Contrast agents

Abstract

IntroductionSince the first concepts for the potential for using clinical ultrasound were developed in the late 1940s and early 1950s, there has been a slow but progressive advance in the utilization of ultrasound. This advance has occurred as new technologies have been developed, including gray-scale, pulsed and color Doppler. Improvements in technology have led to the ability of ultrasound to obtain increasingly more anatomical detail and to detect flow in smaller vessels. Because of the introduction of each new advance over the past 50 years, the utilization of ultrasound has progressed to the point where almost 25% of all imaging studies worldwide are ultrasound examinations. In fact, the World Health Organization is recommending the utilization of ultrasound after basic X-ray, as opposed to more advanced imaging procedures such as CT and MRI, because of the wide accessibility around the world and usefulness of this technique.The decade of the 1990s has seen the introduction of ultrasound contrast agents under evaluation in multiple centers around the world, with some agents having already been approved for use in humans (Goldberg 1997Goldberg B.B. Ultrasound contrast agents. Martin Dunitz, London1997Google Scholar). What is occurring, it seems, is the beginning of a revolution that will dramatically increase the utilization of ultrasound by significantly improving its diagnostic capabilities. It is estimated that, at the present time, more than US $1 billion has been spent by research centers and pharmaceutical companies in the development and evaluation of a wide variety of these agents. They have already shown the potential to significantly increase Doppler sensitivity, both pulsed and color, and to improve the ability to detect flow in deep as well as small vessels throughout the body (Nanda et al 1997Nanda NC, Schlief R, Goldberg BB, eds. Advances in echo imaging using contrast enhancement (2nd ed.). Dordrecht: Kluwer Academic, 1997.Google Scholar). A number of these agents can also produce gray-scale enhancement (Forsberg et al 1995Forsberg F. Liu J.B. Merton D.A. Rawool N.M. Goldberg B.B. Parenchymal enhancement and tumor visualization using a new sonographic contrast agent.J Ultrasound Med. 1995; 14: 949-957Crossref PubMed Scopus (75) Google Scholar). This has resulted in the identification of areas of myocardial infarction, as well as improved tumor detection in areas such as the liver and kidney. In animal models, liver tumors as small as 2–3 mm in diameter have been detected by utilizing tissue-specific agents taken up by the reticuloendothelial system (Goldberg et al 1994Goldberg B.B. Liu J.B. Forsberg F. Ultrasound contrast agents A review.Ultrasound Med Biol. 1994; 20: 319-333Abstract Full Text PDF PubMed Scopus (457) Google Scholar).New developmentsOther unique products are under development that will, for instance, attach to blood clots allowing them to be much more easily visualized, with the possibility of clot-dissolving agents being encapsulated within some of these coated bubbles. By increasing the sound energy, the bubble-containing agent will rupture, forcing the clot-dissolving agent to penetrate the clot resulting in targeting treatment. The same concept is being investigated in tumors, with the ability of these agents to circulate within the tumor microvascularity, increasing not only diagnostic capabilities but also allowing some of these bubbles to contain agents toxic to the tumor. Ultrasound energy is then used to rupture the bubbles and release the toxic materials only within the tumors. New advances in ultrasound technology, including harmonic imaging that increases the ability to display the presence of contrast agents because of their specific harmonic characteristics, will significantly increase tissue contrast resolution as well as the length of time during which the agent is diagnostically useful. Three-dimensional ultrasound using both gray-scale and color modes will improve the ability of these agents to differentiate benign from malignant tumors by displaying vascularity similar to X-ray angiography. These and other unique agents, not yet fully developed, will become available over the next decade. As a result, there will be a dramatic effect on the utilization of ultrasound in a wide variety of areas, some of which will have a significant impact on currently accepted diagnostic pathways. Ultrasound, which is the first study of choice in obstetrics and cardiology, will become the primary imaging study for all soft tissue abnormalities, with CT, MRI, nuclear medicine and angiography being relegated to a secondary position when ultrasound cannot adequately provide diagnostic information.It is predicted with this revolution in ultrasound contrast agents that by the year 2010, ultrasound, with the utilization of a variety of these agents, will account for more than 50% of all soft tissue imaging studies. There will be a significant reduction in the use of radionuclide scanning for the detection of myocardial infarction, as it will be replaced by contrast-enhanced echocardiography that will be able to differentiate viable from nonviable cardiac muscle. Within the abdomen, there will be a significant impact on the utilization of CT and MRI. With the use of a variety of ultrasound contrast agents, the increase in tissue contrast resolution and, more specifically, agents that distinguish normal from abnormal tissue, will improve the ability to detect tumors in a variety of soft tissue organs, such as the liver, kidney and pancreas. Presently, approximately one-third of all tumors may have the same echogenicity as normal tissue. It is the difference in echogenicity that allows one to distinguish between normal and abnormal tissue. With CT and MRI, the use of contrast agents results in improved detection of masses, often related to the improvement in contrast resolution and the differential in vascularity between normal tissue and tumors. The same results, or even improved results, will be obtained with ultrasound, with the advantages of lower cost for equipment as well as for its use. It is also anticipated that organ-specific agents will significantly improve the ability to detect tumors within the prostate, identifying those tumors not presently seen because of their similar echogenicity to normal tissue.It will be possible to differentiate benign from malignant lesions. For instance, the slower flow within hemangiomas will be easily detected, and the differentiation between malignant-type vascular patterns compared to benign vascularity with the use of a variety of harmonic techniques along with 3-D color Doppler imaging will also be possible. Ultrasound contrast agents will also be able to determine the potential for tumor spread by measuring the degree of tumor vascularity.At present, the common methods for examination of the gastrointestinal (GI) tract are X-ray with barium and endoscopy. Their shortcomings include the fact that they often cannot delineate mural structures of the GI tract. Limitations to the sonographic assessment of the upper GI tract and adjacent organs include patient body habitus and the presence of gas-filled bowel that can produce shadowing artifacts. The ideal oral contrast agent should have the ability to improve the assessment of the GI tract and adjacent structures by absorbing and displacing bowel gas that otherwise limits visualization of structures such as the pancreas, renal arteries, or para-aortic lymphadenopathy. Ingestion of an oral agent results in a homogeneous transmission of sound through the contrast-filled stomach. It produces uniform reflections within the bowel and eliminates artifacts owing to bowel gas. It can also provide an acoustic window for evaluation of organs adjacent to the stomach, especially the pancreas. These agents will be used in combination with intravenous agents to detect pancreatic tumors (Goldberg 1997Goldberg B.B. Ultrasound contrast agents. Martin Dunitz, London1997Google Scholar).The need for increased training in ultrasound will result in the development of an extensive worldwide training network, as increasing numbers of physicians enter this area of imaging. Unfortunately for radiologists, their emphasis on CT and MRI will lead to greater diffusion of ultrasound among many other specialties, to an even greater extent than is present today. Clinical specialists will be able to increase their diagnostic capabilities through the use of a variety of ultrasound contrast agents without the need to refer their patients for CT, MRI or nuclear medicine imaging. However, strategic partnerships with these specialists by enlightened radiologists will lead to cooperative agreements, with the expertise of both the ultrasound radiologist and the clinical specialist working together in a central unit to provide the optimum diagnostic and therapeutic capabilities of ultrasound.By the year 2010, we will see the introduction of a wide variety of therapeutic ultrasound contrast agents, a portion of which will contain materials other than gas which will be toxic to a variety of tumors, as well as agents that will adhere to clots and, when released, agents that will dissolve these clots. Education will play a key role in ensuring that the benefits of ultrasound contrast agents are maximized to improve patient care and treatment. Turf battles over ultrasound utilization will decrease significantly with the concept of cooperation and the knowledge that each specialty has something to contribute to the now dominant modalities of diagnostic and therapeutic ultrasound. IntroductionSince the first concepts for the potential for using clinical ultrasound were developed in the late 1940s and early 1950s, there has been a slow but progressive advance in the utilization of ultrasound. This advance has occurred as new technologies have been developed, including gray-scale, pulsed and color Doppler. Improvements in technology have led to the ability of ultrasound to obtain increasingly more anatomical detail and to detect flow in smaller vessels. Because of the introduction of each new advance over the past 50 years, the utilization of ultrasound has progressed to the point where almost 25% of all imaging studies worldwide are ultrasound examinations. In fact, the World Health Organization is recommending the utilization of ultrasound after basic X-ray, as opposed to more advanced imaging procedures such as CT and MRI, because of the wide accessibility around the world and usefulness of this technique.The decade of the 1990s has seen the introduction of ultrasound contrast agents under evaluation in multiple centers around the world, with some agents having already been approved for use in humans (Goldberg 1997Goldberg B.B. Ultrasound contrast agents. Martin Dunitz, London1997Google Scholar). What is occurring, it seems, is the beginning of a revolution that will dramatically increase the utilization of ultrasound by significantly improving its diagnostic capabilities. It is estimated that, at the present time, more than US $1 billion has been spent by research centers and pharmaceutical companies in the development and evaluation of a wide variety of these agents. They have already shown the potential to significantly increase Doppler sensitivity, both pulsed and color, and to improve the ability to detect flow in deep as well as small vessels throughout the body (Nanda et al 1997Nanda NC, Schlief R, Goldberg BB, eds. Advances in echo imaging using contrast enhancement (2nd ed.). Dordrecht: Kluwer Academic, 1997.Google Scholar). A number of these agents can also produce gray-scale enhancement (Forsberg et al 1995Forsberg F. Liu J.B. Merton D.A. Rawool N.M. Goldberg B.B. Parenchymal enhancement and tumor visualization using a new sonographic contrast agent.J Ultrasound Med. 1995; 14: 949-957Crossref PubMed Scopus (75) Google Scholar). This has resulted in the identification of areas of myocardial infarction, as well as improved tumor detection in areas such as the liver and kidney. In animal models, liver tumors as small as 2–3 mm in diameter have been detected by utilizing tissue-specific agents taken up by the reticuloendothelial system (Goldberg et al 1994Goldberg B.B. Liu J.B. Forsberg F. Ultrasound contrast agents A review.Ultrasound Med Biol. 1994; 20: 319-333Abstract Full Text PDF PubMed Scopus (457) Google Scholar). Since the first concepts for the potential for using clinical ultrasound were developed in the late 1940s and early 1950s, there has been a slow but progressive advance in the utilization of ultrasound. This advance has occurred as new technologies have been developed, including gray-scale, pulsed and color Doppler. Improvements in technology have led to the ability of ultrasound to obtain increasingly more anatomical detail and to detect flow in smaller vessels. Because of the introduction of each new advance over the past 50 years, the utilization of ultrasound has progressed to the point where almost 25% of all imaging studies worldwide are ultrasound examinations. In fact, the World Health Organization is recommending the utilization of ultrasound after basic X-ray, as opposed to more advanced imaging procedures such as CT and MRI, because of the wide accessibility around the world and usefulness of this technique. The decade of the 1990s has seen the introduction of ultrasound contrast agents under evaluation in multiple centers around the world, with some agents having already been approved for use in humans (Goldberg 1997Goldberg B.B. Ultrasound contrast agents. Martin Dunitz, London1997Google Scholar). What is occurring, it seems, is the beginning of a revolution that will dramatically increase the utilization of ultrasound by significantly improving its diagnostic capabilities. It is estimated that, at the present time, more than US $1 billion has been spent by research centers and pharmaceutical companies in the development and evaluation of a wide variety of these agents. They have already shown the potential to significantly increase Doppler sensitivity, both pulsed and color, and to improve the ability to detect flow in deep as well as small vessels throughout the body (Nanda et al 1997Nanda NC, Schlief R, Goldberg BB, eds. Advances in echo imaging using contrast enhancement (2nd ed.). Dordrecht: Kluwer Academic, 1997.Google Scholar). A number of these agents can also produce gray-scale enhancement (Forsberg et al 1995Forsberg F. Liu J.B. Merton D.A. Rawool N.M. Goldberg B.B. Parenchymal enhancement and tumor visualization using a new sonographic contrast agent.J Ultrasound Med. 1995; 14: 949-957Crossref PubMed Scopus (75) Google Scholar). This has resulted in the identification of areas of myocardial infarction, as well as improved tumor detection in areas such as the liver and kidney. In animal models, liver tumors as small as 2–3 mm in diameter have been detected by utilizing tissue-specific agents taken up by the reticuloendothelial system (Goldberg et al 1994Goldberg B.B. Liu J.B. Forsberg F. Ultrasound contrast agents A review.Ultrasound Med Biol. 1994; 20: 319-333Abstract Full Text PDF PubMed Scopus (457) Google Scholar). New developmentsOther unique products are under development that will, for instance, attach to blood clots allowing them to be much more easily visualized, with the possibility of clot-dissolving agents being encapsulated within some of these coated bubbles. By increasing the sound energy, the bubble-containing agent will rupture, forcing the clot-dissolving agent to penetrate the clot resulting in targeting treatment. The same concept is being investigated in tumors, with the ability of these agents to circulate within the tumor microvascularity, increasing not only diagnostic capabilities but also allowing some of these bubbles to contain agents toxic to the tumor. Ultrasound energy is then used to rupture the bubbles and release the toxic materials only within the tumors. New advances in ultrasound technology, including harmonic imaging that increases the ability to display the presence of contrast agents because of their specific harmonic characteristics, will significantly increase tissue contrast resolution as well as the length of time during which the agent is diagnostically useful. Three-dimensional ultrasound using both gray-scale and color modes will improve the ability of these agents to differentiate benign from malignant tumors by displaying vascularity similar to X-ray angiography. These and other unique agents, not yet fully developed, will become available over the next decade. As a result, there will be a dramatic effect on the utilization of ultrasound in a wide variety of areas, some of which will have a significant impact on currently accepted diagnostic pathways. Ultrasound, which is the first study of choice in obstetrics and cardiology, will become the primary imaging study for all soft tissue abnormalities, with CT, MRI, nuclear medicine and angiography being relegated to a secondary position when ultrasound cannot adequately provide diagnostic information.It is predicted with this revolution in ultrasound contrast agents that by the year 2010, ultrasound, with the utilization of a variety of these agents, will account for more than 50% of all soft tissue imaging studies. There will be a significant reduction in the use of radionuclide scanning for the detection of myocardial infarction, as it will be replaced by contrast-enhanced echocardiography that will be able to differentiate viable from nonviable cardiac muscle. Within the abdomen, there will be a significant impact on the utilization of CT and MRI. With the use of a variety of ultrasound contrast agents, the increase in tissue contrast resolution and, more specifically, agents that distinguish normal from abnormal tissue, will improve the ability to detect tumors in a variety of soft tissue organs, such as the liver, kidney and pancreas. Presently, approximately one-third of all tumors may have the same echogenicity as normal tissue. It is the difference in echogenicity that allows one to distinguish between normal and abnormal tissue. With CT and MRI, the use of contrast agents results in improved detection of masses, often related to the improvement in contrast resolution and the differential in vascularity between normal tissue and tumors. The same results, or even improved results, will be obtained with ultrasound, with the advantages of lower cost for equipment as well as for its use. It is also anticipated that organ-specific agents will significantly improve the ability to detect tumors within the prostate, identifying those tumors not presently seen because of their similar echogenicity to normal tissue.It will be possible to differentiate benign from malignant lesions. For instance, the slower flow within hemangiomas will be easily detected, and the differentiation between malignant-type vascular patterns compared to benign vascularity with the use of a variety of harmonic techniques along with 3-D color Doppler imaging will also be possible. Ultrasound contrast agents will also be able to determine the potential for tumor spread by measuring the degree of tumor vascularity.At present, the common methods for examination of the gastrointestinal (GI) tract are X-ray with barium and endoscopy. Their shortcomings include the fact that they often cannot delineate mural structures of the GI tract. Limitations to the sonographic assessment of the upper GI tract and adjacent organs include patient body habitus and the presence of gas-filled bowel that can produce shadowing artifacts. The ideal oral contrast agent should have the ability to improve the assessment of the GI tract and adjacent structures by absorbing and displacing bowel gas that otherwise limits visualization of structures such as the pancreas, renal arteries, or para-aortic lymphadenopathy. Ingestion of an oral agent results in a homogeneous transmission of sound through the contrast-filled stomach. It produces uniform reflections within the bowel and eliminates artifacts owing to bowel gas. It can also provide an acoustic window for evaluation of organs adjacent to the stomach, especially the pancreas. These agents will be used in combination with intravenous agents to detect pancreatic tumors (Goldberg 1997Goldberg B.B. Ultrasound contrast agents. Martin Dunitz, London1997Google Scholar).The need for increased training in ultrasound will result in the development of an extensive worldwide training network, as increasing numbers of physicians enter this area of imaging. Unfortunately for radiologists, their emphasis on CT and MRI will lead to greater diffusion of ultrasound among many other specialties, to an even greater extent than is present today. Clinical specialists will be able to increase their diagnostic capabilities through the use of a variety of ultrasound contrast agents without the need to refer their patients for CT, MRI or nuclear medicine imaging. However, strategic partnerships with these specialists by enlightened radiologists will lead to cooperative agreements, with the expertise of both the ultrasound radiologist and the clinical specialist working together in a central unit to provide the optimum diagnostic and therapeutic capabilities of ultrasound.By the year 2010, we will see the introduction of a wide variety of therapeutic ultrasound contrast agents, a portion of which will contain materials other than gas which will be toxic to a variety of tumors, as well as agents that will adhere to clots and, when released, agents that will dissolve these clots. Education will play a key role in ensuring that the benefits of ultrasound contrast agents are maximized to improve patient care and treatment. Turf battles over ultrasound utilization will decrease significantly with the concept of cooperation and the knowledge that each specialty has something to contribute to the now dominant modalities of diagnostic and therapeutic ultrasound. Other unique products are under development that will, for instance, attach to blood clots allowing them to be much more easily visualized, with the possibility of clot-dissolving agents being encapsulated within some of these coated bubbles. By increasing the sound energy, the bubble-containing agent will rupture, forcing the clot-dissolving agent to penetrate the clot resulting in targeting treatment. The same concept is being investigated in tumors, with the ability of these agents to circulate within the tumor microvascularity, increasing not only diagnostic capabilities but also allowing some of these bubbles to contain agents toxic to the tumor. Ultrasound energy is then used to rupture the bubbles and release the toxic materials only within the tumors. New advances in ultrasound technology, including harmonic imaging that increases the ability to display the presence of contrast agents because of their specific harmonic characteristics, will significantly increase tissue contrast resolution as well as the length of time during which the agent is diagnostically useful. Three-dimensional ultrasound using both gray-scale and color modes will improve the ability of these agents to differentiate benign from malignant tumors by displaying vascularity similar to X-ray angiography. These and other unique agents, not yet fully developed, will become available over the next decade. As a result, there will be a dramatic effect on the utilization of ultrasound in a wide variety of areas, some of which will have a significant impact on currently accepted diagnostic pathways. Ultrasound, which is the first study of choice in obstetrics and cardiology, will become the primary imaging study for all soft tissue abnormalities, with CT, MRI, nuclear medicine and angiography being relegated to a secondary position when ultrasound cannot adequately provide diagnostic information. It is predicted with this revolution in ultrasound contrast agents that by the year 2010, ultrasound, with the utilization of a variety of these agents, will account for more than 50% of all soft tissue imaging studies. There will be a significant reduction in the use of radionuclide scanning for the detection of myocardial infarction, as it will be replaced by contrast-enhanced echocardiography that will be able to differentiate viable from nonviable cardiac muscle. Within the abdomen, there will be a significant impact on the utilization of CT and MRI. With the use of a variety of ultrasound contrast agents, the increase in tissue contrast resolution and, more specifically, agents that distinguish normal from abnormal tissue, will improve the ability to detect tumors in a variety of soft tissue organs, such as the liver, kidney and pancreas. Presently, approximately one-third of all tumors may have the same echogenicity as normal tissue. It is the difference in echogenicity that allows one to distinguish between normal and abnormal tissue. With CT and MRI, the use of contrast agents results in improved detection of masses, often related to the improvement in contrast resolution and the differential in vascularity between normal tissue and tumors. The same results, or even improved results, will be obtained with ultrasound, with the advantages of lower cost for equipment as well as for its use. It is also anticipated that organ-specific agents will significantly improve the ability to detect tumors within the prostate, identifying those tumors not presently seen because of their similar echogenicity to normal tissue. It will be possible to differentiate benign from malignant lesions. For instance, the slower flow within hemangiomas will be easily detected, and the differentiation between malignant-type vascular patterns compared to benign vascularity with the use of a variety of harmonic techniques along with 3-D color Doppler imaging will also be possible. Ultrasound contrast agents will also be able to determine the potential for tumor spread by measuring the degree of tumor vascularity. At present, the common methods for examination of the gastrointestinal (GI) tract are X-ray with barium and endoscopy. Their shortcomings include the fact that they often cannot delineate mural structures of the GI tract. Limitations to the sonographic assessment of the upper GI tract and adjacent organs include patient body habitus and the presence of gas-filled bowel that can produce shadowing artifacts. The ideal oral contrast agent should have the ability to improve the assessment of the GI tract and adjacent structures by absorbing and displacing bowel gas that otherwise limits visualization of structures such as the pancreas, renal arteries, or para-aortic lymphadenopathy. Ingestion of an oral agent results in a homogeneous transmission of sound through the contrast-filled stomach. It produces uniform reflections within the bowel and eliminates artifacts owing to bowel gas. It can also provide an acoustic window for evaluation of organs adjacent to the stomach, especially the pancreas. These agents will be used in combination with intravenous agents to detect pancreatic tumors (Goldberg 1997Goldberg B.B. Ultrasound contrast agents. Martin Dunitz, London1997Google Scholar). The need for increased training in ultrasound will result in the development of an extensive worldwide training network, as increasing numbers of physicians enter this area of imaging. Unfortunately for radiologists, their emphasis on CT and MRI will lead to greater diffusion of ultrasound among many other specialties, to an even greater extent than is present today. Clinical specialists will be able to increase their diagnostic capabilities through the use of a variety of ultrasound contrast agents without the need to refer their patients for CT, MRI or nuclear medicine imaging. However, strategic partnerships with these specialists by enlightened radiologists will lead to cooperative agreements, with the expertise of both the ultrasound radiologist and the clinical specialist working together in a central unit to provide the optimum diagnostic and therapeutic capabilities of ultrasound. By the year 2010, we will see the introduction of a wide variety of therapeutic ultrasound contrast agents, a portion of which will contain materials other than gas which will be toxic to a variety of tumors, as well as agents that will adhere to clots and, when released, agents that will dissolve these clots. Education will play a key role in ensuring that the benefits of ultrasound contrast agents are maximized to improve patient care and treatment. Turf battles over ultrasound utilization will decrease significantly with the concept of cooperation and the knowledge that each specialty has something to contribute to the now dominant modalities of diagnostic and therapeutic ultrasound.