Contrast media

Chapter 28 Contrast media



Susan Cutler


Contrast media are substances used to highlight areas of the body in radiographic contrast to their surrounding tissues. Contrast media enhance the optical density of the area under investigation so that the tissue/structure absorption differentials are sufficient to produce adequate contrast with adjacent structures, enabling imaging to take place. There are numerous types of radiographic contrast media used in medical imaging, which have different applications depending on their chemical and physical properties. When used for imaging purposes contrast media can be administered by injection, insertion or ingestion.



History of radiographic contrast media


Radiographic contrast has been used for over a century to enhance the contrast of radiographic images. In 1896, in the year after X-rays were discovered, inspired air became the first recognised contrast agent in radiographic examinations of the chest. In 1898, the first contrast studies were carried out on the upper gastrointestinal tract of a cat using bismuth salts. These salts were very toxic, and by 1910 barium sulphate and bismuth solutions were being used in conjunction with the fluoroscope, barium sulphate having been used with differing additives ever since for imaging of the gastrointestinal tract.


Images of the urinary system were achieved in the early 1920s. In the early 1920s, syphilis was treated with high doses of sodium iodide. During this treatment the urine in the bladder was observed to be radio-opaque owing to its iodine content. In 1923 the first angiogram and opacification of the urinary tract was performed using sodium iodide. Sodium iodide was too toxic for satisfactory intravenous use, necessitating a need to find a less toxic iodinated compound.


The first iodine-based contrast used was a derivative of the chemical ring pyridine, to which a single iodine atom could be bound in order to render it radio-opaque. Iodine-based contrast media have been used ever since. These media, however, produced varying adverse reactions, and it was realised that a contrast agent was needed that was both safe to administer and enhanced the contrast of the radiographic image. Modern ionic contrast agents were introduced in 1950 and were derivatives of tri-iodo benzoic acid; this structure enabled three atoms of iodine to be carried, rendering it more radio-opaque. However, the agents still caused adverse effects, as they were still of high osmolarity; the term is explained below.


Ionic media dissociate in water; their injection into the blood plasma results in a great increase in the number of particles present in the plasma. This has the effect of displacing water. Water moves from an area of greater concentration to an area of lesser concentration by the process of osmosis, the physical process that occurs whenever there is a concentration difference across a membrane and that membrane is permeable to the diffusing substance. Osmolality (which is generally considered interchangeable with the term ‘osmolarity’) is defined as the number of solute particles, i.e. the contrast medium molecules, dissolved in 1 L (1000 g) of water. These media exert tremendous osmotic activity on the body. The osmolality of normal human blood is given as around 290–300 mOsm/kg (milliosmoles per kilogram).


There remained a need to find a water-soluble iodine-based contrast agent with reduced toxicity but which still produced satisfactory radio-opacity on images. In the 1970s and 1980s non-ionic low-osmolality contrast media became widely available, with the first non-ionic contrast medium being introduced in 1974, representing a major advancement in diagnostic imaging. Most recently the non-ionic dimers have emerged. These media are highly hydrophilic, resulting in lower chemotoxicity, and they are iso-osmolar with the respective body fluids, meaning they can be used for examinations such as angiography and computed tomography (CT) arteriography, which require high doses of contrast media to be administered and where low toxicity is essential.



Requirements of ‘the ideal’ contrast medium and types of contrast agent


There is currently no contrast medium on the market that is considered to be ideal, but the ideal contrast medium should fulfil certain requirements for safe and effective application. It should be:



• easy to administer


• non-toxic


• a stable compound


• concentrated in the required area when injected


• rapidly eliminated when necessary


• non-carcinogenic


• of appropriate viscosity for administration


• tolerated by the patient


• cost-effective.


Contrast media are divided into two main categories. The first is negative contrast media, which are radiolucent and of low atomic number, causing the part in which they are placed to be more readily penetrated by X-rays than the surrounding tissue; as they attenuate the X-ray beam less effectively than body tissue, they appear darker on the X-ray image. Gases are commonly used to produce negative contrast on radiographic images. The second type is positive contrast media; these are radio-opaque and of a high atomic number, causing the part in which they are placed to be less readily penetrated by X-rays than the surrounding tissue. Consequently, this contrast agent-filled area appears denser than body tissue.


Barium- and iodine-based solutions are used in medical imaging to produce positive contrast. Both positive and negative contrast can be used together in double-contrast examinations to produce a radiographic image. Double contrast is used primarily in the alimentary tract, but is also used in arthrography of joints. The positive contrast medium is used to coat the walls of the cavity and the negative contrast, in the form of a gas, is used to distend the area being imaged. Double-contrast examinations permit optimum visualisation by producing a high inherent contrast while allowing adequate penetration of the area under examination. Use of a small amount of contrast agent in conjunction with the distended cavity allows coating of the structures in the cavity (or in the case of the alimentary tract, the mucosal lining), which provides better detail of the area when the thin coating is shown in contrast to the gas-filled area, rather than using large amounts which may be dense enough to mask important information.



Negative contrast media


The following gases create negative contrast on radiographic images:



• Air: Introduced by the patient during a radiographic examination, e.g. inspiration during chest radiography, or can be introduced by the radiographer as part of the examination in a double-contrast barium enema


• Oxygen: Introduced into cavities of the body, for example in the knee during arthrography to demonstrate the knee joint


• Carbon dioxide: Introduced into the gastrointestinal tract in conjunction with a barium sulphate solution to demonstrate the mucosal pattern, e.g. double-contrast barium meal. For the barium meal it is formulated as effervescent powder (e.g. ‘Carbex’ granules) or ready-mixed carbonated barium sulphate (e.g. ‘Baritop’). Carbon dioxide can also be introduced into the colon when performing a double-contrast barium enema. It has been recommended that carbon dioxide be used as the negative contrast agent in a double-contrast barium enema, rather than air, as it causes less immediate abdominal pain1 as well as less post-procedural pain and discomfort.2 However, some studies have shown that carbon dioxide produces inferior distension and additional insufflations are required to maintain adequate quality distension.3 Carbon dioxide can also be used as an alternative contrast to iodinated contrast for diagnostic angiography and vascular interventions in both the arterial and the venous circulation. The gas produces negative contrast owing to its low atomic number and low density compared with adjacent tissues.



Positive contrast media


Barium and iodine solutions are used to create positive contrast on radiographic images.



Barium sulphate solutions (BaSO4) used in gastrointestinal imaging


Barium solutions are the universal contrast media used for radiographic examinations of the gastrointestinal tract. The following characteristics make barium solutions suitable for imaging of the gastrointestinal tract:



• High atomic number (56) producing good radiographic contrast


• Insoluble


• Stable


• Relatively inexpensive


• Excellent coating properties of the gastrointestinal mucosa


Barium suspensions are composed from pure barium sulphate mixed with additives and dispersing agents, held in suspension in water. Compounds to stabilise the suspension are added; these act on the surface tension and increase the viscosity of the solution. A dispersing agent is added to prevent sedimentation, ensuring an even distribution of particles within the suspension. Also added to the suspension is a defoaming agent, used to prevent bubbles that may mimic pathology in the gastrointestinal tract. Flavourings are usually added to oral solutions, making them more palatable for patients.


The concentration of barium in the solution is normally stated as a percentage weight to volume ratio (w/v). A 100% w/v solution contains 1 g of barium sulphate per 100 mL of water; the density of the barium solution is therefore dependent upon the weight/volume. There are many varieties of barium suspension available and the type used depends on the area of the gastrointestinal tract being imaged. It also depends greatly upon the individual preferences of the practitioner.


Patients rarely have allergic reactions to barium sulphate but may react to the preservatives or additives in the solutions. Barium sulphate preparations are usually safe as long as the gastrointestinal tract is patent and intact. A severe inflammatory reaction may develop if it is extravasated outside the gastrointestinal tract; this is most likely to occur when there is perforation of the tract. If barium sulphate escapes into the peritoneal cavity, inflammation and peritonitis may occur. Escaped barium in the peritoneum causes pain and hypovolaemic shock and, despite treatment which includes fluid replacement therapy, steroids and antibiotics, there is still a 50% mortality rate; of those who survive, 30% will develop peritoneal adhesions and granulomas.4 Aspiration of barium solutions during upper gastrointestinal tract imaging is considered to be relatively harmless, most frequently affecting the elderly patient. Physiotherapy is usually required to drain the aspirated barium and should be performed before the patient leaves the department.


Oral barium sulphate should not be administered in cases of obstruction as it may inspissate behind an obstruction, compounding the patient’s condition. Sedated patients should not undergo radiological examinations of the upper gastrointestinal tract as their swallowing reflex may be diminished, increasing the risk of aspiration.


When preparing barium solutions for administration it is important to check expiry dates and ensure the packaging is intact. Solutions administered rectally should be administered at body temperature to improve patient tolerability and also reduce spasm of the colon. It is important that the administrator knows the patient’s full medical history and checks for any contraindications prior to administration. Barium sulphate solutions are contraindicated for the following pathologies:



• Suspected perforation


• Suspected fistula


• Suspected partial or complete stenosis


• Paralytic ileus


• Haemorrhage in the gastrointestinal tract


• Toxic megacolon


• Prior to surgery or endoscopy


• If the patient has had a recent gastrointestinal wide bore biopsy (usually within 3–5 days) or a recent anastomosis


When barium sulphate solutions are contraindicated for gastrointestinal imaging, a water-soluble iodine-based contrast medium (e.g. Gastrografin or Gastromiro) should be used. These can be administered orally, rectally or mechanically, e.g. via stomas. The iodine concentration of Gastrografin is 370 mg/mL and of Gastromiro 300 mg/mL. When used for imaging the gastrointestinal tract, water-soluble contrast produces a lower-contrast image than barium owing to its lower atomic number.


The patient’s consent must be given prior to the administration of barium contrast solutions. The patient should be given a full explanation, be reassured about the examination and given the opportunity to ask questions. It is important when using barium sulphate solutions that associated pharmacological agents such as buscopan and glucagon are fully understood and the indications and contraindications ensuring their safe application adhered to.



Iodine-based contrast media used in medical imaging and their development


The largest group of contrast media used in imaging departments are the water-soluble organic preparations in which molecules of iodine are the opaque agent. These compounds contain iodine atoms (iodine has an atomic number of 53) bound to a carrier molecule. This holds the iodine in a stable compound and carries it to the organ under examination. The carrier molecules are organic, containing carbon, and are of low toxicity and high stability. Iodine is used as it is relatively safe and the K edge = 32 keV (binding edge of iodine K-shell electron), thus being close to the mean energy of diagnostic X-rays. Selection of kVp for imaging examinations using iodine-based contrast plays a part in providing optimum attenuation. The absorption edge of iodine (35 keV) predicts that 63–77 kVp is the optimal range. The iodine-based compounds are divided into four groups (Fig. 28.1) depending on their molecular structure, as follows:



1 Ionic monomers


2 Ionic dimers


3 Non-ionic monomers


4 Non-ionic dimers


image

Figure 28.1 Classification of ionic contrast media.



Ionic monomers – high osmolar contrast media (HOCM) (Fig. 28.2)


The basic molecule of all water-soluble iodine-containing contrast media is the benzene ring. Benzene itself is not water soluble; to make it soluble, carboxyl acid (COOH) is added. Three of the hydrogens in this molecule are replaced by iodine, rendering it radio-opaque, but it still remains quite toxic. The remaining two hydrogens (R1 and R2 in Fig. 28.2) are replaced by a short chain of hydrocarbons, making the compound less toxic and more acceptable to the body. The exact nature of these compounds differs between different contrast media, but they are usually prepared as sodium or meglumine salts as these help to provide solubility.


image

Figure 28.2 Molecular structure of an ionic monomer (HOCM).


Ionic compounds dissociate (dissolve) into charged particles when entering a solution. They dissociate into positively charged cations and negatively charged anions. For every three iodine molecules present in ionic media, one cation and one anion are produced when it enters a solution. Their ‘effect’ ratio is therefore 3 : 2. These solutions are highly hypertonic, with an osmolality approximately five times higher than human plasma (1500–2000 mOsm/kg H2O compared with 300 mOsm/kg H2O for plasma).



Ionic dimers – low osmolar contrast media (LOCM) (Fig. 28.3)


As contrast agents developed in the 20th century, it was acknowledged that a contrast medium with reduced osmotic effects was needed. As previously stated, the higher the ‘effect’ ratio the lower the osmolarity of the contrast media. An attempt was made to increase the ‘effect’ ratio and produce a contrast medium with lower osmolarity. This was achieved by linking together two conventional ionic contrast media molecules. The resulting dimeric ionic contrast medium was an improvement on the HOCM. Reduced osmolality (600 mOsm/kg H2O) made the contrast more tolerable for patients. The ionic molecule still dissociates into two particles, a positive cation and a negative anion. However, there are now twice as many particles in solution with twice the osmolarity. Each molecule carried six iodines (as opposed to three in the HOCM), hence there is an iodine atom-to-particle ratio of 6 : 2; so only half the number of molecules are needed to achieve the same iodine concentration. This means a lower volume of contrast medium is therefore required for an examination.


image

Figure 28.3 Molecular structure of ionic dimer (LOCM).



Non-ionic monomers (LOCM) (Fig. 28.4)


These are low osmolar agents and do not dissociate into two particles in a solution, making them more tolerable and safer to use than ionic contrast. For every three iodine molecules in a non-ionic solution, one neutral molecule is produced. Non-ionic contrast media are therefore referred to as 3 : 1 compounds. They substitute the sodium and meglumine side chains with non-ionising radicals (OH)n. Two major advantages arise through the change in chemical structure: the first is that the negative carboxyl group is eliminated, thereby reducing the neurotoxicity; and the second is that the elimination of the positive ion reduces osmolality to 600–700 mOsm/kg H2O. Non-ionic LOCM is recommended for intrathecal and vascular radiological procedures.


image

Figure 28.4 Molecular structure of non-ionic monomer.



Non-ionic dimers (isotonic) – the gold standard (Fig. 28.5)


Clearly, the closer the osmolality of a contrast agent is to that of blood plasma, and the better an isotonic solution, i.e. that the contrast solution has similar osmolality to blood plasma (approximately 300 mOsm/kg H2O), is a most ideal option. Non-ionic dimers are dimeric non-dissociating molecules; for every one molecule there are six iodine atoms. The ratio is therefore 6 : 1, double that of the non-ionic monomers. An important feature of these is that they are isotonic. Their iso-osmolality, combined with a slower diffusion of the larger molecules across vessel walls from the vascular space, plays a significant role in imaging venous phase images following arterial injections (and arterial phase images following venous injections). These compounds represent a gold standard water-soluble iodine contrast medium.


image

Figure 28.5 Molecular structure of non-ionic dimer.



The percentage solution


The percentage solution indicates the amount of solute in the solvent. The percentage solution does not indicate the percentage iodine content, as demonstrated in the following table.


Percentage iodine content in contrast media























Contrast media Percentage solution Iodine concentration of solution
Urografin 150 30 146 mg/mL
Urografin 370 76 370 mg/mL
Gastrografin 76 370 mg/mL
Niopam 370 75.5 370 mg/mL

The solvent affects the viscosity of the contrast agent. Viscosity is the resistance to flow of a contrast medium and relates to the concentration, molecular size and temperature of the contrast. The volume and density of contrast used is dependent upon the examination being undertaken, the pathology being investigated, the age of the patient and the patient’s medical status.



Essential criteria for the ‘ideal’ intravenous contrast agent




• Water soluble


• Heat/chemical/storage stability


• Non-antigenic


• Available at the right viscosity and density


• Low viscosity, making them easy to administer


• Persistent enough in the area of interest to allow its visualisation


• Selective excretion by the patient when the examination is complete


• Same osmolarity as plasma or lower


• Non-toxic, both locally and systemically


• Low cost



Possible side-effects of ionic-based contrast media


Any water-soluble ionic contrast introduced into the vascular system can potentially cause physiological adverse effects. These effects are caused by the high osmolarity and chemotoxic effects of the medium. Although both ionic and non-ionic iodine media have physiological effects on the body, ionic media are of higher osmolarity and potentially cause more side effects in the patient. An ionic contrast has approximately five times the osmolarity of human plasma. Water-soluble organic iodine contrast media have two effects: the desirable primary effect of attenuating X-rays and providing the radiographic image with adequate contrast, and the unwanted secondary effect of inducing potential side effects in patients.



Primary effect – image contrast


Optimum attenuation is achieved by selecting the appropriate concentration of iodine in solution for the planned examination. Two solutions with the same iodine content should provide the same iodine concentration in blood after intravenous injection. This is not the case, however, and the concentration may be affected by small molecules diffusing out of the blood vessel lumen, or by solutions of high concentration within the blood vessel drawing water out of adjacent cells by osmosis (therefore diluting the solution), as mentioned in the introduction to this chapter. To illustrate this, remembering that osmolality is defined as the number of solute particles (e.g. the contrast media molecules) dissolved in 1 L (1000 g) of water, a comparison between normal blood plasma osmolality and different contrast agents is shown below:



• Normal blood plasma ~300 mOsm/kg water


• Ionic monomer ~1200–2400 mOsm/kg water, making it very hypertonic


• Ionic dimers, and non-ionic monomers and dimers (LOCM) are still hypertonic but to a much lesser degree, reducing the osmotic activity. They are, however, more expensive. Isotonic iodixanol (Visipaque) has approximately a third the osmolality of the non-ionic media and a sixth of that of the monomeric ionic media.


When comparing two contrast media with the same iodine concentration, a higher venous concentration of iodine is obtained when diffusion of contrast medium is slowed down by using large molecules (dimers) and osmotic effects are reduced by reducing the number of molecules/ions in solution (monomers).



Secondary effect – adverse events


Contrast media are specifically designed to minimise secondary effects or adverse reactions. The ‘perfect’ contrast agent would cause no adverse effects at all. Although reactions to contrast media are rare, it is essential that every effort is made to minimise the risk. Acute adverse reactions do occur and are defined as reactions that occur within 1 hour after administration of a contrast medium. Adverse reactions to contrast media or drugs are generally classified into two categories:



1 Idiosyncratic reactions are dose dependent and usually anaphylactoid in nature. These are unpredictable, having a prevalence of 1–2% (0.04–0.22% severe), and are fatal in 1 in 170 000.5


2 Non-idiosyncratic reactions are divided into chemotoxic and osmotoxic. Chemotoxic effects can be minimised through the use of LOCM. As LOCM are available at a reasonable cost the use of higher-toxicity substances could be challenged medicolegally.6

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Mar 3, 2016 | Posted by in GENERAL RADIOLOGY | Comments Off on Contrast media

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