rè yuán fǎn yìng
2 English referencepyrogen reaction [WS/T 203
pyrogen reaction [WS/T 203 -2001 Commonly used terms in blood transfusion medicine]
3 OverviewPyrogen reaction refers to a febrile reaction caused by endotoxin of Gram-negative bacilli or other trace amounts of pyrogenic substances [1].
Clinically, when a large number of fluids are infused intravenously, due to the presence of pyrogens in the medicinal solution, the patient will experience cold shivering, high fever, sweating, dizziness, vomiting and other symptoms within 0.5 to 1h, and the body temperature can be up to 40℃ in case of hyperthermia, and the severe cases may even go into shock, which is known as pyrogenic reaction.
The main cause of pyrogenic reaction is caused by contaminated pyrogens in the injection fluid or infusion set. The amount of heat caused by pyrogens varies according to the strain of bacteria, such as gram-negative bacilli have the strongest ability to cause heat; due to the different routes of injection, the degree of fever caused by the different also varies.
4 Name of the disease
pyrogen reaction pyrogen reaction
5 Reasons for pyrogen reactionThe pathway of pyrogenic contamination of injections is mainly in the following aspects:
1. From the solvent to bring in such as water for injections storage time is too long, contaminated by bacteria, the bacteria multiply very quickly, and a large number of pyrogens can be produced in a short period of time, although there is a subsequent sterilization operation, but there is already a large amount of pyrogens, which can be generated in a short period of time. Although there is a subsequent sterilization operation, but there has been the existence of pyrogens, it is not easy to remove, thus producing a pyrogenic reaction. Therefore, when preparing injections, fresh water for injection should be used, and it is better to use it with steaming. The 1995 edition of the Chinese Pharmacopoeia stipulates that water for injection should be used within 12h after preparation.
2. Brought in from the raw materials Raw materials are contaminated by pyrogens for a number of reasons, such as packaging does not meet the requirements or stored for a long time, as well as many of the drugs themselves are suitable for the growth of microorganisms, so the selection of raw materials should be paid attention to.
3. From the utensils or containers brought in the preparation of injectable devices, utensils, pipes and containers, such as not washed or sterilized, are prone to contamination with pyrogens. Therefore, it should be strictly dealt with in accordance with the provisions of the water for injection and no pyrogen repeatedly rinsed qualified before use.
4. Pollution in the preparation process The entire preparation process of injections should be carried out in a clean studio to minimize the opportunity for microbial contamination.
5. due to packaging is not tight or sterilization is incomplete and produce pyrogen
(1) in the preparation of injections, if the packaging materials are not strictly selected, such as the bottom of the glass bottle or the neck of the neck of the micro-perforation, the bottle edge is incomplete, the rubber stopper is not good quality, etc., can make the injection bottle has a leakage phenomenon and the breeding of bacteria, produce pyrogen. Therefore, the packaging materials should be selected to meet the quality requirements, sterilization should pay attention to the temperature, pressure and time to prevent incomplete sterilization.
(2) Before clinical application, attention should be paid to the injection vials in accordance with the notes on the strict inspection, does not meet the requirements, absolutely can not be applied. Our geriatric ward had a serious case of infusion pyrogenic reaction. After our examination, we found that the infusion bottle near the bottom of a collision caused by a small crack and lead to infusion leakage contamination, the nurse in the patient's medication without careful inspection and lead to pyrogenic reactions.
6. brought in from the infusion set Sometimes the injection itself does not contain pyrogens, but after injection, but the pyrogen reaction, which is likely to be due to the infusion set contaminated with pyrogens. The current use of disposable infusion device manufacturers have many, the quality of good and bad, our hospital has occurred in a number of infusion pyrogen reaction, after examination are disposable infusion device (Jiangxi xxxxxx county production) pyrogen failure.
7. In the injection process brought into the drug addition pollution: ① in the infusion of other drugs, such as the addition of the drug itself has been contaminated pyrogen; ② add the poor cleanliness of the operating room, disinfection and operation is not tight; ③ add the drug placed for a long time. It is reflected in some hospitals, individual wards in the morning, the phenomenon of infusion in the afternoon, which is perennial high room temperature in the southern region is very dangerous.
8. Other factors leading to pyrogenic reactions
(1) with the season (such as spring and summer, temperature, humidity suitable for bacterial growth) and the patient's physical condition and the severity of the disease. A certain amount of pyrogenic substances may produce different reactions in different patients, and clinically, patients with weak physiques and their own allergies have more pyrogenic reactions.
(2) and infusion speed: the infusion speed is not enough to monitor, the results not only affect the efficacy of the drug, but also produce fever, allergy, nausea and vomiting, and drug toxicity and side effects such as enhancement of adverse reactions, and may lead to pulmonary edema, cardiac failure, coma and other serious complications.
(3) pyrogen reaction is also related to the body's internal environment: such as neuroinhibitory (including pathological inhibition), the relative insensitivity to pyrogens; pyrogens in an excited state of the body (especially pathogenic factors caused by the excitement), more sensitive.
(4) the temperature of the infusion: because of the clinical application of infusion dose is large, so the temperature of the infusion to close to the body temperature is appropriate.
(5) The particles in the infusion can also cause allergic reactions, pyrogen-like reactions.
6 thermogenic principle1. Physical and chemical properties of pyrogens ① heat resistance: pyrogens at 60 ℃ heating 1h unaffected, 100 ℃ will not occur pyrolysis. But the heat resistance of pyrogens have certain limits, such as 120 ℃ heating 4h can destroy 98%, in 180 ℃ to 200 ℃ dry heat more than 2h or 250 ℃ heating 30′ can be completely destroyed. However, due to the different sources of pyrogens, their heat resistance also varies, such as from E. coli pyrogens produced by low temperature (40 ℃ ~ 50 ℃) has been unstable, the domestic use of two hot pressurization can destroy the pyrogens reported. ② filtration: pyrogens are small in size, about 1μm to 5μm, so they can pass through the sterilization filter and enter the filtrate. ③ Water solubility and non-volatility: pyrogens are soluble in water. The pyrogen itself is not volatile, but because of the water solubility, can be entrained into the distilled water with the water droplets, so the preparation of water for injection of redistilled water device has a foam isolation device. Other: pyrogens can be destroyed by strong acids and alkalis, and also by oxidizing agents such as KMnO4 or H2O2 or ultrasonic waves, and adsorbed by activated charcoal, asbestos or adsorbents. Pyrogens have a certain charge in solution and can be adsorbed by certain ion exchange resins. (Strong alkaline anion exchange resins have the best effect in removing pyrogens, while strong acidic cation exchange resins have a weak ability to remove pyrogens. (When removing pyrogens with ion exchange resins, attention must be paid to the effect on the contained drugs).
2. The biochemical properties and structure of pyrogens
Pyrogens are macromolecular substances with molecular weights between 105 and 107, which exist between the outer membrane of the cell and the solid membrane, and can only be released when the bacterial cell is lysed.
The chemical structure of pyrogens is a complex composed of proteins and phospholipid polysaccharides (LPS), and LPS is the thermogenic activity center of pyrogens.LPS is a phospholipid polysaccharide, so it is heat-resistant.The pyrogens produced by Bacillus subtilis are the strongest in terms of thermogenicity, and the G+ bacteria, molds, viruses and so on can produce pyrogens as well, but with a weaker pyrographic activity, and also are not heat-resistant.LPS is made up of three parts: ①0 characteristic side chain; ② core LPS consists of three parts: ①0 characteristic side chain; ② core polysaccharide; ③ phospholipid A. The latter two are LPS, which is the thermogenic activity center of pyrogen. Phospholipid A is a lipophilic group, can be combined with the cell membrane of the blood vessel wall, change the vascular permeability, so that the blood pressure drops leading to shock.
3. The thermogenic principle of pyrogens
The thermogenic reaction of pyrogens can be counteracted by salicylic acid antipyretic agents, which also proves that pyrogens are caused by LP and prostaglandins to cause the body's feverish reaction, because antipyretic agents can reduce the generation of LP, and inhibit the catalytic role of prostaglandin synthetase to prevent the increase of prostaglandins, so that the LPS does not cause a thermogenic effect.
Detection methods
(1) Rabbit method [2, 7] This method is a statutory method for detecting pyrogens in injections as stipulated in the pharmacopoeias of various countries. The advantage of this method is that it has been proved by long-term application that its detection results are basically consistent with the results of clinical application. However, this method requires certain conditions, such as raising qualified rabbits should have a relatively constant temperature of the animal room and laboratory, the test operation requirements are more stringent, should be skillful operation skills, in order to make the test results reliable.
(2) Horseshoe crab test method [2, 4, 5, 7] This method is the application of horseshoe crab deformed cell lysate detection of pyrogens (endotoxin) biochemical methods. This method of endotoxin detection specificity, high sensitivity, easy to operate, the U.S. Pharmacopoeia (USP) and the Chinese Pharmacopoeia (CP) have been included in this method, the CP provides that some drugs can be used in this method. The principle is as follows:
Due to the influence of the pH value of the drug, the solvent and the additional agents in the drug (such as surfactants, antioxidants, etc.), the horseshoe crab test method has more false-positive reactions, and so it can not completely replace the rabbit method at present. In recent years, the development of quantitative determination of pyrogens with chromogenic substrates [1, 6], thus, creating a new era of pyrogen detection from qualitative to quantitative.
7 The disposition of pyrogenic reaction
1. Immediately stop the infusion, change to other factory or different batch number of infusion, and according to the patient's specific situation for clinical treatment.
2. Carefully fill out the infusion reaction registration form (in duplicate) write: ① patient's name, gender, age; ② diagnosis of disease, drug allergy history and the basic condition of the pre-infusion; ③ name of the infusion, manufacturer, batch number; before the use of the infusion of the appearance of the check (according to the infusion label on the precautions to be taken to check); ④ add drug a. the name of the drug added, the manufacturer and batch number; the amount of each drug added; after the addition of the drug, the amount of the drug added. The amount of drug added; the appearance of the drug added to check the situation; b. When to add the drug mixture, when to start infusion, infusion speed; disposable infusion device manufacturer, lot number; c. After the infusion found that the patient had infusion reaction time; d. Infusion reaction caused by clinical symptoms; e. Adding drugs and infusion operators, nursing staff.
3. Send the remaining infusion solution with reaction and infusion reaction registration form to the pharmacy department.
4. Pharmacy received the registration form, on the one hand, a serious review, on the one hand, immediately sent the pharmacist in charge of production and quality of the infusion reaction to the department and all relevant departments of the hospital for a comprehensive and in-depth understanding of the situation, according to the understanding of the facts to decide whether to immediately stop the use of the batch of products. At the same time, the batch of products and added drugs for sampling, for pyrogen retest, if necessary, sent to the local drug testing center for retest. The infusion device should also be a comprehensive quality check.
5. The results of the inspection by the Pharmacy Department to the relevant departments, the Nursing Department and the Medical Department to provide a written report.
6. If it involves major medical issues, if necessary, convene a meeting of the Hospital Pharmacy Committee to study and deal with.
8 preventive treatmentIn recent years, many clinicians have accumulated a lot of experience in the prevention and treatment of infusion pyrogenic reactions, and received good results. In the past, isoprinosine was often used as the first choice of drugs for the treatment of pyrogenic reactions. In recent years, many data at home and abroad confirmed that scopolamine (6542) has its unique advantages in the prevention and treatment of pyrogenic reactions compared with promethazine. ① Antagonize vasoconstriction caused by activation and release of harmful active substances when the body is damaged, protect the cell membrane, reduce vascular endothelial damage, thereby improving capillary permeability, reducing blood exudation and absorption of tissue fluids into the blood, increase perfusion to improve microcirculatory disorders, so that the blood pressure back up; ② regulate the function of vegetative nerves, so that the shocked person's heart rate slows down the fast ones, the slow ones become faster, the high-temperature ones cool down, and the low-temperature ones warm up; ③ Favorable removal of microbial endotoxin and various shock factors.6542 With the advantages of small dosage, rapid action and no obvious side effects, it is the ideal drug for clinical prevention and treatment of pyrogenic reactions. Isoprinosine can be used as an auxiliary drug.
In the prevention of pyrogenic reactions, 6542 10mg ~ 20mg can be added to the infusion of static drip; treatment, according to 0.5 ~ 2mg / kg / times / static injection. Repeated doses may be given if necessary (contraindicated in patients with glaucoma). The reaction can be terminated 15 minutes to 20 minutes after the drug is administered.
In addition, antipyretics (aspirin, aminopyrine, paracetamol, etc.) prevent the production of thermogenic leukocyte pyrogens from phospholipopolysaccharides in vivo and inhibit the synthesis and release of prostaglandins. Thus, administration of the drug 30 minutes before the infusion also prevents the development of pyrogenic reactions. When a pyrogenic reaction occurs, the antipyretic effect is enhanced by combining it with 6542. Severe pyrogenic reaction, should be taken to give oxygen, glucocorticoids, low molecular dextrose anhydride, cediran and other comprehensive therapeutic measures.