The main mechanisms by which ultrasound can induce biological effects as it passes through the body are thermal and mechanical in nature. The mechanical effects are primarily related to the presence of gas, whether drawn out of solution by the negative going ultrasound pressure wave (acoustic cavitation), a naturally occurring gas body (such as lung alveoli), or deliberately introduced into the blood stream to increase imaging contrast (microbubble contrast agents). Observed biological effects are discussed in the context of these mechanisms and their relevance to ultrasound safety is discussed.
ChurchC. C.‘Frequency, pulse length, and the mechanical.’Acoust. Res. Lett. Online6 (2005): 162–168
6.
ChurchC. C.‘Spontaneous, homogeneous nucleation, inertial cavitation and the safety of diagnostic ultrasound.’Ultrasound Med. Biol.28 (2002): 1349–1364
7.
CoussiosC. C.FarnyC. H.ter HaarG. R.RoyR.‘Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU).’Int. J. Hyperthermia23 (2) (2007): 105–120
8.
RooneyJ. A.‘Shear as a mechanism for sonically induced biological effects.’J. Acoust. Soc. Am.52 (1972): 1718–1724
9.
MillerD. L.ThomasR. M.WilliamsA. R.‘Mechanisms for hemolysis by ultrasonic cavitation in the rotating exposure system.’Ultrasound Med. Biol.17 (1991): 171–180
10.
‘Tutorial paper: genetic effects.’ Eur. J. Ultrasound1 (1994): 91–92
11.
ChildS. Z.HartmanC. L.ScheryL. A.CarstensenE. L.‘Lung damage from exposure to pulsed ultrasound.’Ultrasound Med. Biol.16 (1990): 817–825
12.
PenneyD. P.SchenkE. A.MaltbyK.Harman-RaemanC.ChildS. Z.CarstensenE. L.‘Morphological effects of pulsed ultrasound in the lung.’Ultrasound Med. Biol.19 (1993): 127–135
13.
FrizzellL. A.ChenE.LeeC.‘Effects of pulsed ultrasound on the mouse neonate: Hind limb paralysis and lung haemorrhage.’Ultrasound Med. Biol.20 (1994): 53–63
14.
FrizzellL. A.O'BrienW. D.ZacharyJ. F.‘Effect of pulse polarity and energy on ultrasound-induced lung hemorrhage in adult rats.’J. Acoust. Soc. Am.113 (2004): 2912–2926
15.
TarantalA. F.CanfieldD. R.‘Ultrasound induced lung haemorrhage in the monkey.’Ultrasound Med. Biol.20 (1994): 65–72
16.
O'BrienW. D.DengC. X.HarrisG. R.HermanB. A.MerrittC. R.SanghviN.ZacharyJ. F.‘The risk of exposure to diagnostic ultrasound in postnatal subjects — thermal effects.’J. Ultrasound Med.27 (2008): 517–535
17.
RaemanC. H.DaleckiD.ChildS. Z.MeltzerR. S.CarstensenE. L.‘Albunex does not increase the sensitivity of the lung to pulsed ultrasound.’Echocardiography14 (1997): 553–557
18.
ChurchC. C.O'BrienW. D.‘Evaluation of the threshold for lung hemorrhage by diagnostic ultrasound and a proposed new safety.’Ultrasound Med. Biol.33 (2007): 810–818
19.
DaleckiD.RaemanC. H.ChildS. Z.CarstensenE. L.‘Intestinal hemorrhage from exposure to pulsed ultrasound.’Ultrasound Med. Biol.21 (8) (1995): 1067–1072
20.
ChurchC. C.CarstensenE. L.NyborgW. L.CarsonP. L.FrizzellL. A.BaileyM. R.‘The risk of exposure to diagnostic ultrasound in postnatal subjects — nonthermal mechanisms.’J. Ultrasound Med.27 (2008): 565–592
MortonK. I.ter HaarG. R.StratfordI. J.HillC. R.‘The role of cavitation in the interaction of ultrasound with V79 Chinese hamster cells in vitro.’Br. J. Cancer45 (1982): 147–150
25.
HallowD. M.MahajanA. D.McCutchenT. E.PrausnitzM. R.‘Measurement and correlation of acoustic cavitation with cellular bioeffects.’Ultrasound Med. Biol.32 (70) (2006): 1111–1122
26.
LaiC. Y.WuC. H.ChenC. C.LiP. C.‘Quantitative relations of acoustic inertial cavitation with sonoporation and cell viability.’Ultrasound Med. Biol.32 (12) (2007): 1931–1941
27.
ElwartJ. W.BrettelH.KoberL. O.‘Cell membrane damage by ultrasound at different cell concentrations.’Ultrasound Med. Biol.14 (1988): 43–50
28.
BraymanA. A.ChurchC. C.MillerM. W.‘A re-evaluation of the concept that high cell concentrations ‘protect’ cells in vitro from ultrasonically induced lysis.’Ultrasound Med. Biol.22 (1996): 497–514
29.
ClarkeP. R.HillC. R.‘Biological action of ultrasound in relation to the cell cycle.’Exptl Cell Res.58 (1969): 443
30.
ter HaarG.‘Therapeutic applications of ultrasound.’Prog. Biophys. Molecular Biol.93 (2007): 111–129
31.
WilliamsA. R.SykesS. M.O'BrienW. D.‘Ultrasonic exposure modifies platelet morphology and function in vitro.’Ultrasound Med. Biol.2 (4) (1977): 311–317
32.
DengC. X.XuQ.ApfelR. E.HollandC. K.‘In vitro measurements of inertial cavitation thresholds in human blood.’Ultrasound Med. Biol.22 (1996): 939–948
33.
DaleckiD.RaemanC. H.ChildS. Z.CoxC.FrancisC. W.MeltzerR. S.CarstensenE. L.‘Hemolysis in vivo from exposure to pulsed ultrasound.’Ultrasound Med. Biol.23 (1997): 307–313
34.
PoliachikS. L.ChandlerW. L.MouradP. D.BaileyM. R.BlochS.ClevelandR. O.KaczkowskiP.KeilmanG.PorterT.CrumL. A.‘Effect of high intensity focused ultrasound on whole blood with and without microbubble contrast agent.’Ultrasound Med. Biol.25 (1999): 991–998
35.
MillerD. L.NyborgW. L.WhitcombC. C.‘Platelet aggregation induced by ultrasound under specialised conditions in vitro.’Science205 (1979): 505–507
36.
RooneyJ. A.‘Haemolysis near an ultrasonically pulsating gas bubble.’Science169 (1970): 869–871
37.
WilliamsA. R.MillerD. L.‘Photometric detection of ATP release from human erythrocytes exposed to ultrasonically activated gas-filled pores.’Ultrasound Med. Biol.56 (1980): 1640–1643
38.
BraymanA. A.AzadnivM.MakinI. R. S.MillerM. W.CarstensenE. L.ChildS. Z.RaemanC. H.MeltzerR. S.EverbachE. C.‘Effect of stabilised microbubblecontrast agent on haemolysis of human erythrocytes exposed to high intensity pulsed ultrasound.’Echocardiography12 (1995): 13–21
MillerD. L.ThomasR. M.‘Thresholds for hemorrhages in mouse skin and intestine induced by lithotripter shock waves.’Ultrasound Med. Biol.21 (1995): 249–257
42.
BraymanA. A.StricklerP. L.LuanH.BarnedS. L.RaemanC. H.CoxC.MillerM. W.‘Hemolysis of 40% hematocrit, Albunex7-supplemented human erythrocytes by pulsed ultrasound: Frequency, acoustic pressure and pulse length dependence.’Ultrasound Med. Biol.23 (1997): 1237–1250
43.
MillerM. W.EverbachE. C.CoxC.KnappR. R.BraymanA. A.ShermanT. A.‘A comparison of the hemolytic potential of Optison7 and Albunex7 in whole human blood in vitro: Acoustic pressure, ultrasound frequency, donor and passive cavitation detection considerations.’Ultrasound Med. Biol.27 (2001): 709–721
44.
MillerM. W.EverbachE. C.MillerW. M.BattagliaL. F.‘Biological and environmental factors affecting ultrasound induced hemolysis in vitro: 2. Medium dissolved gas (pO2) content.’Ultrasound Med. Biol.29 (2003): 93–102
45.
EverbachE. C.MakinI. R.AzadnivM.MeltzerR. S.‘Correlation of ultrasound-induced hemolysis with cavitation detector output in vitro.’Ultrasound Med. Biol.23 (1997): 619–624
46.
ChenW. S.BraymanA. A.MatulaT. J.CrumL. A.‘Inertial cavitation dose and hemolysis produced in vitro with or without Optison7.’Ultrasound Med. Biol.29 (2003): 725–737
47.
ChenW. S.BraymanA. A.MatulaT. J.CrumL. A.MillerM. W.‘The pulse length-dependence of inertial cavitation dose and hemolysis.’Ultrasound Med. Biol.29 (5) (2003): 739–748
48.
DaleckiD.ChildS. Z.RaemanC. H.CoxC.‘Haemorrhage in murine fetuses exposed to pulsed ultrasound.’Ultrasound Med. Biol.25 (1999): 1139–1144
49.
BigelowT. A.MillerR. J.BlueJ. P.O'BrienW. D.‘Haemorrhage near fetal rat bone exposed to pulsed ultrasound.’Ultrasound Med. Biol.33 (2007): 311–317
50.
GrossD. R.MillerD. L.WilliamsA. R.‘A search for ultrasonic cavitation within the canine cardiovascular system.’Ultrasound Med. Biol.11 (1985): 85–97
51.
HwangJ. H.BraymanA. A.ReidyM. A.MatulaT. J.KimmeyM. B.CrumL. A.‘Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo.’Ultrasound Med. Biol.31 (2005): 553–564
52.
MillerD. L.QuddusJ.‘Diagnostic ultrasound activation of contrast agent gas bodies induces capillary rupture in mice.’Proc. Natl Acad. Sci.97 (2000): 10179–10184
53.
KobayashiN.YasuT.YamadaS.KudoN.KurokiM.KawakamiM.MiyatakeK.SaitoM.‘Endothelial cell injury in venule and capillary induced by contrast ultrasonography.’Ultrasound Med. Biol.28 (7) (2002): 949–956
54.
KobayashiN.YasuT.YamadaS.KudoN.KurokiM.MiyatakeK.KawakamiM.SaitoM.‘Influence of contrast ultrasonography with perflutren lipid microspheres on microvessel injury.’Circulation J.67 (7) (2003): 630–636
55.
LiP.CaoL. Q.DouC. Y.ArmstrongW. R.MillerD. L.‘Impact of myocardial contrast echocardiography on vascular permeability: An in vivo dose response study of delivery mode, ultrasound power and contrast dose.’Ultrasound Med. Biol.29 (2003): 1341–1349
56.
LiP.ArmstrongW. F.MillerD. L.‘Impact of myocardial contrast echocardiography on vascular permeability: Comparison of three different contrast agents.’Ultrasound Med. Biol.30 (1) (2004): 83–91
57.
MillerD. L.LiP.ArmstrongW. F.‘The effect of time and of vasoactive drugs on capillary leakage induced during myocardial contrast echocardiography.’Echocardiography21 (2004): 125–132
58.
WibleJ. H.GalenK. P.WojdylaJ. K.HughesM. S.KlibanovA. L.BrandenburgerG. H.‘Microbubbles induce renal hemorrhage when exposed to diagnostic ultrasound in anesthetized rats.’Ultrasound Med. Biol.28 (2002): 1535–1546
59.
MillerD. L.DouC.WigginsR. C.‘An in vivo rat model simulating imaging of human kidney by diagnostic ultrasound with gas-body contrast agent.’Ultrasound Med. Biol.33 (2007): 129–135
60.
WilliamsA. R.WigginsR. C.WharramB. L.GoyalM.DouC.JohnsonK. J.MillerD. L.‘Nephron injury induced by diagnostic ultrasound imaging at high mechanical gas body contrast agent.’Ultrasound Med. Biol.33 (8) (2007): 1336–1344
61.
HynynenK.McDannoldN.SheikovN. A.JoleszF. A.VykhodtsevaN.‘Local and reversible blood—brain barrier disruption by non-invasive focused ultrasound at frequencies suitable for trans-skull sonications.’Neuroimage24 (2005): 12–20
62.
AngE. S.GluncicV.DuqueA.SchaferM. E.RakicP.‘Prenatal exposure to ultrasound waves impacts neuronal migration in mice.’Proc. Natl Acad. Sci.103 (34) (2006): 12903–12910
63.
GressensP.HuppiP. S.‘Are prenatal ultrasounds safe for the developing brain?’Pediatr. Res.61 (3) (2007): 265–266
64.
MillerM. W.MillerR. K.BattagliaL. F.DeweyW. C.EdwardsM. J.NyborgW. L.CoxC.AbramowiczJ.‘The ΔT thermal dose concept 1: in vivo teratogenesis.’J. Thermal Biol.29 (2004): 141–149
65.
MillerM. W.NyborgW. L.DeweyW. C.EdwardsM. J.AbramowiczJ. S.BraymanA. A.‘Diagnostic ultrasound during pregnancy: Effects of new standards on tissue heating and their relevance to hyperthermic teratogenicity.’Int. J. Hyperthermia18 (2002): 361–384
66.
EdwardsM. J.‘Hyperthermia and birth defects [editorial].’Cornell Vet83 (1993): 1–7
67.
ShawG. M.TodoroffK.VelieE. M.LammerE. J.‘Maternal illness, including fever, and medication use as risk factors for neural tube defects.’Teratology57 (1998): 1–7
68.
ChanceP. F.SmithD. W.‘Hyperthermia and meningomyelocele and anencephaly.’Lancet1 (1978): 769–770
LynbergM. C.KhouryM. J.LuX.CocianT.‘Maternal flu, fever, and risk of neural tube defects: A population-based case-control study.’Am. J. Epidemiology140 (1994): 244–255
72.
WerlerM. M.LouikC.MitchellA. A.‘Heat source exposure and neural tube defect risk.’Am. J. Epidemiology142 (1995): 369
73.
DugganP. M.LigginsG. C.BarnettS. B.‘Ultrasonic heating of the brain of the fetal sheep in utero.’Ultrasound Med. Biol.21 (1995): 553–560
74.
HorderM. H.BarnettS. B.VellaG. J.EdwardsM. J.WoodA. K. W.‘In vivo heating of the guinea-pig fetal brain by pulsed ultrasound and estimates of thermal index.’Ultrasound Med. Biol.24 (1998): 1467–1474
75.
HorderM. H.BarnettS. B.VellaG. J.EdwardsM. J.WoodA. K. W.‘Ultrasound-induced temperature increase in guinea-pig fetal brain in utero: third-trimester gestation.’Ultrasound Med. Biol.24 (1998): 1501–1510
76.
MakikallioK.TekayA.JoupilaP.‘Yolk sac and umbilicoplacental hemodynamics during early human embryonic development.’Ultrasound Obstet. Gynaec.14 (1999): 175–179
DugganP. M.MurcottM. F.McPheeA. J.BarnettS. B.‘The influence of variations in blood flow on pulsed Doppler ultrasonic heating of the cerebral cortex of the neonatal pig.’Ultrasound Med. Biol.26 (2000): 647–654
79.
80.
ApfelR. E.HollandC. K.‘Gauging the likelihood of cavitation from short-pulse, low-duty cycle diagnostic ultrasound.’Ultrasound Med. Biol.17 (1991): 179–185
81.
ICRU. Tissue substitutes, phantoms and computational modelling in Medical Ultrasound. ICR Report 61, International Commission on Radiological Units and Measurement, Bethesda, MD, USA1991.
82.
NelsonT. R.FowlkesJ. B.AbramowiczJ. S.ChurchC. C.‘Ultrasound biosafety considerations for the practicing sonographers and sonologist.’J. Ultrasound Med.28 (2009): 139–150
83.
MarsalK.‘The output display standard: Has it missed its target?’Ultrasound Obstet. Gynaec.25 (2005): 211–214
84.
ter HaarG.‘Results of a survey of exposure conditions used in ultrasound scans in the UK, February 2007.’Ultrasound16 (2) (2008): 110–113
85.
BMUS. Guidelines for the safe use of diagnostic ultrasound equipment (British Medical Ultrasound Society) available from http://www.bmus.org.
86.
VermaP.‘Observations of MI values during neonatal cardiac ultrasound scanning.’Ultrasound16 (4) (2008): 203–207
87.
‘Exposure criteria for medical diagnostic ultrasound: 1.’ Criteria based on all known mechanisms, NCRP report 140, National Council on Radiation Protection and Measurements, Bethesda, Maryland2002.
88.
IEC 60601, Part 2–37, edition 2. Medical electrical equipment: particular requirements for the safety of ultrasound diagnostic and monitoring equipment, 2007 (International Electrotechnical Commission, Geneva).
89.
Requirements for the declaration of the acoustic output of medical diagnostic equipment (International Electrotechnical Commission1992)
90.
‘Information for manufacturers seeking marketing clearance of diagnostic ultrasound systems and transducers.’ Division of Reproductive, Abdominal, Ear, Nose, Throat and Radiological Devices: Office of Device Evaluation. US Department of Health and Human Services: Food and Drug Administration1997, available from www.fda.gov/cdrh/ode/ulstran.pdf.
91.
Medical ultrasound safety (American Institute of Ultrasound in Medicine1994)
92.
‘Thermal and mechanical indices, ECMUS safety committee tutorial.’Eur. J. Ultrasound4 (1996): 145–150 Available from www.efsumb.org.
93.
‘Conclusions and recommendations on thermal and non-thermal mechanisms for biological effects.’Ultrasound Med. Biol.24 (Suppl. 1) (1998): xv–xvi.
KielerH.‘Epidemiological studies on adverse effects of prenatal ultrasound — Which are the challenges?’Progr. Biophys. Molecular Biol.93 (2007): 301–308
