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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5786_Библиотеки_им_академика_М_И_Перельмана.pdf
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Table 2.1 Summary of median and maximum values of spatial peak, temporal average
intensity, I
Median value, mW cm
A- or M-mode 81 604
Real-time B-mode 94 1330
Colour Doppler 328 2030
Spectral Doppler 1420 7500
, from a 1998 survey
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22
−2
Maximum value, mW cm
−2
There have been a number of published surveys of output, and these have
been summarized by Whittingham.22 He shows that the peak rarefaction pressure
used for all modes is about the same, with median about 2.5 MPa and maximum
about 5 MPa, whether operating in imaging mode, M-mode, spectral Doppler
or Doppler imaging. Thus gas body effects are equally likely to occur whatever
mode is in use. The situation is different when considering I
This is shown
spta.
in Table 2.1, which summarizes the median and maximum values reported
by Whittingham for a 1998 survey. Two remarks may be made. First, on average, intensities become higher as the mode is changed from M-mode, through
B-mode and colour Doppler, to become highest in spectral Doppler mode. This
trend occurs in both the maximum and median values. Therefore, on average,
the highest intensities and hence probably the greatest heating are associated
with Doppler modes, particularly spectral Doppler. However, the second remark
is perhaps of greater general importance. The overlap between peak intensities
in each mode is very large. It is possible to find B-mode intensities on one scanner which exceed the highest Doppler intensities on another. Moreover, for any
selected transducer it is often true that the intensity used for Doppler imaging
exceeds that used for spectral Doppler. For this reason it is now becoming common only to give general advice on safety rather than to give specific advice for
the use of pulsed Doppler.
Surveys have also demonstrated a trend towards increased output during the
past 20 years or so. Increases have occurred in output from ultrasound scanners
used for obstetrics, partly due to the changed regulations in the USA, and partly
because of a general trend to design scanners that operate towards the top end of
the available performance range.
Biological effects and safety aspects
TISSUE WARMING BY DIAGNOSTIC ULTRASOUND
The fundamental biochemical processes controlling the behaviour and function
of living cells depend strongly on temperature. Mammalian tissues can survive
and operate effectively within quite a small range of temperatures, and elevated
temperatures sustained for extended times may alter cell function and can result
in cell death. Temperature elevation is a potent teratogen, and thus it is appropriate to establish the extent by which ultrasound scanners are capable of increasing
temperature within tissue.
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Ultrasound pulses lose energy as they penetrate tissue, a fact ultimately limiting the ability to scan to great depths. Almost all the energy lost from the
ultrasound wave is deposited as heat in the tissue and this causes small rises in
temperature in this tissue.3 The temperature rise is affected by a number of factors. The first is the energy in the beam: the higher the intensity, the greater
the heating. The energy distribution is also important, for example whether the
beam is narrowly focused, and whether it is scanned. The thermal and acoustic
properties of tissue also determine the temperature elevation. Amongst these
properties, the two most important are the acoustic absorption coefficient of
the tissue and its blood perfusion rate. Bone is the tissue which absorbs ultrasound energy to the greatest extent and so, wherever the ultrasound scan plane
intercepts bone, it will be here that the temperature rise will be most rapid and
of greatest elevation. In obstetric scanning, the developing fetal skeleton warms
first and to the highest temperature. As the fetal bones mature throughout gestation, the absorption of ultrasound increases, and so does the temperature they
may attain (see Fig. 2.1).
Ultrasound in obstetrics and gynaecology
Blood perfusion controls temperature elevation, returning local temperature
towards the core temperature. This effect is seen most strongly near large blood
vessels. Fetal tissue is adequately, though not strongly, perfused, and so this may
not be a significant factor in controlling ultrasound-induced warming.
Tissues may also be warmed as a secondary effect from an elevated temperature in a nearby structure. This is important when considering heating of fetal
central nervous tissue, which is known to be particularly sensitive to thermal
damage.3 Whilst fetal brain itself has a relatively low ultrasound absorption coefficient, the brain tissue which lies alongside the skull heats as a secondary effect of
skull heating. It is therefore the bone temperature that is critical for safety judgements. The second situation when secondary heating may be important is transducer self-heating. Ultrasound transducers heat because the electrical power is
converted rather inefficiently into ultrasound power, the remaining power being
dissipated as heat in the transducer. Tissues close to the transducer can have their
temperature raised by several degrees, by contact heating. Whilst this probably is
not important for a skin-coupled transducer, a transducer for transvaginal scanning could, in principle, pose a problem. International standards for transducer
design now limit the contact temperature rise to 6°C, and the contact temperature to 43°C.
9
Currently available clinical scanners are capable of causing temperature elevations in bone which approach 10°C, and in soft tissues of about 3°C, when
operating in pulsed Doppler mode. Whilst these results relate to rather extreme
experimental conditions, which omit the protection given by any overlaying tissue layers, they emphasize that present clinical scanners are easily able to cause
significant heating within tissues when operated at the extreme upper limits of
output. One example of bone heating is shown in Figure 2.1, which shows measured temperature rises in samples of human fetal vertebrae, exposed to ultrasound in vitro.5 In this case the frequency was 3 MHz, and the acoustic power,
24
50 mW, can be easily achieved in vivo with modern scanners.
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0.0
050 100 150 200 250
0.2
0.4
Temperature rise, C
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Time, seconds
39 weeks
14 weeks
Biological effects and safety aspects
Fig. 2.1 Measured surface heating curves for two human fetal vertebrae, exposed in vitro to
3 MHz focused ultrasound at a diagnostic power (50 mW); 14 weeks and 39 weeks gestation.
Redrawn from reference 5 with permission.
From the scientific evidence of the effects of hyperthermia, it is generally
accepted that tissues containing a large component of actively dividing cells are
particularly sensitive to heat. Abnormalities in cell pathology and biochemical
processes can occur following an increase in temperature above normal basal
levels. There are critical periods during gestation when the embryo and fetus are
particularly sensitive to thermal effects. During formation of the neural plate and
closure of the neural tube, animal studies have demonstrated that elevated temperature can result in neural defects, retarded brain development, exencephaly
and microphthalmia. Exposure at preorganogenesis stages can result in cardiovascular abnormalities, whilst later heating can affect skeletal and visceral systems. There is now a substantial literature on thermal teratology7 which suggests
that an elevated temperature of 2–2.5°C, if sustained for an extended period, is
sufficient to cause major developmental abnormalities, at least in small mammals. Recognizing the difficulty of transferring animal data to humans, these data
still serve as a reminder that remarkably small changes in fetal temperature are
capable of causing developmental changes of major significance.
It is not possible to interpret thermal bioeffects studies without considering
the time over which the temperature elevation is generated and the time for
which it is sustained. Review of the thermal teratology literature has led the World
Federation for Ultrasound in Medicine and Biology to recommend that ‘a diagnostic
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’.
ner such that regions are not examined continuously for more than a few seconds at
11,12
Of course, clinical scanning commonly takes place in a man-
a time. Exceptions to this are most probably in cardiovascular studies, when the
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time variation of a particular region is of interest. Exposed bone can approach a
steady-state temperature within about 30 seconds (see Fig. 2.1), soft tissue somewhat longer. Assuming that bone may be exposed anywhere within the examined
volume, it is prudent to take particular care to limit output if the examination
requires the probe to be stationary for more than 30 seconds.
NON-THERMAL MECHANISMS AND THEIR SAFETY IMPLICATIONS
Ultrasound pulses can alter cells in other ways than by heating the tissue. Broadly,
heating changes rates of biochemical reactions, whereas the damage from mechanical effects is primarily to the cellular and tissue structures. Non-thermal mechanisms fall into two classes: those which involve ‘gas bodies’ and those which
do not.
GAS BODY EFFECTS OF DIAGNOSTIC ULTRASOUND
It is now accepted that diagnostic ultrasound does not cavitate soft tissues. That
Ultrasound in obstetrics and gynaecology
is, microscopic gas bubbles are not generated within tissue by diagnostic ultrasound pulses under normal conditions. However, cells and tissue can be damaged
when exposed to diagnostic ultrasound pulses if they lie close to a region of gas
already contained within tissue. The shear forces generated at the tissue/gas interface may be sufficient to cause damage. Known examples include the rupture of
capillaries at the lung surface, resulting in extravasation of blood components into
the extracellular space, and the formation of petechiae in the intestine. Gas bubble contrast agents are being introduced into the practice of clinical ultrasound
and similar shear forces are created at the surface of these agents when exposed
to ultrasound. A process known as ‘sonoporation’ can occur, which is the transient opening of ‘pores’ or gaps in cell membranes, allowing the passage of larger
biomolecules into the intracellular space. At sufficiently high acoustic pressures,
haemolysis occurs.
The response of gas-filled structures to an ultrasound field has been termed
‘gas body activation’ because it differs in many respects from acoustic cavitation.
One common factor, however, is that all effects are related to thresholds in acoustic pressure. Judgements about safety therefore depend on an estimate of these
thresholds, and a comparison with estimates of acoustic pressure in vivo. The displayed MI is intended to inform these judgements.
In the context of obstetric ultrasound, much of the safety discussion about gas
bodies has little relevance. Cavitation is not initiated in soft tissues. There are no
pre-existing gas bubbles within the uterus so no gas body activation can occur.
It is appropriate to use caution when using gas bubble contrast agents for hysterocontrast salpingography, using the displayed MI to limit the possibility of inertial
cavitation of free bubbles released when the contrast agent is destroyed.
Present advice is to avoid the use of intravenous contrast agents during pregnancy, because it is yet to be determined whether fragments may pass the placen-
26
tal barrier and enter the fetal circulation.
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OTHER MECHANICAL BIOEFFECTS MECHANISMS
A brief mention should be made of a further means of interaction between ultrasound and tissue – radiation pressure. Ultrasound waves push the material through
which they pass. If the medium is a liquid, such as amniotic fluid or blood, the
result is movement of the liquid. This is called acoustic streaming and may sometimes be observed with modern scanners. Whilst streaming itself is not apparently
a hazard, the radiation pressure causing it is also exerted on all tissues within the
beam. The forces are small but it is important to recognize that little is known of
their effects. Radiation pressure can induce neurological and auditory effects at
sufficiently high levels, and some cells can respond to the effects of external shear
forces. Caution is needed here as elsewhere as diagnostic techniques are being
developed.
EVIDENCE FROM EPIDEMIOLOGY
This section summarizes briefly the outcome of the more important epidemiological studies into ultrasound exposure in utero. Fuller reviews may be found
elsewhere.
There have been three well-managed case–control studies into ultrasound and
childhood malignancies, all of which were of sufficient size to have statistical
validity. No association between childhood malignancy was found in any study.
Some early studies suggested an association between exposure and birthweight
or subsequent growth, but subsequent studies have been unable to demonstrate
such an association. In view of the conflicting evidence presented by these studies, the present consensus is that there is no association between exposure to
ultrasound and birthweight.
A range of neurological functions has been examined and no association
between ultrasound exposure in utero and subsequent hearing, visual acuity,
cognitive function or behaviour has been found. An association with dyslexia
reported earlier14 was not found in later larger studies.
gested a possible association between ultrasound exposure and handedness,17
with a gender-biased tendency towards left-handedness.18 At present, there
is no explanation of this association and no firm conclusions can be drawn.19
A controlled randomized study from Australia indicated the relationship
between repeated Doppler examinations and growth restriction in the fetus20
but the same research group could not find any effect on postnatal follow-up
of the children.
In summary, there is no independently verified evidence to suggest that ultrasound exposure in utero may cause an alteration in the development and growth
of the fetus. All studies have either proved to be negative, or, when positive findings have appeared, they have not been verified or have been shown to result from
poorly designed studies. New studies will be difficult to structure, because of the
difficulty of finding an unexposed control group, resulting from the widespread
use of ultrasound during pregnancy throughout the world. It is necessary to sound
10
15,16
Studies have sug-
21
Biological effects and safety aspects
27
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a note of caution, however. There are no studies which have explored outcomes
following exposure to pulsed Doppler or Doppler imaging, where intensities and
powers are known to be higher than in pulse-echo imaging. While the results of
epidemiological studies so far are comforting, they cannot be used to support an
argument that it is safe to extend exposure in utero to higher levels. Further epidemiological studies focused specifically on Doppler exposure would be needed
before such confidence can be claimed.
THE MANAGEMENT OF SAFETY
The successful management of safety in medical ultrasound practice operates at
several levels. It involves manufacturers, users and international and national professional and regulatory bodies. Manufacturers must comply with standards and
regulations intended to make the equipment safe. Users must make sure that they
use the equipment in an appropriate and safe manner. Basic scientists provide the
evidence from which safety judgements are made, and which informs the recommendations of national and international bodies.
Ultrasound in obstetrics and gynaecology
4
THE USERS' RESPONSIBILITY
Clinicians using ultrasound equipment should have specific training in safety
aspects of its use. From this training they are expected to be able to use the
real-time safety indices to manage the machine settings with appropriate attention to safety. A summary of the meaning and function of these safety indices
follows.
28
Thermal indices
Since it is impossible for the user to know the temperature increase in the body,
thermal indices (or TI) have been developed to provide guidance. A TI is a rough
estimate of the increase in temperature that occurs in the region of the ultrasound scan. A TI of 2.0 suggests that a temperature rise may reach 2°C, if the
transducer is held stationary for long enough. There are three thermal indices –
one for soft tissue (TIS), one for bone at depth (TIB) and one for bone at the surface (TIC). These TI values are more helpful than any other information available
to the user, because they are informative about the state of the machine output as
it is being used. However, the methods for calculating TI include some important
simplifications and as a result the true temperature rise may be somewhat higher
or lower than the value indicated, perhaps by as much as a factor of 2. Whilst the
displayed TI values are the best information currently available, they should be
used only as rough, rather than absolute, indicators of the thermal hazard. They
may be useful, however, to identify which machine settings are more likely to
generate significant temperature increases in tissue, so that particular care may be
made to avoid their use for critical examinations.
On current equipment, TI values can usually be found around the edge of the
scanner screen, often in the top right corner, indicated by the letters TIS, TIB or TIC
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followed by a number which changes when the scanner controls are altered. The
most cautious approach is to display TIB most of the time. TIS should be displayed only if there is no bone, developing bone or cartilage anywhere in the
region being scanned.
Mechanical index
At high enough pressure amplitudes, cavitation becomes ‘inertial’ and its potential
for damage increases considerably. An analysis of inertial cavitation has resulted
in the formulation of a mechanical index (MI). The MI was developed to quantify the likelihood of onset of inertial cavitation, for which a threshold of MI 0.2 if
bubbles pre-exist has been suggested. The MI is proportional to the peak rarefactional pressure, and has a weak frequency dependency. It has since been related also
to thresholds for lung damage, and contrast behaviour. The MI is displayed on the
scanner screen together with, or instead of, the TI. For applications in obstetrics and
gynaecology, the MI is of use primarily when contrast agents are to be used.
THE MANUFACTURERS' OBLIGATIONS
The Medical Device Directive in Europe and the Food and Drug Administration
(FDA) regulations in the USA both make demands of manufacturers regarding
the safe design and performance of their scanners and provision of output information to users. Europe sets no upper limit to the allowed output from ultrasound equipment; the USA, through the FDA, has such limits in place. Intensity
(I
) must not exceed 720 mW cm–2 and the MI must not exceed 1.9. In order to
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use these output levels, manufacturers must provide a real-time display of safety
information by means of the TI and MI.
international standards as set by the International Electrotechnical Commission
for electrical and thermal safety.
9
1,9
Manufacturers must also comply with
Biological effects and safety aspects
SAFETY PRACTICE
Keeping up to date with current thinking on ultrasound safety and risk minimization allows clinicians to make the best decisions on how to maximize the benefit
to the patient whilst reducing the risk. Present estimates of risk encourage clinicians primarily to use equipment in such a way as to maximize the opportunity
to make a good diagnosis. There is more chance of causing harm by misdiagnosis
than through heating or cavitation. With this in mind, the following sections summarize the particular safety considerations relating to obstetric scanning early and
late in pregnancy, and to the scanning of patients with fever.
DIAGNOSTIC ULTRASOUND DURING THE FIRST TRIMESTER
Probably the most critical question concerns the exposure of the embryo during the early stages of pregnancy.6 This is a period of rapid development and
complex biochemical change, which includes organ creation and cell migration.
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There is widespread evidence that during this period the developing embryo is
particularly sensitive to external agents, whose effect on subsequent development may range from fatal developmental malformation to minor and subtle
biochemical disturbance. It is because of this sensitivity that the ISUOG13 and
EFSUMB8 have recommended caution with the use of Doppler in early
pregnancy. The EFSUMB have advised that ‘until further scientific evidence
is available, investigations using pulsed or colour Doppler should be carried
out with careful control of output levels and exposure times’.8 This statement
recognizes both that there are gaps in our knowledge and understanding of
the way in which ultrasound may interact with embryonic tissue, and that any
adverse effect may result in developmental problems because of the particular
sensitivity of the tissue at this time. Moreover, this sensitivity may be cyclic,
with some tissues being sensitive only during particular time-bands of rapid
cell development and differentiation. Heat is a teratogen and any temperature
increase from the absorption of ultrasound can disturb subsequent development, if of sufficient magnitude and maintained for sufficiently long. Fortunately,
the tissue with the greatest tendency to heat, bone, only starts to condense at
Ultrasound in obstetrics and gynaecology
the end of the first trimester. In the absence of bone, current evidence suggests that temperature elevations greater than 1.5°C are unlikely to occur within
embryonic tissue at present diagnostic exposures. This suggests that significant
developmental changes probably do not occur. The kinetics of biochemical processes are known to be temperature sensitive, however, and little research
has investigated the influence of small temperature changes induced locally on
membranes and signal transduction pathways. There is no evidence for cavitation,
as there are no gas bubbles to activate within the uterus. The effects of radiation
pressure on the developing embryo and fetus are unknown. Thus, although our
current understanding suggests that present practice is safe, there is sufficient
uncertainty about the detailed interaction processes to advise caution.
30
SCANNING DURING THE SECOND AND THIRD TRIMESTERS
Bone ossification is the main developmental change during the second and third
trimesters of pregnancy that is of significance to ultrasound safety. As bone condenses, it forms local regions of high ultrasound absorption. Ultrasound energy is
absorbed more by the fetal skeleton than by fetal soft tissues, and so it is preferentially heated. This is important in part because soft tissues alongside this bone
will also be warmed by thermal conduction, reaching a higher temperature than
expected from ultrasound absorption alone. Neurological tissues are known to
be particularly sensitive to temperature rise, and the development of brain tissue, and of the spinal cord, could be affected if adjacent skull or vertebral bone
were heated too much. Within the fetal haematopoietic system, the bone marrow
is the main site of blood formation in the third trimester of pregnancy. Neither
cavitation nor gas body activation will occur because of the absence of nucleation
sites and pre-existing bubbles.
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OBSTETRIC SCANNING ON PATIENTS WITH FEVER
It is noted in the WFUMB recommendations12 that ‘care should be taken to
avoid unnecessary additional embryonic and fetal risk from (heating due to)
ultrasound examinations of febrile patients’. If a mother has a temperature, her
unborn child is already at risk of maldevelopment as a result of the elevated
temperature. This being so, it is sensible not to increase this risk unnecessarily.
This does not mean withholding obstetric scanning from patients if they have
a temperature. The methods of limiting exposure, including minimizing the TI,
limiting the duration of the scan and avoiding casual use of Doppler techniques,
should be employed with particular vigilance in these cases.
CONCLUSION
Ultrasound has an enviable record for safety. Indeed, it is partly its lack of toxicity which has allowed it to grow to the point where ‘more than one out of
every four imaging studies in the world is an ultrasound study’. All the evidence
points to the conclusion that past and current practice presents no actual risk
to the patient, and may be considered as safe. Nevertheless, there is ample evidence that modern scanners, designed in accordance with national and international standards and regulations, can warm tissues by several degrees under some
circumstances. If gas bubbles or other pockets of gas lie in the ultrasound field,
the tissues may be damaged from stresses caused by cavitation-like oscillations.
Current scanning equipment displays safety indices, allowing users greater feedback for safety judgements to be made. Safety in diagnostic ultrasound depends
both on manufacturers to produce equipment that is safe to use, and on the users
of ultrasound in managing their scanning practice.
Biological effects and safety aspects
References
1. American Institute for Ultrasound
in Medicine/National Electrical
Manufacturers' Association. UD 3-1992:
standard for real-time display of thermal
and mechanical acoustic output indices
on diagnostic ultrasound equipment.
American Institute for Ultrasound
in Medicine/National Electrical
Manufacturers' Association, Rockville,
MD, 1992
2. Barnett SB, Kossoff, G (eds). Safety of
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