting that if a tissue is exposed to time-varying temperature T(t) over time t, then the bio-effect would be the same as if the tissue were maintained at a reference temperature of 43 C for time t43. This quantity is called ‘‘thermally equivalent time’’ in an IEC document (IEC 2013). The thermal dose t43 is sometimes symbolized by cumulative equivalent minutes (CEM43). If T(t) is measured at n discrete time intervals represented by Dti, discretization of eqn (1) results in the summation t43 5

n X

 CÞ=C T

RðTi 243

Dti

(2)

i51

where Ti is the average temperature over interval Dti. Further, if T(t) is a constant, T, then eqn (1) becomes  CÞ=C

t43 5 t RðT243

T

(3)

Equation (3) indicates that if an effect occurs at temperature T (in  C) in heating time t, then it would occur at 43 C in time t43. All of the thermal safety guidelines discussed herein follow from eqn (3). PRENATAL AND NEONATAL THERMAL SAFETY PRACTICE GUIDELINES Miller and Ziskin analysis of thermally induced biological effects on the fetus Figure 1 is a plot from Miller and Ziskin (1989), which also has been reproduced in AIUM (1993), National Council on Radiation Protection and Measurements ([NCRP] 1992) and NCRP (2002). This plot

THERMAL DOSE Temperature alone, be it in the form of an absolute temperature, temperature rise or thermal index, is insufficient for evaluating the risk of a thermal bio-effect for two reasons: the risk of thermal injury increases exponentially rather than linearly with temperature, and it also increases with exposure duration. Thermal biology studies have led to the following quantification of a thermal dose concept that expresses the exponential and temporal dependencies: ðt  (1) t43 5 R½TðtÞ243 C=CT dt 0

Fig. 1. Reported teratologic effects of hyperthermia in animals. Data indicate the temperature of the medium (air or water) to which the maternal animals were exposed as a function of the duration of their exposure to that medium. From Miller and Ziskin (1989).

Comparison of thermal safety practice guidelines d G. R. HARRIS et al.

contains a summary of reported teratologic effects of hyperthermia in animals. The equation for the dashed  boundary line is t=tc 5 4ð43 C2TÞ=CT , where t is the duration of exposure in minutes of the maternal animal to the elevated temperature T of the surrounding environment, either heated air or heated water; tc 5 1 min, a constant to render the quotient on the left-hand side dimensionless; and T is in degrees Centigrade. Although this equation has the same form as a t43 of 1 min (see eqn 3), the data in Figure 1 are not thermal doses because they are based on the temperature of the environment rather than an animal’s core temperature; that is, they are not based on the temperature of the fetal tissue. The AIUM (1993) said that ‘‘this boundary could serve as a guide for determining whether or not an adverse biological effect due to hyperthermia would be likely. Combinations of temperature elevation and exposure durations falling below this boundary would be considered unlikely to produce any harm; exposure conditions falling above this boundary would have a significant possibility of damage.’’ The NCRP (1992) stated that ‘‘an ultrasound examination need not be withheld because of concern for thermally mediated adverse effects if the duration of the exposure (t, in min) and the maximum anticipated temperature (T, in  C) satisfy the inequality t , 4(43–T).’’ (Note that the inequality in this quotation is formally incorrect with respect to dimensions and should be modified to contain a unitless exponent, as is done elsewhere in this article.) With T 5 37 C 1 DT (i.e., DT is the temperature rise above a baseline temperature of 37 C), eqn (3) with t43 5 1 min becomes t  5 4ð6 C2DTÞ=CT tc

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following intrauterine hyperthermia [Webster and Edwards 1984]) ii. ‘‘water immersion body heating of rats yielded the development of encephalocoeles in the rat fetuses in as little as 1 minute at a temperature elevation of 5 C above normal physiological temperature’’ (based on Germain et al. 1985). The Health Canada guidelines cited a WFUMB report for both of these findings (WFUMB 1998). These two temperature–time data points are represented as red squares on a redrawing of the Miller and Ziskin (1989) boundary line plot in Figure 2. Note that the Miller and Ziskin (1989) boundary, illustrated in blue for times .1 min as in Figure 1, is now expressed as a temperature rise, DT, relative to 37 C. The points lie below the line because the former are thermal doses, whereas the latter is based on thermal exposures; thermal doses will always be less than the exposures required to produce them. That is, a thermal dose based on the actual in situ temperature profile will always be less than one based on the external applied temperature because of the thermal inertia of the tissue (see Miller et al. 2002). The red line in Figure 2 beginning at t 5 1 min is the boundary recommended by Health Canada (2001). The equations corresponding to eqns (4) and (5) for this line are t  5 4ð5 C2DTÞ=CT tc

(6)

and DT,5 C2

CT t log 0:6 10 tc

(7)

(4)

Equation (4) can be rewritten to express a ‘‘no-effects’’ temperature rise of DT,6 C2

CT t log10 tc 0:6

(5)

Health Canada guideline for prenatal temperature–time safety boundary In Section 4.1.2 of Health Canada’s safe use guideline (Health Canada 2001), a more conservative boundary than t43 5 1 min was proposed based on the following two statements: i. ‘‘a diagnostic ultrasound exposure that elevates embryonic and fetal in situ temperature above 41 C (4 C above normal temperature) for 5 minutes or more should be considered potentially hazardous;’’ (based on exencephaly in mice

Fig. 2. DT- or TI-versus-exposure time safety guideline boundaries for prenatal scanning. Selected individual time–temperature rise bio-effects points also are plotted (red and green squares and purple triangles). Recommended exposure time– temperature rise (or TI) combinations lie in the regions below and to the left of the boundaries. The equations for the three  labeled  lines are (a) t=tc 5 4ð6 C2DTÞ=CT , (b) t=tc 5 4ð5 C2DTÞ=CT and (c) t=tc 5 4ð4:5 C2DTÞ=CT . DT 5 temperature rise; TI 5 thermal index.

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From eqn (3), this boundary represents a t43 of 0.25 min. A break point in the Health Canada (2001) boundary occurs at (128 min, 1.5 C). The boundary remains at 1.5 C beyond this time, consistent with the WFUMB statement, ‘‘A diagnostic ultrasound 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’’ (WFUMB 1998:xv). AIUM statement on mammalian in vivo ultrasonic biological effects According to part 1.b of the AIUM (2008a) mammalian bio-effects statement, ‘‘For fetal exposures, no effects have been reported for a temperature increase above the normal physiologic temperature, DT, when DT , 4.5 2 (log10t)/0.6, where t is exposure time ranging from 1 to 250 min, including off time for pulsed exposure (Miller et al. 2002).’’ For dimensional correctness, this inequality should be DT,4:5 C2

CT t log 0:6 10 tc

The thermal dose equation similar to eqns (4) and (6) for this inequality is t  5 4ð4:5 C2DTÞ=CT tc

(8)

Equation (8) is plotted as the green line in Figure 2 and, again from eqn (3), represents a t43 of 0.125 min. Note that in comparing eqns (4), (6) and (8) with eqn   (3), the value for t43 is tc 4ðB C26 CÞ=CT , where B is 6, 5 and 4.5, respectively. Note, too, that eqn (4) was derived for thermal exposures, whereas eqns (6) and (8) were derived from data for thermal doses. Regarding the rationale for using ‘‘4.5,’’ the article by Miller et al. (2002), who are cited in this AIUM statement, contains a reanalysis of existing data, in which a more rigorous calculation of the thermal dose is performed using eqn (2). Their analysis also concentrates on temperature rise above normal rather than absolute temperature because of differences in normal physiologic temperature for the various animals used in the studies examined. The article states that ‘‘there is a possibility that a teratogenic effect will not occur until a threshold dose of t4.0 of 5 min or more is achieved’’ (Miller et al. 2002). (Here the symbol t4.0 refers to a thermal isodose effect occurring at a temperature rise of 4 C above normal.) This (5 min, 4 C) data point is the same as the rightmost red square in Figure 2 (from Webster and Edwards [1984], and also cited in WFUMB [1998] and Abramowicz et al. [2008]). It lies above the AIUM

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(2008a) line (green), but it is also above the Health Canada (2001) line (red), so this statement from Miller et al. (2002) would seem to support the red line and eqn (6). However, five individual data points analyzed in Miller et al. (2002) also are plotted in Figure 2 (purple triangles). For four of the five, the green ‘‘4.5’’ line is a reasonably conservative boundary, supporting the AIUM (2008a) statement. As explained in the next paragraph, the fifth point at (13 min, 1.8 C) seems questionable; this point is from Kimmel et al. (1993), about which Church and Barnett (2012) say, ‘‘While the data collected by Kimmel et al. (1993) include seemingly minor anomalies and also those with high natural background rates, prudence suggests that the ‘‘safe’’ line be drawn at t3.5 5 1 min in Figure 4.3, as shown by the dotted line; this is equivalent to t4.0 5 0.5 min.’’ The boundary line suggested in Church and Barnett  (2012), t=tc 5 4ð3:5 C2DTÞ=CT , is not drawn in Figure 2, but it would contain the point (1 min, 3.5 C) and fall just below (13 min, 1.8 C). The AIUM (2008a) statement appears to have given less weight to the Kimmel et al. (1993) finding at (13 min, 1.8 C). During the preparation of this report, considerable effort was made to evaluate the calculations behind this data point. On the basis of the original publication, the only apparent way to obtain this datum was to make use of an exposure condition for which the authors did not claim a statistically significant effect on fetal outcome. Therefore, the validity of this datum is questionable, and it seems reasonable to discount it in defining a thermal safety boundary. Further support for eqn (8) and the AIUM (2008a) statement comes from NCRP (2002), which says ‘‘A risk–benefit decision is especially important if the anticipated temperature rise of an embryo or fetus exceeds 3 C for a duration of 10 min.’’ This (10 min, 3 C) point is the single green square in Figure 2. It is based on an analysis of 34 experiments in which core temperatures of pregnant animals were measured versus time in a heated environment (see the discussion in NCRP [2002]). Part 1.a of the AIUM (2008a) statement does not mention temperature rise, but it does include the thermal index, saying, ‘‘No effects have been observed for an unfocused beam having free-field spatial-peak temporal-average (SPTA) intensities* below 100 mW/cm2, or a focused** beam having intensities below 1 W/cm2, or thermal index values of less than 2. *Free-field SPTA intensity for continuous wave and pulsed exposures. **Quarter-power (26-dB) beam width smaller than 4 wavelengths or 4 mm, whichever is less at the exposure frequency.’’

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The origin of this dates back to 1976 when the AIUM Bioeffects Committee first introduced the 100 mW/cm2 level (AIUM 1993; Nyborg 2003). Various updates have occurred over the years, and the TI , 2 addition assumed that TI represents a reasonable upper bound for temperature rise, and that for temperature increases up to 2 C above normal, no significant, adverse biological effects have been observed (see AIUM [2009] Statement on Heat). Both of these assumptions are considered in the Discussion and Recommendations section of this report. The TI 5 2 boundary is not illustrated in Figure 2, but it would intersect the AIUM (green) line at t 5 32 min. British Medical Ultrasound Society The BMUS (2010) also has published safe use guidelines that contain TI range-versus-maximum exposure time charts for four categories: (i) obstetric (including gynecologic examinations when pregnancy is possible); (ii) neonatal transcranial and spinal; (iii) adult trans-cranial; (iv) general abdominal, peripheral vascular and other scanning (except the eye). For categories (i) and (ii), the BMUS guidelines come from information in Table 1. The neonatal brain and spine were included with prenatal because of the still rapidly developing central nervous system in the neonate. Columns 1 and 2 in Table 1 are based on WFUMB (1998) and eqn (6), similar to the Health Canada (2001) analysis. However, the BMUS (2010) guidelines state that ‘‘The 64 and 256 minute maximum exposure times have been reduced to 30 and 60 minutes respectively as a safety precaution to reflect the present lack of knowledge about possible subtle bio-effects associated with prolonged moderate temperature elevation.’’ Also, the value of 16 min that would be calculated from eqn (6) was changed to 15 min. Regarding column 3 in Table 1, based on studies by Shaw et al. (1998) and Jago et al. (1999), the BMUS (2010) guidelines state that ‘‘TI values can underestimate the temperature elevation by a factor of up to two.’’ This

Table 1. Basis for British Medical Ultrasound Society maximum exposure time-versus-TI guidelines for both obstetric and neonatal transcranial and spinal examinations DT ( C)

Maximum time (min)

TI 5 0.5*DT/CT

TI range

Time (min)

5 4 3 2 1

1 4 16 / 15 64 / 30 256 / 60

2.5 2 1.5 1 0.5

2.5–3.0 2.0–2.5 1.5–2.0 1.0–1.5 0.7–1.0

,1 ,4 ,15 ,30 ,60

TI 5 thermal index.

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underestimation can occur, for example, when the ultrasound beam passes through a layer of relatively unattenuating liquid, such as urine or amniotic fluid, before focusing on fetal bone. Therefore, when formulating the TI range versus recommended exposure times in columns 4 and 5, the TI values in column 3 were used, with the TI range values in column 4 being relaxed by 0.5; for example, the first recommended time and TI range combination is ,1 min, 2.5–3.0. For 30 , t , 60 min exposure times, TI 5 0.7 was used instead of 0.5 to be consistent with the WFUMB (1998) statement quoted above that a temperature rise of no more than 1.5 C above normal (37 C) may be used clinically with no reservation on thermal grounds. The pink diamonds plotted in Figure 2, with connecting lines, are the BMUS (2010) guidelines from Table 1 for BMUS categories 1 and 2. The horizontal segments of the line connect the higher value in one TI range to the lower value in the next higher TI range, for example, the line from (4 min, 2.5) to (1 min, 2.5). For these embryonic, fetal or neonatal central nervous system scans, TI settings .3 are not recommended, resulting in the horizontal line for t , 1 min; for TI settings ,0.7, no time restrictions are specified for these two categories, resulting in the horizontal line for t . 60 min. As to which TI to display and monitor during pregnancy, the BMUS recommends the TIS up to week 10 after the last menstrual period, and the TIB thereafter, based on the fact that ossification begins during weeks 10–14 post–last menstrual period, first in the spine (weeks 10–11) and then in the skull and long bones (weeks 13–14). AIUM (2013) has a similar guideline. Choosing an exact gestational age is somewhat arbitrary because there is a continuum in the degree of bone mineralization, with the absorption steadily increasing from the soft tissue to the ossified bone value. However, the 10th week is a reasonable transition time to begin monitoring the TIB instead of the TIS. Although there will be many instances when bone is not in the focus, the BMUS (2010) guidelines state that using the TIB ‘‘avoids the complication of constantly switching attention between TIS and TIB according to whether or not bone is being insonated, and introduces a safety factor since TIB values are always greater than or equal to TIS values.’’ Nelson et al. (2009) As part of the Journal of Ultrasound in Medicine’s Reverberations series, Nelson et al. (2009) published practical safety guidelines for clinical practitioners. Included were the following maximum scanning time guidelines for selected TI settings for prenatal examinations:  TI values ,0.5 likely can be used for scanning times on an extended basis.

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 TI values .0.5 and #1 should be limited to scanning times less than 30 minutes.  TI values greater than 2.5 should be limited to scanning times less than 1 minute. These three guidelines lead to a boundary defined by points t 5 1 min, TI 5 2.5; t 5 30 min, TI 5 1; and t 5 30 min, TI 5 0.5, and the regions t , 1 min, TI . 2.5 and t . 30 min, TI , 0.5. The boundary is illustrated in Figure 2 as dashed black lines connecting the three points (black dots). The region below the boundary line for 1 min # t # 30 min is given approximately by TI , 2.5 2 log(t/tc). For t . 1 min, these guidelines are somewhat more conservative than the BMUS (2010) guidelines. POSTNATAL THERMAL SAFETY PRACTICE GUIDELINES AIUM statement on mammalian in vivo ultrasonic biological effects According to parts 1.c and 1.d of the AIUM (2008a) statement: ‘‘For postnatal exposures producing temperature increases of 6 C or less, no effects have been reported when DT , 6 2 (log t)/0.6, including off time for pulsed exposure. For example, for temperature increases of 6.0 C and 2.0 C, the corresponding limits for the exposure durations t are 1 and 250 min (O’Brien et al. 2008).’’ ‘‘For postnatal exposures producing temperature increases of 6 C or more, no effects have been reported when DT , 6 2 (log t)/0.3, including off time for pulsed exposure. For example, for a temperature increase of 9.6 C, the corresponding limit for the exposure duration is 5 s (5 0.083 min) (O’Brien et al. 2008).’’ Again, note that the inequalities in these quotations are formally incorrect and should be modified to contain unitless logarithmic arguments, for example, DT,6 C2

Fig. 3. DT- or TI-versus-exposure time safety guideline boundaries for postnatal scanning. Recommended exposure time– temperature rise (or TI) combinations lie in the regions below and to the left of the boundaries. DT 5 temperature rise; TI 5 thermal index.

British Medical Ultrasound Society Similar to Table 1, Table 2 contains information related to the BMUS guidelines (2010) for category (iv) described earlier: general abdominal, peripheral vascular and other scanning (except the eye). Columns 1 and 2 in Table 2 are based on the same data as in O’Brien et al. (2008), which are referenced in the AIUM (2008a) postnatal statements regarding mammalian in vivo bio-effects discussed in the previous section. As in Table 1, the 256-min maximum exposure time has been reduced by the BMUS, in this case to 120 min, again as a safety precaution to reflect the present lack of knowledge about possible subtle bio-effects associated with prolonged moderate temperature elevation. Again, other times in column 2 have been adjusted slightly by the BMUS for convenience (e.g., 15 min instead of 16 min). With TI 5 0.5 3 DT/CT (column 3), columns 4 and 5 have been constructed as in Table 1 and are represented by the green triangles and lines in Figure 3. For TI settings below 1.0, no time restriction is specified, and TI . 6 is not recommended. The Table 2. Basis for British Medical Ultrasound Society maximum exposure time-versus-TI guidelines for exams other than obstetric, neonatal head and spine and adult transcranial

CT t log10 tc 0:3

The boundary line corresponding to these two statements is plotted in Figure 3 for times from 0.0625 to 256 min (blue line). It represents a t43 of 1 min. The break point occurs at (1 min, 6 C). As O’Brien et al. (2008) point out, this ‘‘line for t43 5 1 min represents a conservative, tissue-nonspecific boundary for assessing thermal safety for nonfetal exposures.’’ From Table 2 in O’Brien et al. (2008), t43 values associated with damage for various adult tissues, organs and animal species range from 20 to 240 min.

DT ( C)

Maximum time (min)

TI 5 0.5*DT/CT

TI range

Time (min)

10 8 6 5 4 2 1

0.07 / 5 s 0.25 (15 s) 1 4 16 / 15 64 / 60 256 / 120

5 4 3 2.5 2 1 0.5

5.0–6.0 4.0–5.0 3.0–4.0 2.5–3.0 2.0–2.5 1.5–2.0 1.0–1.5

,5 s ,15 s ,1 ,4 ,15 ,60 ,120

TI 5 thermal index.

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BMUS (2010) guidelines also recommend this boundary line for neonatal scanning except for the head and spine, in which case Table 1 applies. The BMUS document obtains the ranges for TI given in column 4 of Table 2 again by dividing the values for DT in column 1 by a safety factor of 2 and then using a stepwise approach for the recommended TI–time combinations. Based on Shaw et al. (1998), a factor of 1.5 instead of 2 may be reasonable for the TIB. For example, in comparing TIBs calculated from field measurements to test object measurements of temperature rise on commercial scanners, Shaw et al. (1998) found that ‘‘ODS TIB values are mostly within 650% of the test object value (m 5 1.10, s 5 0.23) and so seem to be reasonable, but not conservative, estimates of the temperature measured.’’ (m and s are respectively the mean and standard deviation of the ratio of the TIB to the rise in temperature, both measured by the authors.) There are also situations in which a safety factor of 2 may be overly conservative for the TIS in postnatal scanning, Shaw et al. (1998) state, ‘‘All ODS TIS values are higher than the equivalent measured values (m 5 1.36, s 5 0.35), indicating that TIS is generally a slightly conservative estimate of the three minute temperature rise away from the transducer face.’’ On the other hand, closer to the transducer face they found that the ratio of TIS to measured values was ,1.0 in almost all cases. Transducer self-heating was likely a major factor in this latter case. In a computational study comparing the TIS with a more exact model of the maximum temperature rise, O’Brien and Ellis (1999) compared TIS with DTmax for 192 cases of circular apertures, finding significant disagreement (i.e., at values of DTmax .0.5 C) in only 10 cases, all at either 9 or 12 MHz. For rectangular apertures, O’Brien et al. (2004) made 594 comparisons, finding only a single instance for which DTmax . TIS; for that case DTmax , 0.2 C. However, no companion measurements of temperature rise were made, so it is not known how well the computed DTmax values represent actual temperature rises. A more compelling reason for relaxing the safety factor between the TI and temperature rise in postnatal scanning is that the data to which this safety factor is applied are conservative. As discussed previously, the temperature rise boundary in O’Brien et al. (2008) represents a t43 of 1 min, a convenient but conservative value for adult tissues. Therefore, even considering transducer self-heating, a reduction of the factor from 2 to 1.5 seems acceptable for the postnatal case. The pink diamonds and lines in Figure 3 are the BMUS guideline for category 3, adult transcranial exams. As a precautionary step regarding central nervous system tissue, the BMUS set these guidelines to be the same as those for the neonatal brain in Figure 2 (pink), except

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that there is no time restriction when TI # 1. Adult transcranial scanning is not recommended at TI . 3, as represented by the horizontal line below t 5 1 min. The BMUS (2010) guidelines do not provide a justification for making the limits for adult transcranial scanning the same as those for OB and the neonatal head and spine. This equivalence may be overly conservative in some cases for the following reasons. First, the maximum temperature rise will occur on the outer side of the bone (i.e., in the scalp). In the brain, the temperature rise will be relatively less in an adult because of the thicker cranial bone, although this difference would be less for small children. Second, the responses of a range of adult somatic tissues (including skin) to heating are known, and there is no evidence of a subtle effect arising at some time after the exposure. Third, in the absence of transducer self-heating, there is evidence to support the implicit assumption that the maximum temperature rise in surface bone is given to reasonable accuracy by TIC. In NCRP (2002), sections 11.6 and B.4.3, values of TIC are compared with calculations or measurements of temperature rise in bone, showing relatively good agreement. However, this same NCRP report notes that transducer self-heating can be greater than heating because of acoustic absorption in some cases, citing Wu et al. (1995) and stating in section B.4.3 that ‘‘In other studies it is shown that when a transducer is in near contact with bone, selfheating from the transducer can cause the temperature to rise much more than expected from Eqn B1 [the TIC equation].’’ The self-heating effect is mitigated somewhat by the fact that the postnatal temperature rise data on which the TI guidelines are based are conservative, as noted previously (O’Brien et al. 2008). Nelson et al. (2009) Nelson et al. (2009) reported the following maximum scanning time guidelines for selected TI settings during postnatal examinations:  TI values ,2 likely can be used for scanning times on an extended basis.  TI values .2 and #6 should be limited to scanning times ,30 min.  TI values .6 should be limited to scanning times ,1 min. Regarding the last point, the guidelines given by Nelson et al. (2009) were for devices cleared by the U.S. Food and Drug Administration (FDA). Because the FDA’s guidance for manufacturers requests that the reason for any TI . 6 be explained, Nelson et al. (2009) implicitly assumed that TI values exceeding 6 would be unlikely. These three guidelines lead to a boundary defined by points t 5 1 min, TI 5 6; t 5 30 min, TI 5 6; and t 5 30 min, TI 5 2, and the regions t , 1 min, TI . 6 and t . 30 min, TI , 2. The boundary is illustrated in Figure 3 as

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dashed black lines connecting the three points (black dots). These guidelines are for the most part considerably less conservative than the other postnatal guidelines for the TI. Furthermore, the lack of intermediate time points between 1 and 30 min implies that when a TI of 6 is exceeded, the recommended scanning time drops abruptly from 30 to 1 min. RELATIONSHIP OF PRACTICE GUIDELINES TO THERMAL DOSE INDEX OF ZISKIN (2010) In recognition of the shortcomings in temperature rise or TI alone as an indicator of thermal risk (i.e., thermal bio-effects depend linearly on time and exponentially on temperature), Ziskin (2010) has proposed a thermal dose index, or TDI, for display on the device and use by clinicians during an exam. The TDI is defined as TDI 5

4TI ,t N

(9)

where t is exposure time in minutes, and N is a ‘‘normalizing factor’’ with dimension of time. This same quantity is defined in an IEC Technical Report (IEC 2013), but it is called the thermally equivalent time index instead of TDI to reflect the preference for calling t43 ‘‘thermally equivalent time’’ rather than ‘‘thermal dose’’ because the dimension of this quantity is time. Equation (3) leads to eqn (9) as follows. Consider temperatures below 43 C, so R 5 4. Then in eqn (3) let T 5 37 C 1 DT, and replace the temperature rise DT above 37 C by TICT. The result is   

t43 5 t4

TI26C C T

(10)

which can be re-arranged to 4TI ,t 51 t43 46 C=CT

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uncertainties in the relationship between the TI and an actual temperature rise under clinical conditions, Ziskin (2010) introduced a safety factor of 2 in the TI just as BMUS (2010) did, so that for an exposure duration of t 5 1 min, a TI of 3 rather than 6 should cause the TDI to equal 1. Thus, eqn (12) becomes 4TI ,t 51 43 min

(13)

and the TDI for obstetric examinations is 4TI,t/43 min, or TDIOB 5

4TI ,t 64 min

(14)

The TDI would update continuously as the scanning time t increases. The relationship between eqn (14) and the BMUS (2010) and Nelson et al. (2009) prenatal TI-versusexposure time guidelines in Figure 2 can be seen by noting that the TDIOB 5 1 boundary of eqn (14) corresponds to   t 54 tc

3 C2TI CT

(15)

This line is shown in Figure 4 for 0 , TI , 4, along with the BMUS (2010) and Nelson et al. (2009) TI-versus-exposure time lines from Figure 2. The three guidelines are similar for t . 1 min, with the TDI becoming relatively more conservative with increasing exposure time. It is noted that if DT were replaced by TICT in eqns (4), (6) and (8), then the corresponding values for N in the TDI (eqn 9) would be 4096, 1024 and 512 min, respectively. Ziskin (2010) concentrated on the obstetric case, but he mentioned that for other applications, larger values for

(11)

Ziskin (2010) called this ratio the TDI, but with de nominator N instead of t43 46 C=CT 5 t4346, N being chosen so that if the TI and exposure duration t combine to make the ratio ,1, then there would be no risk of an adverse thermal bio-effect during the examination. For an obstetric examination, Ziskin chose N 5 64 min as follows: First, he set t43 5 1 min based on the Miller and Ziskin (1989) thermal dose plot in Figure 1. With t43 5 1 min, eqn (11) becomes 4TI ,t 51 46 min

(12)

The ratio on the left side of eqn (12) could have been used to define an obstetric TDI, but because of

Fig. 4. TI-versus-exposure time safety guideline boundaries for prenatal scanning. Points on the solid line (see eqn 15) correspond to a thermal dose index of one (TDIOB 5 1). Recommended time–TI combinations lie in the regions below and to the left of the boundaries. TI 5 thermal index.

Comparison of thermal safety practice guidelines d G. R. HARRIS et al.

N might be appropriate. One would begin with the product t43 46 in eqn (11) and choose relevant values for t43 and a safety factor as was done to reach eqn (14). Figure 5 contains the plots from Figure 3 for BMUS (2010) categories 3 and 4, along with TDI 5 1 boundaries for N 5 128 and 512 min to illustrate possible non-OB TDIs in relation to these BMUS postnatal guidelines. The N 5 64 min line from Figure 4 also is shown in Figure 5. The TDI thus would provide the sonographer or physician with a simple indicator, updated in real time, related to overall risk of a thermally induced adverse effect for any clinical ultrasound examination. The interpretation is simple: if the TDI does not reach a value of 1 during the scan, there is little if any risk of harm from an adverse effect caused by a temperature elevation. If the TDI exceeds 1, there may be a risk. The higher the value of the TDI, the greater is the risk. Although the TI is related to thermal risk at any particular moment, the TDI is related to thermal risk for the entire examination. Like all of the practice guidelines discussed herein, the TDI addresses the dependence of thermal risk on both temperature and time. However, its advantage is that it provides a means for implementing the thermal dose concept on a device. In principle, such implementation should not be difficult because the TI is already available. The more difficult task of timing the duration of an exposure (i.e., finding t in eqn [9]) is in knowing when to start and stop. Options include placing a manual start/stop button on the console keyboard and automatically sensing the loss of skin contact. At present, no devices incorporate the TDI. The AIUM has recommended that a ‘‘new indicator of thermal risk that incorporates the time dependence not be implemented at this time but be included in

Fig. 5. TI-versus-exposure time safety guideline boundaries for postnatal scanning. Points on the solid, short-dashed, and longdashed straight lines correspond to a thermal dose index of one (TDI 5 1) for N 5 64, 128 and 512, respectively (see eqn 9). Recommended exposure time–TI combinations lie in the regions below and to the left of the boundaries. TI 5 thermal index.

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continuing efforts toward standards or consensus documents’’ (Bigelow et al. 2011). However, the authors of that report did not consider the TDI proposal. Lastly, it is noted that eqns (7) and (8) in Ziskin (2010) give more general forms for the TDI numerator in eqn (9) when the TI varies during an examination, being equivalent to eqns (1) and (2) (but note that the denominator N was inadvertently omitted in eqn (7) of Ziskin (2010)). DISCUSSION AND RECOMMENDATIONS The prenatal practice guidelines have changed somewhat over time, with the DT-versus-time boundary based on eqns (4) and (5) being supplanted by the similar but more conservative boundaries:  C2DTÞ=C T

t=tc 5 4ðB

and DT,B C2

CT t log10 tc 0:6

where B 5 5 (WFUMB/BMUS/Health Canada) and 4.5 (AIUM). As to which current guideline to use in a particular situation, given the uncertainties associated with the reported bio-effects that led to the various guidelines, placing too much emphasis on the exact location of a safety boundary is not warranted when the differences are small. The prenatal guidelines for TI versus exposure time plotted in Figures 2 and 4 are in reasonable agreement for the most part (e.g., BMUS 2010; Nelson et al. 2009); however, the same is not true of the postnatal guidelines in Figure 3, so confusion of clinical users is understandable. Also, AIUM (2008a) and WFUMB (1998) statements differ as to the threshold temperature rise below which scanning need not be restricted on thermal grounds. The following list summarizes and discusses areas where differences were found or assumptions were questioned.  BMUS (2010) guidelines are unique in that they recommend avoiding TI .3.0 for obstetric, neonatal transcranial, neonatal spinal and adult transcranial scanning [categories (i)–(iii)], and recommend avoiding TI .6.0 for general abdominal, peripheral vascular and other scanning [category (iv)]. No other guidelines contain such recommendations for maximum levels of TI. Specifying such levels helps in formulating a concise set of TI-versus-time recommendations as in Tables 1 and 2, although they may be overly conservative from a thermal dose perspective.  The AIUM (2008a) Statement on Mammalian in Vivo Ultrasonic Biological Effects (part 1.a) says that there have been no observed effects for TI ,2. As noted previously, this statement assumes that TI represents a reasonable upper bound for temperature rise, and that for temperature increases up to 2 C above normal, no

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significant adverse biological effects have been observed. With respect to the first assumption, the problem with equating TI and DT has been discussed in previous sections. For prenatal scanning, studies have indicated that the TI could underestimate the actual temperature rise by a factor of 2. In this case TI 5 2 becomes a DT of 4, which is a value inconsistent with other safety guidelines depicted in Figure 2. Regarding the second assumption, the 2 C temperature rise comes from the AIUM (2009) Statement on Heat. It is based on teratogenic effects data presented in AIUM (1993) and Sapareto and Dewey (1984). AIUM’s analysis was based on temperature data relative to a normal human core temperature of 37 C. However, if the core temperatures of the reported animal models are used, then the resulting threshold temperature rise becomes 1.5 C. This is the temperature rise above normal physiologic levels that WFUMB (1998) considers as the value below which ultrasound may be used clinically without reservation. Therefore, it seems advisable to change TI ,2 in the AIUM (2008a) mammalian bio-effects statement to DT ,1.5 C, and to change the temperature rise value in the AIUM (2009) Statement on Heat from 2 C to 1.5 C, without regard to exposure duration.  The Nelson et al. (2009) postnatal TI-versus-exposure time boundary in Figure 3 is significantly less conservative than the BMUS (2010) guidelines in Figure 3 for times less than 30 min, and it also falls above the AIUM (2008a) boundary for DT in this region. As noted previously, the AIUM postnatal boundary, chosen to be tissue non-specific, is conservative for most adult tissues based on available t43 data. However, for uniformity, it seems reasonable to reconsider the location of the Nelson et al. (2009) boundary in light of the AIUM DT boundary.  The BMUS (2010) guideline for category (iii), adult transcranial scanning (Figure 3, diamonds and pink line) was made the same as for OB and neonatal head and spine, which, as described previously, may be overly conservative and thus unintentionally restrict acoustic outputs and/or scanning times at the expense of the user’s ability to obtain clinically necessary information. A suggested change is given in the recommendation following this discussion.  The BMUS (2010) guideline for category (iv), general abdominal, peripheral vascular and other scanning (except the eye) (Table 2 and Figure 3, triangles and green line), was based on a safety factor of 2 between the TI and temperature rise. Combining this safety factor with the stepwise approach results in TI–time recommendations that fall between 1.5 and 2 times below the reference AIUM DT boundary. This situation is depicted in Figure 6, which illustrates the BMUS guideline

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Fig. 6. DT- or TI-versus-exposure time safety guideline boundaries for postnatal scanning. The short-dashed and long-dashed lines are the AIUM DT plot divided by 1.5 and 2, respectively, to illustrate safety factors that account for possible differences between TI and DT. Recommended exposure time–temperature rise (or TI) combinations lie in the regions below and to the left of the boundaries. DT 5 temperature rise; TI 5 thermal index.

for TI (triangles and green line), the DT line from AIUM (2008a) used by BMUS (black solid line) and this DT line divided by 1.5 (short-dashed red line) and 2 (long-dashed blue line). These two broken lines can be seen essentially to bracket the BMUS plot. As discussed in the previous section on BMUS postnatal guidelines, for the non-obstetric, non-neonatal examinations represented in Table 2, a factor no greater than 1.5 seems reasonable. A larger factor may appear acceptable from the viewpoint of patient safety, but it also may limit exposure times unnecessarily for a large number of clinically relevant situations. This is particularly true for examinations of soft tissues in adults for which TIS is the appropriate safety index. It is important to strike a balance between patient safety, on the one hand, and clinical need, on the other. A suggested change is given in the following recommendation. Given these observations, and based on the analysis presented herein, we propose the following recommendations for TI versus exposure time in two categories, which are combinations of the BMUS (2010) categories. Category A: Obstetric; neonatal trans-cranial and spinal. Recommendation: Follow BMUS (2010) guidelines in Table 1 and Figure 2 (diamonds and pink line). Table 3 contains the TI ranges and times. Category B: Adult transcranial; general abdominal; peripheral vascular; neonatal (except head and spine); other scanning (except the eye). Recommendation: Follow the guidelines in Table 4, which has the same format as the last two columns in Table 2, but with higher TI values.

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Table 3. Recommended maximum exposure time and TI ranges for obstetric (including gynecologic when pregnancy is possible), neonatal transcranial and neonatal spinal examinations* TI range

Time (min)

.3.0 2.5–3.0 2.0–2.5 1.5–2.0 1.0–1.5 0.7–1.0 ,0.7

0 ,1 ,4 ,15 ,30 ,60 No limit

LMP 5 last menstrual period; TI 5 thermal index; TIB 5 bone TI; TIS 5 soft tissue TI. * For obstetric examinations, monitoring of the TIS is recommended through the first 10 wk from the LMP; beginning at 11 wks post-LMP, the TIB should be monitored.

Tables 3 and 4 comprise a recommended set of application-specific thermal safety guidelines for maximum examination time at a given TI value. Figure 7 is a plot of these recommendations. They retain the caps at short exposure times of TI 5 3 for prenatal and TI 5 6 for postnatal (except neonatal head and spine). So Table 3 is the same as the BMUS prenatal guidelines; the times in Table 4 are almost the same as BMUS general postnatal guidance, but the TI values have been calculated as two-thirds of DT instead of one-half of DT, and there has been some rounding. In applying these recommendations, users should keep in mind that a recognized deficiency in the thermal index is that it does not include a contribution due to selfheating of the ultrasound transducer. In some situations, transducer heating may be the dominant source of temperature rise compared with that from absorption of the ultrasound energy. The ODS contains required limits for transducer self-heating (see IEC 2007). However, the BMUS (2010) guidelines note that particular care should be taken when using endocavity transducers if there is noticeable heating of the transducer when operating in air. The same is true regarding the potential Table 4. Recommended maximum exposure time and TI ranges for adult transcranial, general abdominal, peripheral vascular, neonatal (except head and spine), and other scanning examinations (except the eye) TI range

Time (min)

.6.0 5.0–6.0 4.0–5.0 3.0–4.0 2.5–3.0 2.0–2.5 1.5–2.0 ,1.5

0 ,0.25 (15 s) ,1 ,4 ,15 ,60 ,120 No limit

TI 5 thermal index.

Fig. 7. TI-versus-exposure time safety guideline boundaries corresponding to Tables 3 and 4. Recommended maximum exposure time–TI combinations lie in the regions below and to the left of the boundaries. TI 5 thermal index.

for surface heating of cranial bone during neonatal, pediatric and adult transcranial scanning. It is important to point out that following these recommendations provides reasonable assurance, based on available data in the bio-effects literature, that an ultrasound examination can be conducted without risk of producing an adverse effect caused by a thermal mechanism. However, if these guidelines must be exceeded to obtain clinically significant information, the occurrence of an adverse thermal event is still unlikely under most scanning situations because of the mitigating factors discussed in the text, but the general principle of ‘‘as low as reasonably achievable’’ still should be followed as closely as possible. To help clinicians make use of the recommended practice guidelines in Tables 3 and 4, device manufacturers are encouraged to provide easily accessible, understandable and user-configurable presets and controls for selecting the appropriate TI display, TIB, TIS or TIC, in all modes of operation, consistent with the provisions of the ODS (AIUM 2004; IEC 2007) and the recommendations in AIUM (2014). It is noted that if future devices incorporate the TDI, then Tables 3 and 4 could be replaced by this index. Reasonable values for N that would correspond to the two tables and Figure 7 are 64 min for the obstetric case, as in eqn (14), and 512 min otherwise, both illustrated in Figure 5. CONCLUSIONS To make appropriate and informed use of the various thermal safety practice guidelines, it is helpful for clinical users to know the basis for their development and to understand their relationship to each other. Equally important is to understand that exceeding these time– temperature guidelines does not necessarily lead to a harmful bio-effect. It is important to note that following

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these recommendations provides reasonable assurance that an ultrasound examination can be conducted without risk of producing an adverse effect caused by a thermal mechanism. If these practice guidelines are exceeded, the occurrence of an adverse thermal event is still unlikely under most scanning situations because of mitigating factors such as transducer movement and perfusion, which can act to lower the likelihood of a bio-effect caused by heating. For example, the guidelines assume an ultrasound beam that, whether stationary or scanning, maintains its position over the duration of exposure, which is seldom the case, except possibly for some spectral Doppler studies. Thus, the guidelines, including the TDI, do not account for scanning practice, in which during a normal ultrasonic examination the transducer head is moved and the position of maximum exposure (where the indexes are determined) will not be the same for the whole time of the examination. Therefore, in many if not most clinical examinations, the guidelines will overcompensate for any risk. However, the general principle of ‘‘as low as reasonably achievable’’ should be followed. The guidelines serve to promote safety in the performance of ultrasound examinations. Clinical judgment will be needed when the recommended levels are exceeded. Various questions regarding patient-specific conditions and mitigating factors that should be addressed include the following: (i) Was the ultrasound beam focused continually on one structure or was the transducer always in motion? (ii) Was the structure being imaged particularly sensitive to temperature elevation? (iii) Is the structure of interest well perfused or does it have other means of dissipating heat? (iv) Regarding possible transducer self-heating, is the structure of interest within 1 cm from the transducer? The aforementioned questions are aimed at improving the estimate of risk. However, it will also be necessary to evaluate the potential benefits of prolonging an examination. Questions needing to be addressed include: (i) What is the likelihood that important diagnostic information will be gained that was not already obtained? (ii) Will the additional information have any effect on the patient’s treatment or clinical outcome? The answers to these questions will need to be evaluated by the clinician in deciding whether to prolong an examination beyond these guidelines. Lastly, it should be kept in mind that the experimental and computational biological effects studies on which all of these practice guidelines are based suffer from several shortcomings. These deficiencies have been discussed in the bio-effects literature and include extrapolation from whole-body heating in water or air to local heating by ultrasound; the stressful effects of whole-body hyperthermia up to and including maternal

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death; the relatively simple cell and animal models used; the simplified numerical models of heating due to ultrasound; sparse data on local embryonic or fetal heating; the wide scatter in the thermal dose bio-effects data; and the lack of inclusion of real clinical scanning conditions that result in the mitigating factors discussed above. Therefore, to enhance the credibility of these guidelines, it is highly desirable to investigate potential bio-effects via research studies that employ actual ultrasound exposures under conditions more relevant to the human clinical situation.

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