Intravascular contrast media

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Chapter 2 Intravascular contrast media

Historical Development of Radiographic Agents

The first report of opacification of the urinary tract after intravenous (i.v.) injection of a contrast agent appeared in 1923, when Osborne et al. took advantage of the fact that i.v.-injected, 10% sodium iodide solution, which was then used in the treatment of syphilis, was excreted in the urine. In 1928 German researchers synthesized a compound with a number of pyridine rings containing iodine in an effort to detoxify the iodine. This mono-iodinated compound was developed further into di-iodinated compounds and subsequently in 1952 the first tri-iodinated compound, sodium acetrizoate (Urokon), was introduced into clinical radiology. Sodium acetrizoate was based on a 6-carbon ring structure, tri-iodo benzoic acid, and was the precursor of all modern water-soluble contrast media.

Until the early 1970s all contrast media were ionic compounds and were hypertonic with osmolalities of 1200–2000 mosmol kg⁻¹ water, 4–7 × the osmolarity of blood. These are referred to as high osmolar contrast media (HOCM) and are distinguished by differences at position 5 of the anion and by the cations sodium and/or meglumine. In 1969 Almén first postulated that many of the adverse effects of contrast media were the result of high osmolality and that by eliminating the cation, which does not contribute to diagnostic information but is responsible for up to 50% of the osmotic effect, it would be possible to reduce the toxicity of contrast media.¹

Conventional ionic contrast media had a ratio of three iodine atoms per molecule to two particles in solution, i.e. a ratio of 3:2 or 1.5 (Table 2.1). In order to decrease the osmolality without changing the iodine concentration, the ratio between the number of iodine atoms and the number of dissolved particles must be increased.

Table 2.1 Schematic illustration of the development of contrast media

Further development proceeded along two separate paths (Table 2.1). The first was to combine two tri-iodinated benzene rings to produce an ionic dimer with six iodine atoms per anion, the low osmolar contrast medium (LOCM) ioxaglate (Hexabrix). Replacement of one of the carboxylic acid groups with a non-ionizing radical means that only one cation is needed per molecule. The alternative, more successful, approach was to produce a compound that does not ionize in solution and so does not provide radiologically useless cations. Contrast media of this type are referred to as non-ionic and are also LOCM. These include the non-ionic monomers iopamidol (Niopam, Iopamiron, Isovue, and Solutrast), iohexol (Omnipaque), iopromide (Ultravist), iomeprol (Iomeron) and ioversol (Optiray).

For both types of LOCM the ratio of iodine atoms in the molecule to the number of particles in solution is 3:1 and osmolality is decreased. Compared with high osmolar contrast material (HOCM), the LOCM show a theoretical halving of osmolality for equi-iodine solutions. However, because of aggregation of molecules in solution the measured reduction is approximately one-third (Fig. 2.1).

Figure 2.1 A plot of osmolality against iodine concentration for new and conventional contrast media. From Dawson et al.²

(Reproduced by courtesy of the editor of Clinical Radiology.)

A further development in the search for the ideal contrast agent has been the introduction of non-ionic dimers – iotrolan (Isovist) and iodixanol (Visipaque). These have a ratio of six iodine atoms for each molecule in solution with satisfactory iodine concentrations at iso-osmolality; they are, therefore, called iso-osmolar contrast media. The safety profile of the iso-osmolar contrast agents is at least equivalent to LOCM, but any significant advantage of iso-osmolar contrast remains controversial.

The low- and iso-osmolar contrast media are 5–10 times safer than the HOCM.³ Previously, HOCM were much less expensive than LOCM so were widely used despite the higher risk of adverse reaction and nephrotoxicity. LOCM were reserved for use in patients considered to be at increased risk of contrast reaction. Over the past few years, the relative cost of the non-ionic contrast media has fallen and the use of ionic contrast medium for i.v. injection has now ceased almost entirely. Ionic contrast media must never be used in the subarachnoid space.

With development having reached the stage of iso-osmolality, further research is now targeted on decreasing the chemotoxicity of the contrast molecule.

ADVERSE EFFECTS OF INTRAVENOUS WATER-SOLUBLE CONTRAST MEDIA

The toxicity of contrast media is a function of osmolarity, ionic charge (ionic contrast agents only), chemical structure (chemotoxicity) or lipophilicity.

Adverse reactions after administration of non-ionic iodinated contrast media are rare, occuring in less than 1% of all patients.⁴ Of these reactions, the majority are mild and self-limiting. The incidence of severe or very severe non-ionic contrast reaction is 0.044%.⁵

TOXIC EFFECTS ON SPECIFIC ORGANS

Vascular toxicity

It was hoped that the iso-osmolar contrast agents might be less nephrotoxic than LOCM and HOCM. However, clinical trials have so far yielded conflicting results.^9,¹¹ CIN has a complex aetiology and the positive benefit of reduction in osmolarity achieved with iso-osmolar contrast medium may be negated by the accompanying increase in viscosity.¹²

A further hazard for patients who suffer impairment of renal function as a result of intravenous iodinated contrast is reduced clearance of drugs excreted by the kidneys. This is well recognized as a clinical problem with metformin, an oral hypoglycaemic drug which is exclusively excreted via the kidneys. The resultant accumulation of metformin may result in the development of the potentially fatal complication lactic acidosis.

See Table 2.3 for guidelines on prophylaxis of renal adverse reaction to iodinated contrast.

Neurotoxicity

Contrast medium delivered to the brain via the arterial route may cross the blood–brain barrier. Neurotoxicity is caused by both osmolality and chemotoxic effects and i.v. contrast medium may rarely provoke convulsions in patients with epilepsy or cerebral tumours.

Convulsions may also occur secondary to the cerebral hypoxia caused by hypotension ± cardiac arrest after severe contrast reaction.

Thyroid function

1. Thyrotoxicosis may occur in patients with non-toxic goitres or be exacerbated in those with pre-existing thyrotoxic symptoms.¹³

2. Contrast media may interfere with thyroid function tests.

IDIOSYNCRATIC REACTIONS

Excluding death, adverse reactions can be classified in terms of severity as:

1. Major reactions, i.e. those that interfere with the examination and require treatment.

2. Intermediate reactions, i.e. those that interfere with the examination but do not require treatment.

3. Minor reactions, i.e. those that do not interfere with the examination but require patient reassurance.

Minor and intermediate reactions are not uncommon; major adverse reactions are rare (Table 2.2).

Table 2.2 Adverse reaction rates for intravenous ionic* and non-ionic^# contrast media

Fatal reactions

Deaths caused by iodinated contrast agents are very rare, occuring at a rate of 1.1–1.2 per million contrast media packages distributed. Most are attributed to renal failure, anaphylaxis or allergic reaction.¹⁸

Almost all fatal reactions occur in the minutes following injection and patients must be under close observation during this time. The fatal event may be preceded by trivial events, such as nausea and vomiting, or may occur without warning. The majority of deaths occur in those over 50 years of age. Causes of death include cardiac arrest, pulmonary oedema, respiratory arrest, consumption coagulopathy, bronchospasm, laryngeal oedema and angioneurotic oedema.

Non-fatal reactions

1. Flushing, metallic taste in the mouth, nausea, sneezing, cough and tingling are common and related to dose and speed of injection.

2. Perineal burning, a desire to empty the bladder or rectum and an erroneous feeling of having been incontinent of urine are more common in women.

3. Urticaria.

4. Angioneurotic oedema. Most commonly affects the face. May persist for up to 3 days and its onset may be delayed.

5. Rigors.

6. Necrotizing skin lesions. Rare and mostly in patients with pre-existing renal failure (particularly those with systemic lupus erythematosus).

7. Bronchospasm. Predisposed to by a history of asthma and by therapy with ß-blockers. In most patients the bronchospasm is subclinical. Mechanisms include:

a direct histamine release from mast cells and platelets

b cholinesterase inhibition

c vagal overtone

d complement activation

e direct effect of contrast media on bronchi.

8. Non-cardiogenic pulmonary oedema. During acute anaphylaxis or hypotensive collapse and possibly due to increased capillary permeability.

9. Arrhythmias.

10. Hypotension. Usually accompanied by tachycardia but in some patients there is vagal over-reaction with bradycardia. The latter is rapidly reversed by atropine 0.6–2 mg i.v. Hypotension is usually mild and is treatable by a change of posture. Rarely, it is severe and may be accompanied by pulmonary oedema.

11. Abdominal pain. May be a symptom in anaphylactic reactions or vagal overactivity. Should be differentiated from the loin pain that may be precipitated in patients with upper urinary tract obstruction.

12. Delayed-onset reactions – (1 h–1 week after injection) include rashes, headaches, itching and parotid gland swelling. Risk factors for delayed reaction are previous contrast medium reaction and therapy with interleukin-2.¹⁹

MECHANISMS OF IDIOSYNCRATIC CONTRAST-MEDIUM REACTIONS

Idiosyncratic contrast medium reactions are usually labelled anaphylactoid since they have all the features of anaphylaxis but are IgE negative in most cases.²⁰ Possible mechanisms include those outlined below.

Histamine release

Histamine is the primary mediator of anaphylaxis/anaphylactoid reaction and contrast media cause the release of histamine from mast cells and basophils. This could provide a mechanism for the phenomena of flushing, urticaria, metallic taste, hypotension, collapse and angioneurotic oedema. While hyperosmolality is a factor, isosmolar concentrations of contrast media will also stimulate histamine release. Bronchospasm may be due to the effect of contrast medium on pulmonary-bed mast cells and dysrrhythmias from the effect on cardiac mast cells.

Complement activation

Contrast medium may activate the complement system leading to the formation of anaphylatoxins which induce the release of histamine and other biological mediators from basophils and mast cells.²⁰ However, there is uncertainty as some studies have failed to show an increase in complement fraction levels in patients after reaction to i.v. iodinated contrast.

Protein binding, enzyme inhibition and immune receptors

Contrast media are weakly protein bound and the degree of protein binding correlates well with their ability to inhibit the enzyme acetylcholinesterase. Contrast medium side-effects such as vasodilatation, bradycardia, hypotension, bronchospasm and urticaria are all recognized cholinergic effects. It was previously thought that they might be related more to cholinesterase inhibition than osmolality; however, this has not been conclusively proven. More recently, it has been postulated that weakly protein bound drugs, such as iodinated contrast, may directly activate T cells which bear immune receptors. It is thought that these may interact with the drug and that contrast medium may have an effect on cytokine production by helper T cells ²¹ to mediate the acute reaction.

Chemotoxicity

In addition to the toxicity of both ionic and non-ionic contrast media, because of their intrinsic structure, the ionic contrast agents had an electrical charge on the particles. This was almost certainly the cause of the high incidence of severe adverse reactions during intracoronary and intrathecal use of these agents.

Although the major adverse effect on erythrocytes is due to hyperosmolality, even contrast medium which is iso-osmolar with plasma produces changes in red-blood-cell morphology that reveal the intrinsic chemotoxicity of contrast medium molecules.

Anxiety

Many years ago, Lalli ²² postulated that most, if not all, contrast medium reactions are the result of the patient’s fear and apprehension. The high autonomic nervous system activity in an anxious patient will be stimulated further when the patient experiences the administration of contrast medium. Furthermore, contrast medium crossing the blood–brain barrier can stimulate the limbic area and hypothalamus to produce further autonomic activity. This autonomic activity is responsible for contrast medium reactions by the sequence of events illustrated in Figure 2.2.

Figure 2.2 Central nervous system and contrast media reactions. From Lalli.²²

(Reproduced by courtesy of the editor of Radiology.)

PROPHYLAXIS OF ADVERSE CONTRAST MEDIUM EFFECTS

Guidelines for prophylaxis of renal and non-renal adverse contrast media reaction are given in Tables 2.3 and 2.4. Sources used in these tables include documents of the Royal College of Radiologists³ and the European Society of Urogenital Radiology ²³ on contrast medium administration; the full text of these documents can be downloaded from the internet at www.rcr.ac.uk and www.esur.org respectively. General safety issues are:

• a doctor should be immediately available in the department to deal with any severe reaction

• facilities for treatment of acute adverse reaction should be readily available and regularly checked

• a patient must not be left alone or unsupervised for the first 5 min following injection of the contrast agent

• the patient should remain in the department for at least 15 min after the contrast injection. In patients at increased risk of reaction this should be increased to 30 min.

Table 2.3 Guidelines for prophylaxis of renal adverse reactions to iodinated contrast medium

Renal adverse reactions
Identification of patients at increased risk:
1. The referring clinician should identify patients with pre-existing renal impairment and inform the radiology department. 2. Serum creatinine should be measured within 1 week before the administration of contrast in patients: a with previously raised serum creatinine b who are diabetic and taking metformin c who will undergo intra-arterial contrast injection d with clinical history suggesting increased risk of renal impairment (e.g. diabetes, renal surgery or administration of nephrotoxic drugs).

Renal adverse reactions

Identification of patients at increased risk:

1. The referring clinician should identify patients with pre-existing renal impairment and inform the radiology department.

2. Serum creatinine should be measured within 1 week before the administration of contrast in patients:

a with previously raised serum creatinine

b who are diabetic and taking metformin

c who will undergo intra-arterial contrast injection

d with clinical history suggesting increased risk of renal impairment (e.g. diabetes, renal surgery or administration of nephrotoxic drugs).

Precautions for patients with significant renal impairment (any patient with serum creatinine >130 μmol l⁻¹):

1. Consider an alternative imaging method, not using iodinated contrast media.

2. 48 h before the procedure stop any treatment with metformin. This should be withheld for a further 48 h after the procedure and renal function re-assessed before restarting metformin treatment.

3. 24 h before the procedure stop all nephrotoxic drugs, mannitol and loop diuretics.

4. 6 h before the procedure start hydrating the patient either orally, or in the case of high dose or intra-arterial administration, intravenously.

5. Use the smallest possible dose of contrast medium.

6. Use low- or iso-osmolar contrast medium.

There is insufficient evidence to support the use of prophylactic administration of N-acetyl cysteine for patients at high risk of contrast nephropathy. There is no definite evidence that haemodialysis or peritoneal dialysis protect patients with impaired renal function from contrast medium induced nephrotoxicity. Patients with normal renal function on treatment with metformin:

1. If <100 ml of contrast agent is to be used intravenously then no special precaution is required.

2. If >100 ml of contrast is to be used intravenously or the intra-arterial route is to be used, the metformin should be withheld for 48 h after the procedure.

Table 2.4 Guidelines for prophylaxis of non-renal adverse reactions to iodinated contrast medium

Non-renal adverse reactions
Identification of patients at increased risk of anaphylactoid contrast reaction:
It is essential that before administration of iodinated contrast every patient must be specifically asked whether they have a history of: 1. previous contrast reaction – associated with a sixfold increase in reactions to contrast medium.²⁰ Determine exact nature and specific agent used. 2. asthma – history of asthma associated with a six to tenfold increase in risk of severe reaction.²⁴ Determine whether patient has true asthma or COPD and whether asthma is currently well controlled. If asthma not currently well controlled and examination is non-emergency, the patient should be referred back for appropriate medical therapy. 3. previous allergic reaction requiring medical treatment – determine the nature of the allergies and their sensitivity (there is no specific cross reactivity with shellfish or topical iodine in acute reactions).
Precautions for patients at increased risk of anaphylactoid contrast reaction:
1. Consider an alternative test not requiring iodinated contrast. 2. If the injection is considered necessary: a Use a non-ionic low or iso-osmolar contrast agent b For previous reactors to iodinated contrast use a different non-ionic low- or iso-osmolar contrast to that used previously c Maintain close supervision d Leave the cannula in place and observe for 30 min e Be ready to treat promptly any adverse reaction and ensure that emergency drugs and equipment are ready.
There are no conclusive data supporting the use of premedication in the prevention of severe reactions to contrast media in patients at increased risk and clinical opinion remains divided.^25,²⁶
If it is decided to use premedication for patients at increased risk, a suitable regime is prednisolone 30 mg orally given 12 h and 2 h before contrast medium.
Pre-treatment with antihistamines is of no benefit and is associated with an increased incidence of flushing. Pre-testing by applying contrast medium to the cornea or injecting a 1 ml test dose intravenously a few minutes prior to the full injection has also been abandoned.
Other situations:
Pregnancy – In exceptional circumstances, iodinated contrast may be given. Thyroid function of the neonate should be checked during the first week of life.²⁷
Treatment with ß-blockers – ß-blockers may impair the response to treatment of bronchospasm induced by contrast medium.
Lactation – No special precaution required. Breast feeding can continue normally.
Thyrotoxicosis – Intravascular contrast should not be given if the patient is hyperthyroid. Avoid thyroid radio-isotope tests and treatment for 2 months after iodinated contrast medium administration.
Phaeochromocytoma – When detected biochemically it is advised that α and ß-adrenergic blockade with orally administered drugs is arranged before administration of iodinated contrast.
Sickle cell anaemia – There is risk of precipitating a sickle cell crisis. Iso-osmolar contrast should be used.
Myelomatosis – Bence Jones protein may be precipitated in renal tubules. Risk diminished by ensuring good hydration.

References

1 Almén T. Contrast agent design. Some aspects of synthesis of water-soluble contrast agents of low osmolality. J. Theor. Biol.. 1969;24:216-226.

2 Dawson P., Grainger R.G., Pitfield J. The new low-osmolar contrast media: a simple guide. Clin. Radiol.. 1983;34:221-226.

3 The Royal College of Radiologists. Standards for Intravenous Iodinated Contrast Administration to Adult Patients. London: The Royal College of Radiologists, 2005.

4 Mortelé K.J., Oliva M.R., Ondategui S., et al. Universal use of nonionic iodinated contrast medium for CT: evaluation of safety in a large urban teaching hospital. Am. J. Roentgenol.. 2005;184(1):31-34.

5 Katayama H., Yamaguchi K., Kozuka T., et al. Adverse reactions to ionic and non-ionic contrast media. Radiology. 1990;175(3):621-628.

6 Dawson P., McCarthy P., Allison D.J., et al. Non-ionic contrast agents, red cell aggregation and coagulation. Br. J. Radiol.. 1988;61:963-965.

7 Aspelin P., Stacul F., Thomsen H.S., et al. Effects of iodinated contrast media on blood and endothelium. Eur. Radiol.. 2006;16(5):1041-1049.

8 Losco P., Nash G., Stone P., et al. Comparison of the effects of radiographic contrast media on dehydration and filterability of red blood cells from donors homozygous for hemoglobin A or hemoglobin. S. Am. J. Hematol. 2001;68(3):149-158.

9 Benko A., Fraser-Hill M., Magner P., et al. Canadian Association of Radiologists: consensus guidelines for the prevention of contrast induced nephropathy. Can. Assoc. Radiol. J.. 2007;58(2):79-87.

10 Persson P.B., Hansell P., Liss P. Pathophysiology of contrast medium-induced nephropathy. Kidney Int.. 2005;68(1):14-22.

11 Liss P., Persson P.B., Hansell P., et al. Renal failure in 57 925 patients undergoing coronary procedures using iso-osmolar or low-osmolar contrast media. Kidney Int.. 2006;70(10):1811-1817.

12 Brunette J., Mongrain R., Rodés-Cabau J., et al. Comparative rheology of low- and iso-osmolarity contrast agents at different temperatures. Catheter Cardiovasc. Interv.. 2008;71(1):78-83.

13 van der Molen A.J., Thomsen H.S., Morcos S.K., et al. Effect of iodinated contrast media on thyroid function in adults. Eur. Radiol.. 2004;14(5):902-907.

14 Dillman J.R., Strouse P.J., Ellis J.H., et al. Incidence and severity of acute allergic-like reactions to i.v. non-ionic iodinated contrast material in children. Am. J. Roentogenol.. 2007;188(6):1643-1647.

15 Palmer F.J. The R.A.C.R. survey of intravenous contrast media reactions: final report. Australas. Radiol.. 1988;32:426-428.

16 Katayama H., Yamaguchi K., Kozuka T. Adverse reactions to ionic and non-ionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology. 1990;175:621-628.

17 Wolf G.L., Mishkin M.M., Roux S.G. Comparison of the rates of adverse drug reactions. Ionic contrast agents, ionic agents combined with steroids and nonionic agents. Invest. Radiol.. 1991;26:404-410.

18 Wysowski D.K., Nourjah P. Deaths attributed to X-ray contrast media on U.S. death certificates. Am. J. Roentgenol.. 2006;186:613-615.

19 Webb J.A., Stacul F., Thomsen H.S., et al. Late adverse reactions to intravascular iodinated contrast media. Eur. Radiol.. 2003;13(1):181-184.

20 Morcos S.K. Acute serious and fatal reactions to contrast media: our current understanding. Br. J. Radiol.. 2005;78(932):686-693.

21 Böhm I., Speck U., Schild H. Cytokine profiles after nonionic dimeric contrast medium injection. Invest. Radiol.. 2003;38(12):776-783.

22 Lalli A.F. Urographic contrast media reactions and anxiety. Radiology. 1974;112(2):267-271.

23 European Society of Urogenital Radiology Contrast Media Safety Committee. ESUR guidelines on contrast media Version 6.0. www.esur.org, 2007.

24 Morcos S.K., Thomsen H.S. Adverse reactions to iodinated contrast media. Eur. Radiol.. 2001;11(7):1267-1275.

25 Tramèr M.R., von Elm E., Loubeyre P., et al. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review. BMJ. 2006;333(7570):675.

26 Thomsen H.S. Guidelines for contrast media from the European Society of Urogenital Radiology. Am. J. Roentgenol.. 2003;181:1463-1471.

27 Webb J.A., Thomsen H.S., Morcos S.K., et al. The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur. Radiol.. 2005;15(6):1234-1240.

Contrast Agents in Magnetic Resonance Imaging

HISTORICAL DEVELOPMENT

Shortly after the introduction of clinical MRI, the first contrast-enhanced human MRI studies were reported in 1981 using ferric chloride as a contrast agent in the gastrointestinal tract. In 1984, Carr et al. first demonstrated the use of a gadolinium compound as a diagnostic intravascular MRI contrast agent.¹ Currently, around one-quarter of all MRI examinations are performed with contrast agents.

MECHANISM OF ACTION

Whilst radiographic contrast agents use a direct alteration in tissue density to allow the visualization of structures, the MRI contrast agents act indirectly by altering the magnetic properties of hydrogen ions (protons) in water and lipid which form the basis of the image in MRI. To enhance the inherent contrast between tissues, MRI contrast agents must alter the rate of relaxation of protons within the tissues. The changes in relaxation vary and, therefore, different tissues produce differential enhancement of the signal (see Figs 2.3 and 2.4). These figures show that, for a given time t, if the T1 relaxation is more rapid then a larger signal is obtained (brighter images), but the opposite is true for T2 relaxation, where more rapid relaxation produces reduced signal intensity (darker images). There are different means by which these effects on protons can be produced using a range of MRI contrast agents.

Figure 2.3 Signal intensity and T1 relaxation time.

Figure 2.4 Signal intensity and T2 relaxation time.

MRI contrast agents must exert a large magnetic field density (a property imparted by their unpaired electrons) to interact with the magnetic moments of the protons in the tissues and so shorten their T1 relaxation time which will produce an increase in signal intensity (see Fig. 2.3). The electron magnetic moments also cause local changes in the magnetic field, which promotes more rapid proton dephasing and so shortens the T2 relaxation time. All contrast agents shorten both T1 and T2 relaxation times but some will predominantly affect T1 (longitudinal relaxation rate) and other predominantly T2 (transverse relaxation rate).

Agents with unpaired electron spins are potential contrast agents in MRI. These may be classified under three headings:

1. Ferromagnetic. These retain magnetism even when the applied field is removed. This may cause particle aggregation and interfere with cell function, making them unsafe for clinical use as MRI contrast agents.

2. Paramagnetic – e.g. gadolinium. These contrast agents have magnetic moments which align to the applied field, but once the gradient field is turned off, thermal energy within the tissue is enough to overcome the alignment. Gadolinium compounds may be made soluble by chelation and can, therefore, either be injected intravenously or used as an oral preparation. Their maximum effect is on protons in the water molecule, shortening the T1 relaxation time and hence producing increased signal intensity (white) on T1 images (Fig. 2.3).

3. Superparamagnetic – e.g. particles of iron oxide (Fe₃O₄). These cause abrupt changes in the local magnetic field which results in rapid proton dephasing and reduction in the T2 relaxation time, and hence producing decreased signal intensity (black) on T2 images (Fig. 2.4). Superparamagnetic compounds were initially produced only as large particles in a colloid suspension for gastrointestinal contrast. However, more recently they have become available as small particles of iron oxide (SPIO) agents and ultrasmall particles of iron oxide (USPIO) agents. Both SPIO and USPIO agents have submicron global particle diameters and are small enough to form a stable solution which can be injected intravenously.

GADOLINIUM

The gadolinium (GD) chelates represent the largest group of MRI contrast media and are available in three forms:

1. Extracellular fluid (ECF) agents: by far the most commonly used form of gadolinium. Includes (i) Gd-diethylenetriaminepenta-acetic acid (DTPA), dimeglumine gadopentetate (Magnevist, Schering), (ii) Gadodiamide (Gd-DTPA-bismethylamide) (Omniscan, Nycomed Amersham) and (iii) Gd-DO3A, Gadoteridol (ProHance, Bracco, Merck, Squibb). They all contain gadolinium, an 8-coordinate ligand binding to gadolinium and a single water molecule coordination site to gadolinium and all have a molecular weight similar to iodinated contrast agents. After intravenous injection they circulate within the vascular system and are excreted unchanged by the kidneys. The ECF agents do not cross the normal blood–brain barrier but do cross the abnormal blood–brain barrier. ECF agents are used for angiography but rapidly leak out of the vascular space into the interstitial space so are used only for dynamic arterial studies. There is a wide range of indications for these contrast media including improved detection rates and more accurate delineation and characterization of tumours.

2. Liver agents: the excretion pathway of the gadolinium chelates can be altered to produce compounds such as Gd-BOPTA (gadobenate, Multihance) and Gd-DTPA (Primovist), which are taken up by hepatocytes and cleared intact via the hepato-biliary system. Another paramagnetic liver specific contrast agent is the manganese chelate Mn-DPDP (Telescan). These agents are used to improve detection of liver lesions which do not contain hepatocytes (therefore do not take up the contrast), such as liver metastases, and to characterize lesions which do take up the contrast, such as hepatocellular carcinoma. They can also be used to provide positive contrast (T1 weighted) of the hepato-biliary system.

3. Blood pool agents: the blood pool agents remain longer in the vascular space than ECF agents and allow a wider range of vascular imaging. The first of these contrast agents approved for clinical use in Europe, gadofosveset trisodium (Vasovist, Bayer Schering),² has recently been introduced.

Dose

For ECF gadolinium agents, usually 0.1 mmol kg⁻¹ body weight (e.g. 0.2 ml of Magnevist kg⁻¹); up to 0.2 mmol kg⁻¹ when used in low-field magnets.

Adverse reactions

Gadolinium contrast agents are very safe and well tolerated; they have a much lower incidence of adverse reactions than iodinated contrast agents. Adverse reactions to gadolinium are mostly mild and self-limiting and can be divided into acute and delayed reactions. The incidence is shown in Table 2.5.

Table 2.5 Acute adverse reaction rates for gadolinium contrast agents

Acute adverse reactions

These are rare, but the following have been described:

1. Urticaria and rash

2. Nausea/vomiting

3. Dizziness and confusion

4. Dyspnoea, chest discomfort and palpitation

5. Anaphylactoid shock.

Patients with a history of previous adverse reaction to gadolinium contrast agents have up to an eightfold increase in likelihood of experiencing adverse reactions,⁶ and those with asthma, documented allergies or previous adverse reaction to iodinated contrast are also at increased risk of adverse reaction.⁷

Delayed adverse reactions

1. Renal impairment – when used at the standard doses given above, gadolinium contrast agents do not cause significant impairment of renal function. It was initially thought that gadolinium agents might be used as a replacement for iodinated contrast for those at increased risk of contrast nephrotoxicity. However, when used at the high doses required to give equivalent X-ray attenuation, gadolinium-based contrast media have more nephrotoxic potential than iodinated contrast.⁸

2. Nephrogenic systemic fibrosis (NSF) – this systemic disorder, first described in 2000, is characterized by increased deposition of collagen with thickening and hardening of the skin, contractures and, in some patients, clinical involvement of other tissues.⁹ NSF only occurs in patients with renal disease and almost all patients with NSF have been exposed to gadolinium-based contrast agents within 2–3 months prior to the onset of the disease. The mechanism by which renal failure and gadolinium-based contrast agents trigger NSF is not known. The overwhelming majority of reported cases of NSF represent patients who had previously been given gadodiamide (Omniscan, GE Healthcare),¹⁰ but there are some reports of NSF associated with other gadolinium contrast agents. Reported figures from Denmark show that 5% of all patients with severe renal impairment who had been given Omniscan developed NSF.⁷