Side effects of contrast agents

The use of radiocontrast agents poses the greatest danger to patients due to the high frequency and severity of complications. The harmful effects of water-soluble radiocontrast agents (RCAs) used for excretory urography, renal CT, AG and CT angiography, as well as other studies of the kidneys and urinary tract are associated with the chemotactic effect of iodine, carboxyl groups on cells; with osmotic toxicity and local ionic imbalance occurring in the lumen of the vessel with bolus administration of ionic radiocontrast agents. The phenomenon of osmotic toxicity consists in a multiple increase in osmotic pressure at the site of drug administration, which causes dehydration and damage to endothelial cells and blood cells. As a result, erythrocytes lose their elasticity and ability to change shape when moving through the capillaries, an imbalance is observed between the formation of endothelin, endothelial relaxing factor (NO), the production of other biologically active molecules is activated, the regulation of vascular tone and microcirculation is disrupted, and thrombosis occurs.

The toxicity of X-ray contrast agents is determined by the structure of their molecule and its ability to dissociate into ions in an aqueous solution. Until recently, only ionic or dissociating X-ray contrast agents (urografin, verografin, etc.) were used, which consist of salts that dissociate into cations and anions. They are characterized by high osmolarity (5 times higher than that of blood plasma), so they are also called high-osmolar contrast agents and can cause local ion imbalance. When using them, side effects often develop, including the most severe ones. Non-ionic or non-dissociating, low-osmolar X-ray contrast agents (iohexol, iopromide, iodixanol) are safer. They do not dissociate into ions, are characterized by a higher ratio of the number of iodine atoms to the number of drug particles in a unit volume of solution (i.e. good contrast is provided at a lower osmotic pressure), iodine atoms are protected by hydroxyl groups, which reduces chemotoxicity. At the same time, the cost of low-osmolar radiocontrast agents is several times higher than high-osmolar ones. In addition, radiocontrast agents are divided by their structure into monomeric and dimeric, depending on the number of benzene rings with built-in iodine atoms. When using dimeric drugs containing six instead of three iodine atoms in one molecule, a smaller dose of the drug is required, due to which osmotoxicity is reduced. According to the mechanism of development, side effects are divided into:

• anaphylactoid, or unpredictable (anaphylactic shock, Quincke's edema, urticaria, bronchospasm, hypotension);
• direct toxic (nephrotoxicity, neurotoxicity, cardiotoxicity, etc.);
• local (phlebitis, necrosis of soft tissues at the injection site).

Anaphylactoid, or unpredictable, reactions to iodinated contrast media are so called because the cause and exact mechanism of their development are unknown, although certain conditions increase their risk. There is no clear relationship between their severity and the dose of the administered drug. Activation of serotonin and histamine secretion plays a certain role. The difference between anaphylactoid reactions and true anaphylaxis is not significant in practice, since the symptoms and treatment measures for them are the same.

According to severity, side effects are divided into mild (not requiring intervention), moderate (requiring treatment but not life-threatening) and severe (life-threatening or leading to disability).

Mild side effects include sensations of heat, dry mouth, nausea, shortness of breath, headache, and slight dizziness. They do not require treatment, but may be harbingers of more severe effects. If they occur before the contrast agent is administered, it must be stopped. Without removing the needle from the vein, continue to monitor the patient, and prepare medications in case of more severe complications.

If moderate side effects develop (severe nausea, vomiting, rhinoconjunctivitis, chills, itching, urticaria, Quincke's edema), an antidote is administered - sodium thiosulfate (10-30 ml of a 30% solution intravenously), adrenaline (0.5-1.0 ml of a 0.1% solution subcutaneously), antihistamines - diphenhydramine (1-5.0 ml of a 1% solution intramuscularly), chloropyramine (1-2.0 ml of a 2% solution intramuscularly), prednisolone (30-90 mg intravenously in a glucose solution). In the event of tachycardia, a drop in blood pressure, and the appearance of pallor, adrenaline is additionally administered (0.5-1.0 ml intravenously), and oxygen inhalation is started in a volume of 2-6 l/min. When signs of bronchospasm appear, bronchodilators are prescribed in the form of inhalations.

If a severe anaphylactoid reaction or true anaphylactic shock develops (paleness, a sharp drop in blood pressure, collapse, tachycardia, asthmatic status, convulsions), it is necessary to call a resuscitator, set up an intravenous infusion system and begin inhalation of oxygen 2-6 l/min. Sodium thiosulfate (10-30 ml of a 30% solution), adrenaline 0.5-1.0 ml of a 0.1% solution, chloropyramine 1-2.0 ml of a 2% solution or diphenhydramine 1-2.0 ml of a 1% solution, hydrocortisone 250 mg in isotonic sodium chloride solution are administered intravenously. If necessary, a resuscitator performs intubation and artificial ventilation of the lungs.

The development of such a severe complication as acute heart failure may be caused by a violation of the regulation of the heart (hyperactivation of the parasympathetic influence, leading to pronounced bradycardia and a decrease in cardiac output), myocardial damage due to its ischemia and direct toxic effect of the contrast agent with the development of arrhythmia and a drop in the pumping function of the heart, a sharp increase in afterload in the large and small circles of blood circulation due to vasoconstriction and microcirculation disorders. In case of hypotension resulting from a vagal vascular reaction and associated, unlike anaphylactoid hypotension, with pronounced bradycardia, in addition to intravenous administration of isotonic sodium chloride solution, atropine (0.5-1.0 mg intravenously) is used. In acute left ventricular failure, inotropic agents (dopamine, 5-20 mcg/kg/min) are administered intravenously. For normal or high blood pressure, nitroglycerin (0.4 mg sublingually every 5 minutes or 10-100 mcg/min) and sodium nitroprusside (0.1-5 mcg/kg/min) are used to reduce afterload.

NB! A history of adverse reactions to contrast agents is an absolute contraindication for their repeated use.

Risk factors for complications when using iodine-containing contrast agents:

• previous allergic reactions to medications;
• history of allergies;
• bronchial asthma;
• severe heart and lung diseases;
• dehydration;
• chronic renal failure;
• old and senile age.

Prevention of complications involves careful collection of anamnesis and examination before the study by the attending physician in order to identify risk factors. If at least one of them is present and especially if they are combined, a thorough and strict assessment of the potential benefit/risk ratio of the planned study is required. It should be carried out only if its results can influence the treatment tactics and thereby improve the prognosis and quality of life of the patient. The most important preventive measure is the use of low-osmolar (non-ionic) contrast agents, at least in patients at risk. According to numerous studies, the incidence of side effects when using high-osmolar contrast agents is 5-12%, low-osmolar - 1-3%. In case of a reaction, assistance is provided in the diagnostic room, where the necessary set of medications should be at hand. Some centers have adopted premedication with prednisolone for patients at risk in order to prevent anaphylactoid reactions (50 mg orally 13; 5 and 1 hour before the administration of the contrast agent). However, there is no convincing evidence that this preventive measure significantly reduces the risk of complications, so its widespread use should be considered insufficiently justified.

Nephrotoxicity of RCS requires special consideration. It consists of a direct toxic effect of the drug on the epithelium of the renal tubules and the renal endothelium, as well as osmotic toxicity. Severe endothelial dysfunction occurs with increased production of both pressor and vasodilator agents endothelin, vasopressin, prostaglandin E2 _, endothelial relaxing factor (NO), atrial natriuretic peptide; however, there is an earlier depletion of the depressor system with a predominance of vasoconstriction. As a result of this, as well as an increase in blood viscosity and deterioration of microcirculation, glomerular perfusion is impaired, ischemia and hypoxia of the tubulointerstitium develop. Under conditions of hypoxia and increased osmotic load of the epithelial cells of the renal tubules, their death occurs. One of the factors in the damage of the renal tubular epithelium is the activation of lipid peroxidation and the formation of free radicals. Fragments of destroyed cells form protein cylinders and can cause obstruction of the renal tubules. Clinically, kidney damage is manifested by proteinuria and impaired renal function - from reversible hypercreatininemia to severe acute renal failure, which can occur both with and without oliguria. The prognosis for the development of acute renal failure in response to the introduction of radiocontrast agents is serious. Every third patient with oliguric acute renal failure has an irreversible decrease in renal function, with half requiring constant hemodialysis. In the absence of oliguria, chronic renal failure develops in every fourth patient, and every third of them requires constant hemodialysis.

The proven risk factors for acute renal failure when using radiocontrast agents largely coincide with the risk factors for extrarenal complications. These include:

• chronic renal failure;
• diabetic nephropathy;
• severe congestive heart failure;
• dehydration and hypotension;
• high dose and frequency of repeated administration of radiocontrast agents.

In the general population, radiocontrast media nephrotoxicity, defined as an increase in serum creatinine of more than 0.5 mg/dL or more than 50% from baseline, occurs in 2-7% of cases; in patients with impaired renal function (serum creatinine more than 1.5 mg/dL) or other proven risk factors, it occurs in 10-35% of cases. In addition, such probable risk factors for renal function impairment as arterial hypertension, widespread atherosclerosis, impaired liver function, and hyperuricemia should be taken into account. An adverse effect of multiple myeloma and diabetes mellitus without renal impairment on the risk of nephrotoxicity has not been proven.

Prevention of acute renal failure when using RCS includes:

• taking into account risk factors and contraindications;
• conducting studies with RCS in patients included in the risk group only in cases where its results can significantly affect the prognosis;
• use of safer low-osmolar drugs;
• use of the minimum possible doses;
• hydration of patients [1.5 ml/kg h)] for 12 hours before and after the study;
• normalization of blood pressure.

Among the medical prescriptions proposed for the prevention of acute renal failure when using radiocontrast agents, only hydration reliably improves the prognosis of patients. The effectiveness of other methods based on prospective clinical studies is questionable (prescription of dopamine, mannitol, calcium antagonists) or insufficiently proven (prescription of acetylcysteine).

In MRI, drugs containing the rare earth metal gadolinium, whose atoms have special magnetic properties, are used for contrast purposes. The toxicity of gadolinium drugs is significantly lower (10 or more times compared to iodine-containing RCS) due to the fact that its atoms are surrounded by chelate complexes of diethylenetriamidepentaacetic acid. However, severe anaphylactoid side effects similar to the side effects of iodine-containing RCS, as well as cases of acute renal failure, have been described when using it. The tactics of treating these complications do not have fundamental differences compared to complications of radiocontrast agents.

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