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

Venous

1. Pain at the injection site – usually the result of a perivenous injection

2. Pain extending up the arm – due to stasis of contrast medium in the vein. May be relieved by abducting the arm

3. Delayed limb pain – due to thrombophlebitis as a result of the toxic effect on endothelium.

Arterial

Arterial endothelial damage and vasodilatation are mostly related to hyperosmolality. Contrast medium injected during peripheral arteriography may cause a sensation of heat or pain.

Soft-tissue toxicity

Pain, swelling, erythema and even sloughing of skin may occur from extravasated contrast medium. The risk is increased when pumps are used to inject large volumes of contrast medium during computed tomography (CT) examinations. Treatment should consist of the application of cold packs and elevation of the limb. Systemic steroids, non-steroidal anti-inflammatory drugs and antibiotics have all been shown to be useful.

Cardiovascular toxicity

1. Intracoronary injection of contrast media may cause significant disturbance of cardiac rhythm.

2. Increased vagal activity may result in depression of the sino-atrial and atrio-ventricular nodes, causing bradycardia or asystole.

3. The injection of a hypertonic contrast medium causes significant fluid and ion shifts. Immediately after injection there is a significant increase in serum osmolality. This causes an influx of water from the interstitial space into the vascular compartment, an increase in blood volume, an increase in cardiac output and a brief increase of systemic blood pressure. Peripheral dilatation causes a more prolonged fall of blood pressure. Injection into the right heart or pulmonary artery causes transitory pulmonary hypertension and systemic hypotension; injection into the left ventricle or aorta causes brief systemic hypertension followed by a more prolonged fall.

Haematological changes

1. In the presence of a high concentration of contrast medium, such as withdrawal of blood into a syringe of contrast medium, damage to red cell walls occurs and haemolysis follows. Haemolysis and haemoglobinuria have been reported following angiocardiography. It is advisable not to re-inject blood that has been mixed with contrast medium.

2. Red cell aggregation and coagulation may occur in the presence of a high concentration of contrast medium, e.g. 350 mg I ml⁻¹. However, disaggregation occurs easily and this is not likely to be of any clinical significance.⁶

3. Contrast media impair blood clotting and platelet aggregation. Low- and iso-osmolar contrast media have a minimal effect compared to HOCM.⁷

4. Contrast media have a potentiating effect on the action of heparin.

5. Thrombus formation also occurs and is more common when blood is mixed with LOCM. However, the role of the syringe is also significant and thrombus formation is maximal when blood is slowly withdrawn into a syringe so that it layers on top of the contrast medium, against the wall of the syringe. Activation of coagulation by the tube material probably plays a significant role.

6. Contrast media have been shown to cause HbSS blood to sickle in vitro and sickle cell crisis has been provoked by contrast medium. Iso-osmolar contrast agents have a lesser effect and their use is indicated in this disease.⁸

7. When red blood cells are placed in a hypertonic contrast medium, water leaves the interior of the cells by osmosis and they become more rigid and less deformable. Isosmolar solutions may also have an effect on red cell deformability, indicating that there may also be a chemical effect. Red cells that deform less easily are less able to pass through capillaries and may occlude them. This is the explanation for the transient rise in pulmonary arterial pressure during pulmonary arteriography and may also be a factor in contrast-induced nephropathy.

8. Transient eosinophilia may occur 24–72 h after administration of contrast medium.

Nephrotoxicity

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

2. Diabetes mellitus is present in 50% of cases of CIN.

3. Dehydration is a risk factor.

4. Age is also a factor because of the greater incidence of cardiovascular disease in the elderly.

5. Very large doses of contrast medium increase the risks.

6. Multiple myeloma increases the risks.

7. The presence of other nephrotoxic drugs is also a risk factor.

The mechanisms of CIN are summarized below:¹⁰

1. Impaired renal perfusion:

a adverse cardiotoxic effects

b increased peripheral vasodilatation

c renal vascular bed changes (increased blood flow followed by a more prolonged decrease)

d increased rigidity of red cells

e pre-dehydration

f osmotic diuresis.

2. Glomerular injury:

a impaired perfusion

b hyperosmolar effects

c chemotoxic effects.

3. Tubular injury:

a impaired perfusion

b hyperosmolar effects

c chemotoxic effects

(all manifest histologically as cytoplasmic vacuolation).

4. Obstructive nephropathy:

a cytoplasmic vacuolation in tubules

b precipitation of Tamm-Horsfall protein

c precipitation of Bence Jones protein in multiple myeloma.

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

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