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.

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).

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.


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


Haematological changes


Reviews on the incidence of contrast-induced nephrotoxicity (CIN) suggest an incidence of approximately 1–6%. In those affected, the serum creatinine concentration starts to rise within the first 24 h, reaches a peak by 2–3 days and usually returns to baseline by 3–7 days. In rare cases patients may need temporary or permanent dialysis. There are a number of predisposing factors:

1. The most important risk factor is pre-existing impairment of renal function. This is present in 90% of reported cases of CIN. Patients with normal renal function are at very low risk and those with GFR of <30 ml/min are most at risk.9 However, most patients have not had a recent GFR measurement and guidelines recommend the use of serum creatinine level of >130 μmol l−1 as an imperfect, but readily available, indicator of patients at increased risk of CIN.3

The mechanisms of CIN are summarized below:10

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.


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

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

Non-fatal reactions


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