Contrast Agent and contrast Reaction

Contrast Agent (contrast media) is one of the most commonly used drugs in interventional radiology, mainly used for the display of blood vessels and body cavity. There are various types of contrast agents. At present, most of the contrast agents used for interventional radiology are iodine-containing preparations. Since Brooks successfully performed the first femoral angiogram with 1924 sodium iodide in 50%, contrast agent products were constantly updated like interventional radiology. As an ideal contrast agent, it should have the following characteristics: (1) high contrast content (2) Simple Synthesis, high yield (3) good stability inside and outside the body (4) unlimited water solubility (5) low Viscosity (6) No biological activity.

I. Development and classification of Contrast Agent

Generation and development of Iodine contrast agent
In 1950s, Larsen (Sterling-Winthrop) and lan-gacker (Schering AG) both discovered triiodine benzene-the famous amidotrezoic acid ), the resulting contrast media is still widely used, the first time in the history of modern contrast media. Almost all the iodine components of the ionic contrast agent are derived from it.
At the end of 1960s, Almen, a Swedish radiologist, proposed the concept of non-ionic contrast agent. In 1971, he reported the first non-ionic single contrast agent, metrizamide, amipaque ), the appearance of non-ionic single contrast agent is the second leap in the history of modern contrast agent. Although it has the advantages of low osmotic pressure [485 mmol/L (485mosm. kg)] and good tolerance, it has unstable performance.
The first-generation contrast agent was quickly replaced by the second-generation non-ionic single contrast agent, which represented the following drugs: iopamidol (iopamidol, ibitl, Bracco, produced in 1974), iohexol (iohexol, that is, omnipaque, onai Parker, nyegaard, produced in 1976), iopromide (instant ultravist, youweixian, Schering AG, produced in 1979), iomeprol (iomeprol, bracco, produced in 1979), iopentol, (nycomed, produced in 1982)] Ioversol, (mallinckrodt, produced in 1982) and iostman, iobitridol (xenetix, guerbet), etc., these contrast agents have a low osmotic pressure [500 ~ 700 mOsm/kg], good tolerance and other characteristics, stable performance, high temperature disinfection, has been widely used.
At the end of 1970s, Schering AG began to develop a non-ionic dimers contrast agent to further reduce osmotic pressure. Among them, iotrolan (iotrolan, issoxian, isovist) was confirmed to have infinite water solubility, 300mgl/ml and body fluid infiltration, and the function is well tolerated. The disadvantage is that the relative molecular mass is too large (the relative molecular mass is 1626), and the viscosity is high. The emergence of non-ionic dimers is seen as the third leap in the history of modern contrast agents. Similar to iodixanol, visipaque, and nycomed, iodixanol has the same performance.
Iodine contrast agent Classification
Generally, Iodine contrast agent is divided into ionic and non-ionic contrast agent. Ionic contrast agent is divided into monoacid monomer and monoacid dimers by structure. The Representative drugs of monoacid monomer include pan-shadozooamine and iodine-taproproamine. Monic Acid Dimers represent iodine. Ion-type contrast agent has a high incidence of side reactions and poor tolerance of the body. Non-ionic contrast agent can also be divided into monomer and dimers. The former indicates that the drugs include iodine, and the latter has iodine. Non-ionic contrast agent has a low incidence of side reactions and has a good tolerance to the body.
The contrast agent can also be classified by osmotic pressure of the drug, that is, high osmotic, low osmotic and equiosmotic. The drug body of the same infiltration has good tolerance and is too high or too low. There are different levels of stimulus responses.

Ii. Contrast Agent Reaction Mechanism

Contrast reactions can be divided into special heterogeneous reactions and physical-chemical reactions. The former has nothing to do with the dose, while the latter has a clear relationship with the dose.
1. the results of decades of special heterogeneous reactions show that the results of contrast reactions, such as delayed diagnosis, vascular edema, laryngeal edema, bronchial spasm, severe blood pressure reduction, and sudden death, are heterogeneous reactions, the occurrence is related to the following factors.
(1) Both ionic and non-ionic contrast agents can stimulate the release of history in hypertrophy cells. It was found that the content of patients with contrast reaction was significantly higher than that of patients without contrast reaction by determination of human amine or its metabolism in urine.
(2) antigen-antibody response contrast agent is a half antigen. Some of its contrast molecules can combine with serum proteins to form a complete antigen. Many studies have demonstrated that some of the contrast reactions are antigen-antibody reactions.
(3) activating system contrast agent, especially ion-type hypertonic contrast agent, may lead to changes in morphology and function of blood cells and endothelial cells, it can also lead to the release of some media, such as amine, 5-hydroxyamine, slow Kalin, platelet activation factor, and so on.
(4) The effects of the contrast agent on the production of the same effect by inhibiting the activity of the receptor. The results show that many types of Iodine contrast agent have similar effects, therefore, this function is considered to be mainly due to the role of iodine itself.

2. the incidence and severity of physical-chemical reactions are related to the amount of contrast agents used. nausea, vomiting, flushes, fever, and local pain are common causes of contrast reactions, the related factors are as follows.
(1) osmotic pressure because the osmotic pressure of the commonly used contrast agent obviously exceeds the blood, it is 2 ~ 5 times, so it is easy to produce a kind of damage.
1) vascular endothelial and blood-brain barrier damage after contrast agent injection into the vascular, the external fluid osmotic pressure suddenly increases, and the Internal fluid in the cell is quickly discharged, leading to the contraction of vascular endothelial cells, the Inter-cell connection becomes loose and broken, and the blood-brain barrier is damaged. Contrast Agents are infiltrated into the gap between brain tissue, so that nerve cells are exposed to the chemical toxicity hazard of contrast agents.
2) the damage to red blood cells causes the red blood cells to become hard and result in a spine-cell deformity. As a result, red blood cells are difficult or unable to pass through the capillary, resulting in microcirculation disorder.
3) In addition to cell fluid discharge, high osmotic contrast agent can make the interorganizational fluid enter the capillary, so that the blood volume increases rapidly, up to 10% ~ 15%, resulting in increased heart load. However, the volume of blood quickly recovered to normal with the contrast agent penetrating to the vascular and Osmotic diuretic effect.
4) renal toxicity although the total incidence of contrast induced renal failure is low (<1% ). The number of patients with renal insufficiency can reach 10% ~ 20% and 60% of patients with contrast-induced kidney disease have the foundation of N.
5) in addition to the high blood volume caused by contrast agent, high permeability in selective coronary angiogram can directly affect the sinus node to cause slow heart rate. High Permeability can weaken the effect of compartment conduction, indoor conduction and polarization, lead to ECG changes, and increase the incidence of arrhythmia and ventricular fibrillation.
6) pain and vascular extension in Peripheral Blood angiogram, although the endothelial damage caused by hypertonic contrast agent is transient, the vascular pain is very obvious. In addition to osmotic pressure, this is also related to the hydrophobic and ionicity of contrast agent. Contrast Agent can directly act on small artery smooth muscle, causing local arterial expansion, resulting in Thermal Sensation and discomfort.
(2) Water-soluble Contrast Agent will not be used as a foreign body only when it is fully mixed with the surrounding liquid. The ideal contrast agent should have unlimited water solubility, but it is difficult to reach an infinite water solubility because the iodine atoms are highly hydrophobic. The water solubility in ionic contrast agent comes from the salt of the cation, while in the non-ionic contrast agent, the water solubility comes from the molecular core and reduces the combination of it with the biological molecules to reduce the biological activity of the contrast agent and reduce the reaction. Ionic contrast agent of monomer is more water-soluble than non-ionic type, but non-ionic dimers contrast agent iodine flux has a very high water-soluble.
(3) The charge ionic contrast agent is composed of an iodine-containing anionic with contrast function and a cation without contrast function. The former has a negative charge, while the latter has a positive charge. The charge can increase the conductivity of body fluids, disrupt the ionization environment and electrolyte balance, and thus affect normal physiological processes. The charge of contrast agent plays a major role in water-soluble and hydrophobic properties, and can increase the contrast-protein binding.
(4) The viscosity consistency is determined by the concentration and shape of the particles, the effect of the particles on the solution, and the effect between the particles. It is inversely proportional to the temperature change, but proportional to the iodine concentration, for example, when 300mgi/m1 is 37 ℃, the viscosity of iodine flux is 9.1cps, while that of iodine flux is 6.1cps. However, the viscosity of iodine flux 280mgl/ml is similar to that of non-ionic monomer contrast agent iodine flux MGL/ml. After the contrast agent is injected, the viscosity of the mixed blood contrast agent increases, which slows down the blood flow. This situation is only possible in high shear force (such as aorta) and low shear force (venous and capillary circulation), but it is advantageous for improving the quality of development. Therefore, although the non-ionic dimers contrast agent has a higher viscosity than the single contrast agent, the former is incomparable to the latter in terms of its development effect and reaction.
(5) chemical toxicity the chemical toxicity is caused by the combination of the hydrophobic zone in the contrast agent molecules and biological large molecules, which affects its normal function, the so-called "hydrophobic effect ". The first generation of non-ionic agent, methyl pan-Portuguese amine, was quickly eliminated due to the large amount of introduction of hydrophobic groups and the failure to mask them. The next non-ionic contrast agent can effectively mask the hydrophobic core, thus reducing the toxicity significantly.

Iii. High-Risk Factors of Contrast Agent Response

1. There is a history of Contrast Agent allergy
2. allergic constitution, such as eczema, urticaria, neurodermatitis, asthma, food and pollen allergy
3. hyperthyroidism, thyroid enlargement
4. Severe cardiovascular diseases (such as cardiac insufficiency, coronary atherosclerosis, recent myocardial infarction, long-term arrhythmia, and severe hypertension)
5. Weak and dehydrated
6. Severe Kidney Disease
7. Severe Liver Diseases
8. severe diabetes
9. Severe Pulmonary Diseases (respiratory region, pulmonary hypertension, pulmonary embolism, etc)
10. Brain Injury (recent cerebrovascular injury, convulsions, and traumatic brain injury)
11. asparinemia (valdenstön, giant globules, and plasma cell)
12. Hepatic chromioma (Dangerous to the brain crisis)
13. elderly people over 65 years old, infants, and children
14. Excessive anxiety
15. recently used contrast agent
16. Use B-receptor blocking: easily causing bronchial spasm and possibly difficult to treat.
17. long-term use of calcium ion Blocker: easily leads to easing and vascular Extension
18. Use IL-2 and/or interferon for treatment
19. Use diguanine hypoglycemic agents (which may lead to renal insufficiency and lactic acid emia)
20. sickle-cell anemia

Iv. Prevention of Contrast Agent reaction

Although there are no comprehensive methods to prevent contrast reactions, especially severe reactions, the following methods are worth using.
1. correct treatment of contrast agent "allergy test" with the widespread use of non-ionic contrast agent, it is obviously unreasonable to determine the possible reaction of non-ionic contrast agent based on the test results of ionic contrast agent. Because contrast reactions, especially severe reactions, are often unrelated to the dose, a 1 ml trial dose may produce a fatal extra heterogeneous response. In addition, the false positive rate and false negative rate of the test were high due to different levels of understanding of the criteria. To this end, Major radiology conferences abroad and most hospitals do not perform this "allergy test", some are limited to patients with allergic history, but our health department has not given up the test.
2. Preventive measures for high-risk patients
1) use a low-volume non-ionic contrast agent
2) pre-use of the anti-tissue amine drug H1 receptor blocker: chlorpheniramine, 2-4 mg (1-2 ampersand), or non-naogen, 4-8 mg (1-2 ampersand), 10-15 minutes before use of contrast agent, group slow intravenous injection. H2 receptor blocker: cimetidine, 200-400 mg (1-2), slow intravenous injection or fast input with 50 mL sodium chloride solution for injection.
3) oral administration of chitosan: Methyl prednisone, 24 hours before use of contrast agent, 12 hours and 40 mg intravenous administration respectively: Prednisone or methyl prednisone, 250 mg, intravenous injection 30 minutes before use of Contrast Agent
4) stable cardiovascular system
5) maintain water, electrolyte and acid-base balance
6) Avoid the use of renal toxicity drugs (such as non-traditional anti-Rheumatism drugs, azithromycin B, cisplatin, glucosamine and cephalosporin antibiotics, metformin)
7) if the patient needs to be sedated, the oral administration should be 10 mg. Do not cause respiration inhibition!
8) 40 or 20 drops of sodium chloride were used three times a day before and 2 hours after the angiogram to maintain the self-discipline of thyroid hormone function, 15 drops each time
9) patients with hyperthyroidism can only use X-ray contrast when necessary, and they need to increase the use of 20 mg a day for 1-2 weeks.
10) in patients with chromioma, give the receptor a blocking drug, such as urapidil, to avoid the secondary crisis.
3. Using non-ionic contrast agent as much as possible shows that the total incidence of non-ionic contrast agent reaction and the incidence of severe response are significantly lower than those of ionic contrast agent, non-ionic dimming contrast agent is more secure. To this end, despite being expensive, non-ionic contrast agents should be used as much as possible, especially in special areas such as coronary artery, cerebrovascular, heart, pulmonary artery and quadrigraphy. Non-ionic contrast agent, despite its high security, has a large amount of drugs (1 ml contrast agent contains 500 ~ MG drugs), so it is never unresponsive, and there are still deaths, so it can never be taken lightly.
4. Studies on reducing the amount of contrast agent show that the physical-chemical reaction in Contrast Agent reaction has a clear proportional relationship with the amount of contrast agent used, reducing unnecessary amount can reduce or reduce the Agent reaction. Therefore, you should be aware of the problem before each angiogram, and avoid the failure or repeated angiogram due to technical operation factors. Of course, repeated or re-angiogram should be performed if necessary for selective vascular procedures, and a few days later. For selective angiogram in difficult patients, sometimes Selective intubation is performed first for non-selective angiogram to identify the vascular route, which can reduce the contrast and X-ray volume.
5. Note that the incidence of Contrast Agent reaction varies depending on different injection methods. Different injection techniques for different angiogram tests should be strictly controlled to avoid increasing the incidence.

V. classification and treatment of Contrast Agent Response

After contrast agent is used, the patient needs to stay for at least 30 minutes because 90% of the side reactions occurred during this period. High-risk patients should be retained for a longer period of time. Delayed response (abnormal skin changes and cardiovascular disorders) can still occur in rare cases. If the symptoms are serious, the treatment should be observed in intensive care.

Level 1 side reactions
Symptoms: sneezing, coughing, yawning, red skin, low fever, nausea, vomiting, and chills.
Measure: 1. stop injecting drugs. 2. Establish venous channels. 3. Give antispetic drugs, such as trifluoramine and ondansione.
Symptoms: flushes, itching, urticaria, eyelid edema.
Measure: 1. static injection of H1 or H2 receptor blocking drugs, such as dimethyl chloride 8-12 mg (2-3 ampersand), chloroastine (pyrool amine) 4-6 mg (2-3 ampersand) or cimetidine 400 mg (2 ). 2. If necessary, intravenous injection of hormones (equivalent to 250mg prednisone ).

Level 2 side reactions
Symptom: Decreased blood pressure
Measures: 1. Lie down and keep fresh air; 2. Oxygen or mask is given to nasal catheter for oxygen; 3. rapid infusion of plasma substitutes or Linge liquid (1000 ml)
Symptom: when the blood pressure drops and the slow recovery (vascular nerve reaction)
Measure: In addition to the above measures, 0.3 mg of atropine, 0.25-0.5 mg (0.5-1 running), and slow intravenous injection were added.
Symptoms
Measures: In addition to the above measures, 1-2 times of bronchial dilation aerosol injection and 0.24 grams of intravenous injection were added. Take effect after 5-10 minutes after intravenous injection of glucose cortex hormones (equivalent to 250-500 mg prednisone. A half-seat mask is used for oxygen. If necessary, 5 mg of valium can be given to the patient.

Level 3 side effects
Symptoms: shock (tachycardia, sudden drop in blood pressure)
Measures: according to the first aid procedures, immediately notify the First Aid group, anesthesiologist, Emergency Department physician, half-seat mask to oxygen, rapid infusion of plasma substitutes or ringlet liquid (2000 mL-), adrenaline, 0.1-0.3 mg, Static injection. The heart function is checked every 10-15 minutes. The dose depends on the treatment effect, and the maximum dose is 1 mg (1 am adrenaline is diluted at, that is, 1 ml is equivalent to 0.1 mg adrenaline ). If the venous pathway cannot be found in the case of a tight emergency, double dose of intubation can be injected into the bronchial tube, or injection into the inferior acoustic venous plexus by muscle or subcutaneous. H1 or H2 receptor blocker, used in the same way as previously used for level 1 side reactions. Take effect after 5-10 minutes after intravenous injection of glucose cortex (equivalent to-mg prednisone. Dopamine (200 mg, 2 ampoule) was added to the site with 250 mL solution, 15-30 drops per minute, intravenous infusion, and the dose depends on the effect. In the case of reflex low blood pressure, it is given to noradrenaline (5-10 mg added to 250 mL solution ). The dose is determined by patient response.
Symptoms: Bronchial (throat) spasm, panting, acute asthma attack
Measure: The patient is placed in the sitting position, the mask is given to oxygen, ammonia line, 0.24 mg, intravenous injection, adrenaline, 0.1-0.3 mg, intravenous injection, if necessary, increase to 1.0 mg (1 to 1 ml mg of adrenaline ). The expression of H1 or H2 receptor is the same as that of the first side reaction. Take effect after 5-10 minutes after the intravenous injection of glucose cortex hormones (equivalent to 2-Mg of prednisone. 5 mg of Valium and intravenous injection as needed. Endotracheal intubation if necessary.
Symptoms: laryngeal edema
Measures: feasible endotracheal intubation, or a large needle punctures oxygen to the trachea, when necessary, the trachea is cut. Symptom: Pulmonary Edema
Measures: feasible endotracheal intubation, pressurization to oxygen, and intravenous injection of furan aniline acid (fast urine) 40 mg, 10-15 mg for morphine, slow intravenous injection.
Symptoms: convulsions
Measures: stable, 5-10 mg, intravenous injection.

Level 4 side reactions
Symptom: Breathing cycle stopped
Measures: Perform cardiopulmonary resuscitation (external thoracic heart pressure, artificial respiration, etc.) immediately ).

6. Question and Answer of the contrast agent

1. What is contrast agent (formerly called contrast agent )?
2. Why is it necessary to use a contrast agent?
3. What are the benefits of using contrast agents?
4. What is the safety of the contrast agent to the human body?
5. What problems should I pay attention to when selecting contrast agent and injecting contrast agent using the infusion device?
6. How long can the contrast agent be used after the bottle is opened?
7. Which factors will reduce the stability of the X-ray contrast agent? What should I pay attention to when storing the contrast agent?

 

Answer:

1. What is contrast agent (formerly called contrast agent )?
Contrast Agent is a diagnostic drug, and the most important component is iodine. Iodine is characterized by impervious X-ray, so the distribution of iodine in the body can be used for comparison During X-ray photography; or the vascular and soft tissue invisible to normal X-ray films can be clearly reflected, to assist doctors in reliable diagnosis. Contrast Agents can be injected or injected into arteries or veins and quickly distributed in the vascular system. Contrast Agents do not make metabolism ("useless") or changes in the body, they will be discharged from the urinary system.
2. Why is it necessary to use a contrast agent?
Because many of the tissue structures of the human body are not displayed on X-rays, they can only be "deepened" by using contrast agents. Some X-ray techniques, such as angiogram, you cannot leave the contrast agent. In some techniques (such as CT), although the contrast agent is not always necessary, the use of contrast agent will make the diagnostic image clearer and help doctors make a more reliable diagnosis for you.
3. What are the benefits of using contrast agents?
As contrast agents increase the differences between normal and abnormal tissues, they can help doctors detect abnormal morphological and functional damages to human organs. It also allows doctors to detect and identify some early and small lesions (liver lesions, etc ). Without contrast agents, these lesions may not be discovered, resulting in missed diagnosis or misdiagnosis. In addition, the contrast agent can help radiologists identify and diagnose benign lesions that generally do not require treatment and malignant lesions that urgently need treatment.
4. What is the safety of the contrast agent to the human body?
The conventional contrast agent currently used is usually quite safe. However, some patients will still have mild or moderate adverse reactions, and in some cases there may be rare serious adverse reactions. A few years ago, a clinical study of more than 337,000 cases in Japan showed that the incidence of severe reactions was very low, regardless of ionic or non-ionic contrast agents, the incidence of mild adverse reactions is also low. However, non-ionic contrast agent is safer and has fewer adverse reactions than ionic contrast agent.
5. What problems should I pay attention to when selecting contrast agent and injecting contrast agent using the infusion device?
First, use a needle or Infusion Set needle that is as thin as possible and has a long slope to penetrate the contrast agent bottle plug. The use of a rough needle (for example, a 0mm short inclined needle for conventional venous punctures) increases the risk of fragmentation, that is, the rubber particles in the puncture area will fall off. Secondly, repeated punctures in the same part of the rubber stopper should be avoided, because this will greatly increase the risk of fragmentation. Nokor is a special needle with a face and side holes in the shape of a surgical knife. In addition, suction needles such as sterifix needles are also suitable. Due to the viscosity of contrast agent, special needle or suction needle with liquid filtration device cannot be used. On the other hand, the infusion device should use a filter to ensure sufficient liquid flow. When the contrast agent is heated to the body temperature, its viscosity will be reduced by about half, so it is much easier to suck the heated contrast agent (especially the high concentration of preparation) into the syringe.
6. How long can the contrast agent be used after the bottle is opened?
Generally, the remaining contrast agent should be discarded during the check. As the operating principle, after the contrast agent is opened or pumped into another input device, the maximum time between the right and the use of the contrast agent should not exceed 4 hours. The more time it takes, the more likely it will produce a thermal reaction of microbial or bacterial growth. During this period, due to the volatile activity, the crystal species can be produced, which quickly results in the crystallization of the entire bottle. In addition, the risk of drug degradation caused by light also exists. If the injection remains in the memory of a disposable syringe for several hours, it will absorb the vulcanization additives in the piston, which will undoubtedly cause harm to patients.
7. Which factors will reduce the stability of the X-ray contrast agent? What should I pay attention to when storing the contrast agent?
In general, there is a certain difference between long-term storage and temporary storage. From the perspective of drug kinetics, temporary storage has no significant effect on contrast agent. The X-ray contrast agent should be stored at room temperature 15 ~ 25 deg C conditions, and to avoid light. Contrast Agent can be placed in a heating cabinet for a short time, for example, scanning the preparation before injection or infusion to heat the temperature to 37 ℃. Contrast Agent can be stored in a heating cabinet or soaked in hot water to about 40 ℃ for one day or several days. Contrast Agent can also be safely placed in hot water for Short-Time Heating, for example, heating to 60 ~ 80 ℃ can dissolve the crystal of the contrast agent, which reminds us of another problem of the contrast agent change, that is, during winter transportation, the contrast agent liquid will have a pure physical crystallization phenomenon. Remember that the contrast agent we use is usually high, and its concentration is related to the iodine content. The 370 preparation containing 370 mg of iodine per ml, with a concentration of 0.769 grams of ioproamine per ml, that is, 76.9% of the preparation. Liquid Preparations will ice when the temperature is very low. However, experience shows that not all substances in the bottle Will crystallization at low temperatures, because crystallization requires crystal species, the frozen preparation can be heated in hot water or stored at room temperature for a period of time and then retained after shaking. Generally, before using contrast agent, make sure the preparation does not contain any small particles, especially crystals. The effect of light on the Stability of contrast agent is much greater than that of heating. The main change caused by light is the increase of the iodine composition and the decrease of the pH value, which leads to the separation of the acidic substances contained in the ionic agent.
There is no clear rule on how long the contrast agent can be stored under light. The experimental results of Contrast Agent stability require that the contrast agent be stored without light. This is mainly because the degree of degradation caused by light mainly depends on the brightness of light and the near UV spectral area in sunlight and sunlight, which is very active in the photochemistry reaction. These factors depend on the type of light, and the daylight depends on the extent of the blue sky to some geographical location. In general, the stability of contrast agent is not greatly affected when it is exposed to a 600 Lux working outdoor for a whole day. However, in any case, we should avoid sunlight, even in a short time. In addition to high brightness, sunlight also contains a large amount of ultraviolet rays, which can form a strong photochemistry reaction. Contrast Agent may only be damaged by short-wave light and X-ray. Therefore, do not store contrast agent for a long time within the scope of X. However, it is allowed to place the contrast agent for a short period of time during the diagnosis or examination.