Contrast media

Arteriography of a healthy kidney

Contrast media ( CM ) improve the representation of structures and functions of the body in imaging procedures such as X-ray diagnostics , magnetic resonance imaging (MRI) and sonography ( ultrasound ). Contrast media must be differentiated from tracers or radiopharmaceuticals , which are used to represent physiological processes in nuclear medicine.

Legal classification

In Germany, contrast media are drugs according to Section 2 (1) No. 2 of the German Medicines Act (AMG). They are to be distinguished from the medical devices according to the Medical Devices Act (MPG); see also product classification # drug - medical product .

According to the European Directive 93/42 / EEC on medical products , contrast media are to be classified as medical products.

effect

The effect of contrast media is to modify the signal that is registered in the respective examination. The aim of the mission is to gain additional information during the investigation. So you can with X-rays using contrast agents that absorb X-rays more than normal soft tissue. For example, you usually don't see blood vessels on an X-ray. If an iodine-containing solution is injected , the vessels in which the solution enters cast x-ray shadows and are thus visible ( angiography ).

unwanted effects

Contrast media can have undesirable drug effects ( side effects ) that can manifest themselves in various organs including the skin. When considering the indication of a contrast agent examination, the requirements for tolerability are generally stricter than those for the therapeutic use of medication: If one expects a cure or relief from a medication, one is more likely to accept risks than with purely diagnostic applications. This attitude stems in part from experience with the X-ray contrast agent Thorotrast , which was used in the 1930s and caused malignant liver tumors in many patients, sometimes with a delay of decades . Modern contrast media are therefore subject to tolerance studies that are more rigorous than those for therapeutic drugs. In addition, the legislators in most countries prescribe thorough risk information for the patient, although the overall risk in individual cases is usually very small.

Some of the gadolinium group MRI contrast agents can also be deposited in the brain with repeated use. Other possible serious chronic side effects are nephrogenic systemic fibrosis in patients with kidney damage. This mainly applies to the subgroup with a linear molecular structure ( gadobenic acid , gadodiamide , gadopentetate dimeglumine and gadoversetamide ). On the recommendation of the European Medicines Agency , the European Commission suspended the approval of linear gadolinium complexes as contrast agents in November 2017.

Undefined X-ray contrast media were detected in undefined quantities in sewage treatment plants on the Ruhr and in Württemberg. In 2019, unknown amounts of gadolinium were found in drinking water-based cola from fast food chains in Germany. In the Swiss groundwater were amidotrizoic and iopamidol detected most frequently.

Indications

Additional information that can be obtained through the use of contrast media falls into two broad categories: structural ( morphological ) and functional ( physiological ) information. A typical example of the former is double contrast imaging of the large intestine . Here is a viscous barium sulfate suspension instilled rectally . Because of its consistency, it marks the intestinal wall. Then air is pumped into the intestine, whereby the lumen of the intestine becomes visible (on the one hand through the filling, on the other hand through the negative contrast due to the high permeability of air to X-rays). This is how you can recognize morphological changes in the large intestine, such as polyps , bulges , constrictions and inflammations . Functional information can also be obtained with the barium sulphate method: It makes it possible to visualize disorders of the mobility of the esophagus.

Contrast media, especially MR contrast media, are used in exceptional cases, like other drugs, outside of the approved applications, for example in children and for the development of new diagnostic procedures ( off-label use ).

Substances used

X-ray diagnostics

In X-ray diagnostics (e.g. in computed tomography ) the following contrast media are used:

• X-ray positive contrast media
  • Iodine-containing contrast media are water-soluble substances that are either injected intravascularly or injected directly into the tissue / hollow organ to be visualized. Over 90% of them are eliminated through the kidneys . They are used to display the kidneys and urinary tract ( urography / excretory urography ), the veins ( venography ), the arteries ( arteriography ) or other organs . The various iodine-containing contrast media differ primarily in the carrier molecules , in the number of iodine atoms bound per carrier molecule (1 to 6) and in their physico-chemical properties ( osmolality , viscosity , hydrophilicity ). The X-ray density and thus the achievable increase in contrast of a contrast agent depend on the iodine concentration. The osmolality or osmolarity (partially) influences the tolerance of the contrast agent, while the viscosity controls the flow properties (through catheters or when injecting). Possible risks of iodine-containing contrast media include hyperthyroidism .
    • Hyperosmolar, ionic iodine-containing contrast media, e.g. B. for gastrointestinal diagnostics ( amidotrizoic acid , trade names: Gastrolux , Gastrografin , Peritrast ).
    • Nonionic iodine-containing contrast media ( Ultravist , Isovist , Xenetix etc.). These are more expensive, but better tolerated than the ionic iodine-containing contrast media. In Germany, therefore, only these are allowed to be injected intravascularly.
  • Barium sulfate is given to patients as an X-ray contrast medium in the form of a milky suspension to drink, since it is not absorbed by the gastrointestinal tract . It is used to represent the esophagus , stomach , small and large intestines . Aquatized barium ions have a harmful effect on the organism, but the sulfate is extremely difficult to dissolve and only decomposes at temperatures above 1400 ° C, so that it can be administered without hesitation. When used as an X-ray contrast medium , barium sulfate is usually administered in combination with carbon dioxide or methyl cellulose gels in order to inflate the gastrointestinal tract (gastrointestinal tract). This method is known as the double-contrast method and is used for a better relief representation of the inner mucous membranes, as the barium sulfate only remains on the surface as a very thin layer. The impact filling technique, on the other hand, is carried out with barium sulfate alone and allows the entire gastrointestinal tract to be displayed. As an insoluble salt, barium sulfate must not be used if there is suspicion of intestinal perforation or shortly after an operation, nor should it be used for swallowing disorders or small children. Due to the lack of absorbability, these substances can lead to foreign body reactions outside the gastrointestinal tract and must therefore not be used if there is a risk of aspiration or if there is a perforation in the gastrointestinal tract. An intraperitoneal mistake can be fatal in 20 to 50% of cases. In these special situations, water-soluble iodine-containing X-ray contrast media are used instead of barium-containing contrast media. When used correctly, the tolerance is extremely good, as it is practically not absorbed and is excreted unchanged as white stool. In July 2003, twelve people died in Brazil from barium sulfate, which was contaminated with soluble and therefore harmful barium carbonate .
  • Heavy noble gases can be used as X-ray contrast media to visualize lung ventilation. The heaviest non-radioactive noble gas is xenon , which, due to its narcotic effect, can only be used up to a concentration of 35% and may therefore be supplemented with krypton .
• X-ray negative contrast media
  • Gaseous carbon dioxide (CO ₂ ) which, in contrast to the two aforementioned contrast agents, reduces the X-ray density (negative contrast agent) and thus leads to increased radiation permeability. CO ₂ is particularly suitable for arteriography as an alternative to iodine-containing contrast media (in the event of intolerance or hyperthyroidism) and for the targeted display of small branches. Unlike air, CO ₂ can be injected into the vascular system.
  • Air , in double contrast examination of the large intestine .
  • Mannitol solution for contrasting the gastrointestinal tract

Magnetic resonance imaging (MRI)

In magnetic resonance tomography , contrast media with different effects are used. There are two groups of substances:

1. Positive MR contrast media (the so-called "whiteners"). These include contrast media containing gadolinium (Gd) and manganese (Mn).
2. Negative MR contrast media (the so-called “black makers”). These include contrast media containing iron oxide.

They were both developed in 1981/82. In July 2017, the European Medicines Agency (EMA) suspended the marketing authorizations for the intravenous, linear drugs gadodiamide and gadoversetamide and the intravenous formulation of gadopentetic acid. The EMA decision contradicts the US Food and Drug Administration (FDA) , which announced in May 2017 that it would not impose any restrictions.

The effect of this contrast agent is indirect , since the contrast agent itself does not emit a signal, but only influences the signal intensity in its environment. Furthermore, there are contrast media that are directly visible in the image as signal-emitting (or signal-preventing) substances.

• Injectable signal-altering contrast media :
  • Gadolinium - chelates , which, because of the paramagnetic property of the gadolinium atom, lead to a shortening of the relaxation times in the vicinity of the contrast agent and thus to a lighter (higher-signal) representation of structures in T1-weighted images Examples: gadopentetate dimeglumine (trade name: Magnevist and others), gadoteric acid ( Dotarem , Dotagita , Cyclolux ), gadodiamide ( Omniscan ), gadoteridol ( ProHance ), gadobutrol ( Gadovist ), ...
  • Iron oxide nanoparticles ( superparamagnetic iron oxide, SPIO from English superparamagnetic iron oxide ) to represent the reticulo-endothelial system, for example in the liver. In T2-weighted imaging, healthy liver tissue appears to be low-signal due to the iron oxide, while tumors, metastases or other structures (cysts, hemangiomas) stand out with high signal (light); Examples: Ferumoxid ( Endorem ), Ferrixan ( Resovist ). Smaller iron oxide nanoparticles under the abbreviation USPIO (from English. Ultrasmall superparamagnetic iron oxide ) are being developed as vascular contrast media and for differentiating lymph node metastases, e.g. B. Ferumoxtran ( Sinerem ).
  • Manganese compounds such as Mangafodipir (Mn-DPDP, Teslascan ) as liver contrast media (healthy parenchyma appears T1-weighted with high signal, i.e. light, tumors / metastases with low signal, i.e. dark) or for pancreatic issues.

• Signal- modifying contrast media that can be administered orally or enterally for better contrasting the gastrointestinal tract :
  • silicone-coated superparamagnetic iron oxide nanoparticles; The iron oxide preparation Ferumoxsil ( Lumirem ) is clinically approved ,
  • oral non-absorbable gadolinium chelates,
  • Pineapple, raspberry and other juices with a high natural manganese and / or iron content, which due to their paramagnetic properties cancel out the T2-weighted intraluminal signal,
  • Manganese compounds, e.g. B. MnCl ₂ ( LumenHance )

• Signaling contrast media that are themselves directly MR-visible:
  • Water as a natural contrast medium (luminization) is sometimes used for examinations of the gastrointestinal tract, often combined with gel formers such as guar , carboxymethyl celluloses , Indian flea seeds or sugar substitutes such as mannitol or polyethylene glycols for better distension.
  • ¹⁹ substances containing fluorine (e.g. SF ₆ or C ₂ F ₆ gas) are being developed as inhalable contrast media for lung imaging with ¹⁹ F-MRI.
  • There are also attempts to use hyperpolarized substances, such as ³ helium , ¹²⁹ xenon or ¹³ carbon , as contrast media in non- ¹ H MRT (in the development stage).

• Signal-free contrast media (for ¹ H-MRI) with little or no proton content:
  • perfluorinated bromine compounds ( perfluorooctyl bromide , PFOB, perflubron ) without signaling protons (previously approved in the USA),
  • Barium sulfate suspensions, which reduce the proton density and thus the signal.

While magnetic resonance imaging is also safe during pregnancy, the administration of gadolinium-containing contrast media leads to a significantly increased death rate in newborns during or after birth with a hazard ratio (HR) of 3.7 and a higher probability of rheumatological , inflammatory and dermatological diseases with a hazard ratio of 1.36. Therefore, no contrast agent should be used for magnetic resonance imaging during pregnancy.

Sonography

In sonography and echocardiography , gas-filled microbubble contrast media ( microbubbles ) are used in contrast-enhanced ultrasound . They are usually administered intravenously and then increase the echogenicity of the blood . The respirable contrast media were originally developed as signal amplifiers for Doppler and color Doppler examinations. In sonography, they are mainly used to improve the detection and characterization of liver tumors. The contrast media of the 2nd generation have proven themselves here, which with extremely low sound energy (only possible with special software in high-quality new sonography devices) allow continuous, largely non-destructive observation of the inflow and outflow of the microbubble contrast medium. The flow and flow kinetics (arterial phase, portal venous phase, venous phase and late phase) are used to differentiate the liver tumors. Liver metastases usually stain early in the arterial phase and also lose their staining early in the venous phase, so that they no longer contain contrast agent in the late phase and are thus clearly differentiated from liver tissue , which still contains contrast agent. In echocardiography, they improve the investigability of wall movement. Non-respirable contrast media are used to detect holes in the heart septum.

Indocyanine green / ICG diagnostics

Indocyanine green (also ICG , English indocyanine green ) is a fluorescent dye that is used in medicine as an indicator substance , for example for photometric liver function diagnostics and fluorescence angiography for cardiovascular, liver and eye diseases. It is administered intravenously and, depending on liver performance, eliminated from the body with a half-life of around 3–4 minutes. ICG is usually in powder form and can be dissolved in various solvents, but is usually dissolved in aqua ad injectionem . ICG in sterile form is approved for intravenous use in Germany.

Trade names

Examples of commercially available X-ray contrast media: Baricol (A), Barilux (D), CAT-Barium (CH), Microbar (CH), Micropaque (D, A, CH), Microtrast (D), Polibar (CH), Prontobario (A) , Scannotrast (A)

Web links

Commons : Contrast Media  - Collection of images, videos and audio files

Wiktionary: Contrast media  - explanations of meanings, word origins, synonyms, translations

Individual evidence

1. ↑ Böhm I et al. A practical guide to diagnose lesser-known immediate and delayed contrast media-induced adverse cutaneous reactions in Eur Radiol 2006; 16: 1570-9
2. Jump up ↑ Richard C. Semelka, Joana Ramalho, Ami Vakharia, Mamdoh Alobaidy, Lauren M. Burke: Gadolinium deposition disease: Initial description of a disease that has been around for a while . In: Magnetic Resonance Imaging . tape 34 , no. December 10 , 2016, ISSN  1873-5894 , p. 1383-1390 , doi : 10.1016 / j.mri.2016.07.016 , PMID 27530966 .
3. ↑ MRI contrast media with side effects. In: NDR.de. March 20, 2017, accessed January 22, 2018 . 
4. ↑ Marvin Birka, Kristina S. Wentker, Elke Lusmöller, Brigit Arheilger, Christoph A. Wehe: Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis . In: Analytical Chemistry . tape 87 , no. 6 , March 17, 2015, ISSN  1520-6882 , p. 3321-3328 , doi : 10.1021 / ac504488k , PMID 25708271 .
5. ↑ EMA is considering banning four MRI contrast media. In: aerzteblatt.de. March 14, 2017, accessed January 22, 2018 . 
6. ↑ Document C (2017) 7941 final
7. ↑ Homepage. Retrieved August 2, 2017 . 
8. ↑ About MindER. Retrieved August 22, 2017 . 
9. ↑ Katja Schmidt, Michael Bau, Gila Merschel, Nathalie Tepe: Anthropogenic gadolinium in tap water and in tap water-based beverages from fast-food franchises in six major cities in Germany. In: Science of The Total Environment. 687, 2019, p. 1401, doi : 10.1016 / j.scitotenv.2019.07.075 . (German article: MRI contrast agent detected in cola: study finds gadolinium in fast-food drinks in all German cities examined )
10. ↑ Medicines in groundwater. In: bafu.admin.ch. Retrieved February 21, 2020 . 
11. ↑ Antje-Katrin Heinemann: Off-label use of diagnostics using the example of MR contrast media, MPR, magazine for the entire medical product law, 5/2007
12. ^ Radiology dye kills six. In: theage.com.au. July 23, 2003. Retrieved November 26, 2016 . 
13. ↑ Deokiee Chon, Kenneth C. Beck, Brett A. Simon, Hidenori Shikata, Osama I. Saba, Eric A. Hoffman: Effect of low-xenon and krypton supplementation on signal / noise of regional CT-based ventilation measurements. In: J. Appl. Physiol. 2007, 102, pp. 1535-1544, doi: 10.1152 / japplphysiol.01235.2005 .
14. ↑ Christoph de Haën: Conception of the First Magnetic Resonance Imaging Contrast Agents: A Brief History. In: Topics in Magnetic Resonance Imaging . 12, 2001, pp. 221-230, doi: 10.1097 / 00002142-200108000-00002 .
15. ↑ EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans , PM EMA of July 21, 2017, accessed on July 26, 2017
16. ↑ Nicola Siegmund-Schulze: MRI examination during pregnancy: Contrast media can damage the child at any time Deutsches Ärzteblatt 2016, Volume 113, Issue 44 of November 9, 2016, page 1987

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