Trends in contrast media research the last 100 years.

This review focuses on the trends in contrast media (CM) research published in Acta Radiologica during the last 100 years, since the first edition in 1921. The main topics covered are the developments of iodine- and gadolinium-based CM. Other topics include manganese-based CM for magnetic resonance imaging (MRI) and barium for the investigation of the alimentary tract. From a historic point of view, special CM for use in cholegraphy and myelography are addressed in the review. Today, these imaging procedures are obsolete due to the development of computed tomography, MRI, and ultrasound. The historical use of radioactive thorium-based CM for angiography is also addressed. Furthermore, publications on adverse reactions to CM are reviewed.

The history of magnetic resonance imaging and its reflections in Acta Radiologica.

The first reports in Acta Radiologica on magnetic resonance imaging (MRI) were published in 1984, four years after the first commercial MR scanners became available. For the first two years, all MR papers originated from the USA. Nordic contributions started in 1986, and until 2020, authors from 44 different countries have published MR papers in Acta Radiologica. Papers on MRI have constituted, on average, 30%-40% of all published original articles in Acta Radiologica, with a high of 49% in 2019. The MR papers published since 1984 document tremendous progress in several areas such as magnet and coil design, motion compensation techniques, faster image acquisitions, new image contrast, contrast-enhanced MRI, functional MRI, and image analysis. In this historical review, all of these aspects of MRI are discussed and related to Acta Radiologica papers.

Contrast Media-Different Types of Contrast Media, Their History, Chemical Properties, and Relative Nephrotoxicity.

History of contrast dates back to the 1890s, with the invention of the radiograph. Nephrotoxicity has been a main limitation in ideal contrast media (CM). High-osmolar contrast media no longer are in clinical use due to overwhelming evidence supporting greater nephrotoxicity with these CM compared with current CM. Contrast-induced nephropathy (CIN) remains a common cause of in-hospital acute kidney injury. The choice contrast agent is determined mainly by cost and institution practice. This review focuses on the history, chemical properties, and experimental and clinical studies on the various groups of CM and their role in CIN.

Nonrenal Complications of Contrast Media.

Injection of contrast media is the foundation of invasive and interventional cardiovascular practice. Iodine-based contrast was first used in the 1920s for urologic procedures and examinations. The initially used agents had high ionic and osmolar concentrations, which led to significant side effects, namely nausea, vomiting, and hypotension. Newer contrast agents had lower ionic concentrations and lower osmolarity. Modifications to the ionic structure and iodine content led to the development of ionic low-osmolar, nonionic low-osmolar, and nonionic iso-osmolar contrast media. Contemporary contrast agents are better tolerated and produce fewer major side effects.

Three Decades of Ultrasound Contrast Agents: A Review of the Past, Present and Future Improvements.

Initial reports from the 1960s describing the observations of ultrasound contrast enhancement by tiny gaseous bubbles during echocardiographic examinations prompted the development of the first ultrasound contrast agent in the 1980s. Current commercial contrast agents for echography, such as Definity, Optison, Sonazoid and SonoVue, have proven to be successful in a variety of on- and off-label clinical indications. Whereas contrast-specific technology has seen dramatic progress after the introduction of the first approved agents in the 1990s, successful clinical translation of new developments has been limited during the same period, while understanding of microbubble physical, chemical and biologic behavior has improved substantially. It is expected that for a successful development of future opportunities, such as ultrasound molecular imaging and therapeutic applications using microbubbles, new creative developments in microbubble engineering and production dedicated to further optimizing microbubble performance are required, and that they cannot rely on bubble technology developed more than 3 decades ago.

History and Evolution of the Barium Swallow for Evaluation of the Pharynx and Esophagus.

This article reviews the history of the barium swallow from its early role in radiology to its current status as an important diagnostic test in modern radiology practice. Though a variety of diagnostic procedures can be performed to evaluate patients with dysphagia or other pharyngeal or esophageal symptoms, the barium study has evolved into a readily available, non-invasive, and cost-effective technique that can facilitate the selection of additional diagnostic tests and guide decisions about medical, endoscopic, or surgical management. This article focuses on the evolution of fluoroscopic equipment, radiography, and contrast media for evaluating the pharynx and esophagus, the importance of understanding pharyngoesophageal relationships, and major advances that have occurred in the radiologic diagnosis of select esophageal diseases, including gastroesophageal reflux disease, infectious esophagitis, eosinophilic esophagitis, esophageal carcinoma, and esophageal motility disorders.

[Retention of contrast media in the history of radiology : Sequelae of the former use of thorotrast and new challenges]. / Kontrastmittelretention in der Geschichte der Radiologie : Folgen der früheren Thorotrastanwendungen und neue Herausforderungen.

Detection of gadolinium deposits in patients who have repeatedly been administered intravenous gadolinium chelates have given rise to concern regarding the long-term safety of magnetic resonance imaging (MRI) contrast media. Nevertheless, negative long-term clinical effects have not yet been observed. In some publications parallels have been drawn to the sequelae of thorotrast that was formerly used for arterial angiography. In this article the history of thorotrast use is briefly described and in particular why, despite warnings, this substance was used frequently and worldwide. A brief summary of the results of the German Thorotrast Study revealed that high excess rates were only observed for primary malignant liver tumors after a 15-year or longer latency period and to a lesser degree of leukemias, as well as for severe local complications due to paravascular injections, particularly in the neck region. Based on this historical review, we will venture to take stock of the outcome from the "success story" of this contrast agent.

A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA.

The approval of microbubbles with the inert gas sulfur hexafluoride (SF6) and a palmitic acid shell (SonoVue(®), Bracco Geneva, CH) for the diagnostic imaging of liver tumors in adults and children by the FDA in the United States represents a milestone for contrast-enhanced ultrasound (CEUS).This warrants a look back at the history of the development of CEUS. The first publications based on echocardiographic observations of right ventricular contrast phenomena caused by tiny air bubbles following i. v. injection of indocyanine green appeared around 1970 1 2 3. A longer period of sporadic publications but no real progress then followed since, in contrast to X-ray methods, ultrasound works quite well without a contrast agent.It is noteworthy that the foundations for further development were primarily laid in Europe. The development and approval (1991) of the contrast agent Echovist(®) by a German contrast manufacturer for echocardiography unsuitable for passing through lungcapillaries 4 5 resulted in the first extracardiac indications, e. g. for detecting retrovesical reflux and tubal patency, in the mid-1980 s 6 7 8. The sensitivity of color Doppler was not able to compensate for the lack of an ultrasound contrast agent compared to CT with its obligatory contrast administration.Studies of SHU 508 - microbubbles of air moderately stabilized with galactose and palmitic acid - began in 1990 9 10 11 12 13 14 15 and the contrast agent was then introduced in 1995 in Germany as Levovist(®). The most important publications by Blomley, Cosgrove, Leen, and Albrecht are named here on a representative basis 16 17 18 19 20.SHU 508 along with other US contrast agents provided impressive proof of the superiority of CEUS for the diagnosis of liver metastases. However, practical application remained complicated and required skill and technical know-how because of a lack of suitable software on US units 21 22 23 24 25. The monograph regarding the use of contrast agent in the liver by Wermke and Gaßmann is impressive but unfortunately only available in German 26. In addition to being applied in the heart and the liver, CEUS was first used in transcranial applications 27 and in vessels 28, the kidneys 29, and the breast 30. Measurements at transit times were also of particular interest 31. It was difficult to convince ultrasound device manufacturers of the need to adapt US units to US contrast agents and not vice versa.The breakthrough came with low MI phase contrast inversion and the introduction of SonoVue(®) in many European countries in 2001. This more stable US contrast agent is easy to use and is becoming indispensable in diagnostic imaging of the liver 32 33 34 35 36 37 38 39 40. Studies have shown its excellent tolerability 41 and diagnostic reliability comparable to that of MDCT and MRI in the liver 42 43. Today it would be unimaginable to diagnose liver tumors without CEUS 44. This also applies to very small lesions 45 46.EFSUMB published the first CEUS guidelines in 2004 47 which have since been reissued and divided into hepatic 48 and extrahepatic applications 49. The first recommendations regarding quantitative assessment have also been published 50.The increasing scientific interest in CEUS is evident based on the greater number of PubMed hits for Echovist(®) (ca. 130), Levovist(®) (ca. 500) and SonoVue(®) (ca. 1500) as well as on the fact that publications regarding CEUS comprise almost 20 % of UiM/EJU articles in the last 10 years. The number of CEUS articles in UiM/EJU continues to be high 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75.In the clinical reality, CEUS has been able to become established alongside CT and MRI according to the saying "better is the enemy of good" 76 as the method of choice after B-mode ultrasound in the evaluation of liver tumor malignancy in Germany, where the technically challenging method is promoted. In the case of unclear CT and MRI findings, CEUS performed by an experienced examiner/clinician often provides the solution, particularly in the case of small lesions, and is the last resort before US-guided biopsy 45 46. However, there is a lack of competent CEUS examiners and Germany continues to be the world champion of X-ray examinations with no noticeable reverse trend. In almost every doctor's office and hospital, ultrasound costs are by far not fully covered, resulting in an extremely high frequency of CT use with CT being available to everyone regardless of insurance status.The USA is now in the starting position for CEUS. It will be exciting to see how the method will develop there. The FDA's decision to approve sulfur hexafluoride (Lumason(®) = SonoVue(®)) should be considered against the background of the radiation exposure caused by CT examinations and the fact that MRI using gadolinium-containing contrast agents is no longer considered noninvasive because of nephrogenic systemic fibrosis (NSF) and the accumulation of the agent in the cerebrum. An essential point of the campaign regarding the avoidance of diagnostic radiation exposure triggered in the USA by the publications of Brenner et al. 77 78 was that the agent was approved for use in the liver even for children 79 80 - still off label in Europe - without additional comprehensive studies due to the available scientific results and the very low side effects profile of Lumason(®) (= SonoVue(®)). It is admittedly unclear why other indications (except the heart which has been approved since 2014) are excluded even though the microbubbles as a pure blood pool contrast agent can be diagnostically used in the entire vascular system and bed of all organs. To our knowledge, there is no such restriction on the approval of X-ray contrast agents.Like echocardiography and emergency ultrasound, CEUS began in Europe but will probably only establish its final diagnostic value as a "reimport".This is a major opportunity to permanently define the role of Ultrasound as a highly valuable, patient-centered imaging method in the German health care system.This may prompt some of our international readers to reflect upon the role of CEUS in their own countries.

Torsten Almén (1931-2016): the father of non-ionic iodine contrast media.

The Swedish radiologist Torsten Almén is the first clinical radiologist ever to have made a fundamental contribution to intravascular contrast medium design, the development of non-ionic contrast media. He became emotionally triggered by the patients' severe pain each time he injected the ionic "high-osmolar" contrast media when performing peripheral arteriographies in the early 1960s. One day he got a flash of genius that combined the observation of pain, a pathophysiological theory and how to eliminate it with suitable contrast media chemistry. After self-studies in chemistry he developed the concept of iodine contrast media not dissociating into ions in solution to reduce their osmolality and even reach plasma isotonicity. He offered several pharmaceutical companies his concept of mono- and polymeric non-ionic agents but without response, since it was considered against the chemical laws of that time. Contrast media constructed as salts and dissociating into ions in solution was regarded an absolute necessity to achieve high enough water solubility and concentration for diagnostic purposes. Finally a small Norwegian company, Nyegaard & Co., took up his idea 1968 and together they developed the essentially painless "low-osmolar" monomeric non-ionic metrizamide (Amipaque) released in 1974 and iohexol (Omipaque) in 1982 followed by the "iso-osmolar" dimeric non-ionic iodixanol (Visipaque) released in 1993. This has implied a profound paradigm shift with regard to reduction of both hypertonic and chemotoxic side effects, which have been a prerequisite for the today's widespread use of contrast medium-enhanced CT and advanced endovascular interventional techniques even in fragile patients.

Cardiac radiology: centenary review.

During the past century, cardiac imaging technologies have revolutionized the diagnosis and treatment of acquired and congenital heart disease. Many important contributions to the field of cardiac imaging were initially reported in Radiology. The field developed from the early stages of cardiac imaging, including the use of coronary x-ray angiography and roentgen kymography, to nowadays the widely used echocardiographic, nuclear medicine, cardiac computed tomographic (CT), and magnetic resonance (MR) applications. It is surprising how many of these techniques were not recognized for their potential during their early inception. Some techniques were described in the literature but required many years to enter the clinical arena and presently continue to expand in terms of clinical application. The application of various CT and MR contrast agents for the diagnosis of myocardial ischemia is a case in point, as the utility of contrast agents continues to expand the noninvasive characterization of myocardium. The history of cardiac imaging has included a continuous process of advances in our understanding of the anatomy and physiology of the cardiovascular system, along with advances in imaging technology that continue to the present day.

Genesis of ultrasonic microbubbles: a quick historical overview.

Microbubbles were the subject of numerous experiments and theoretical analysis over the past 100 years. Linked with the discovery and evolution of ultrasound, they were considered to be excellent echoenhancers. From the theories on acoustic waves in antiquity and the discovery of ultrasound, to the genesis of microbubbles around 1968, in our paper we trace the magnificent story of these "magical" bubbles.

The characterization of dynamic susceptibility effects.

Understanding and quantifying dynamic susceptibility contrast, which arises from compartmentalized magnetic field perturbers (e.g., deoxyhemoglobin, contrast agents) that affect the water around them, formed the basis of a significant part of the author's fMRI-related research in the early 90's. This short note describes how the scientific work used to help understand and quantify dynamic injections of contrast agents, primarily designed for clinical MRI, was adapted to help quantify and explain BOLD imaging.