PVC infusion sets are widely used in clinical practice in China. Studies have shown that PVC polymer materials are unstable to drugs. When phthalic acid di(DEHP) is added, substances harmful to human body may be released into the drug solution, but most of them will not cause adverse reactions to male fetuses and newborns. Special populations such as men with puberty have potential high-risk risks, and the adsorption of some drugs causes their effective concentration to decrease and is considered to be poor or ineffective. Therefore, it is recommended to develop a safe, non-adsorbing infusion set to replace the PVC infusion set, and strengthen drug compatibility monitoring to facilitate the guidance and supervision of safe medication.

Molecular structure of DEHP
The infusion set is a common disposable medical device that establishes the passage between the vein and the liquid medicine. It is used in China for more than 5 billion sets per year. Traditional infusion sets are made from PVC, and high-performance polyolefin thermoplastic elastomer (TPE) is considered to be a safer and higher performance material for disposable infusion sets. At present, the infusion sets widely used in China are made of PVC materials. Studies have shown that polymer plastic containers may release substances harmful to the human body into the solution during use, especially after the addition of phthalic acid (DEHP), and the polymer material is unstable to the drug. This article focuses on a comprehensive analysis of the impact of medical PVC materials on drugs and their health.

First, the impact of phthalic acid II (DEHP) on the human body
DEHP is an abbreviation of Di-(2-ethylhexyl)phthalate. Its molecular formula is C6H4(CO2C8H17)2, also known as dioctyl phthalate (DOP). It is a colorless, odorless synthetic organic compound that is easily soluble. In gasoline and paint (see the molecular structure diagram at the bottom right). PVC plasticized with DEHP is widely used in the manufacture of artificial leather, agricultural film, packaging materials, syringes, cables, and the like. PVC without plasticization is hard and brittle at room temperature, so plasticizers need to be added to the PVC to improve the softness of the polymer. There are a variety of plasticizers that can be used for plasticizing PVC. Diisooctyl phthalate is the most commonly used plasticizer for medical PVC.

(1) Foreign
The International Agency for Research on Cancer (IARC) divides DEHP into a third class of carcinogens, animal suspected carcinogens, rather than human carcinogens. Because only animal experiments have shown that DEHP may be carcinogenic, there is no human epidemiological data so far. In recent years, the United States and Japan have also made relevant research reports.

In July 2002, the FDA reported in a research report on the safety evaluation of DEHP plasticized PVC medical devices that everyone in daily life almost touched DEHP every day, and some people may have more DEHP because of medical treatment needs. . DEHP will precipitate out of solution in contact with the medical device, and the amount of precipitation will be related to temperature, lipid composition of the liquid, and time of contact. Patients with severe illness require multiple treatments and therefore have access to more DEHP. Animal experiments have shown that DEHP has a wide range of adverse reactions. When DEHP is fed to rats, it can cause infertility in rats, especially in male testes, which can cause irreversible damage to the testis of the male rats, leading to fetal malformation or stillbirth.

In October of the same year, the Japanese Ministry of Health and Welfare issued a "Information on the Safety of Medicine and Medical Supplies". In the report, the medical staff is advised to use as little or no PVC medical supplies as DEHP. DEHP is considered to be a generally toxic compound that has a detrimental effect on human testis with a tolerable daily intake of 40 to 140 ug / kg. Tests have shown that both blood bag and cardiopulmonary bypass machines have exceeded this limit. The US FDA believes that DEHP can tolerate a daily intake of 600ug / kg. In contrast, Japan's requirements are more stringent.
The study found that the harm of DEHP mainly depends on two aspects: First, the sensitivity of patients to DEHP, male fetuses, male newborns and males in puberty are high-risk groups; second, the amount of DEHP absorbed by patients, this aspect It depends on the form, frequency and duration of the patient's treatment.

(2) DEHP safety assessment
1. Crystalline fluid and drug intravenous infusion
The amount of DEHP released into the human body when infused with a crystal infusion bag (eg, saline, D5W, Ringer's solution) is small and harmless to the human body. In addition, the use of PVC bags for storage and infusion requires a carrier to enhance the solubility of the drug, as long as the instructions in the instructions, the amount of DEHP released into the human body is almost no harm to the human body.

2. Total parenteral nutrition
The dose of DEHP in patients receiving total parenteral nutrition is estimated to be lower than the TI value (tolerance intake), suggesting that DEHP-mediated adverse events in these patients may be of no concern. In addition, non-PVC bags and tubing are also commonly used to infuse total parenteral nutrition complexes, further reducing the chance of adverse reactions mediated by DEHP. The dose of DEHP in neonates receiving total parenteral nutrition therapy is not yet determined.

3. Blood transfusion
A patient who enters a large amount of blood and blood products in a short period of time may ingest a relatively high dose of DEHP, such as trauma, surgery, and a large number of blood transfusions. But for high-risk patients, the harm of DEHP is negligible. Infants and young children receive a relatively small amount of DEHP from the blood. The risk of DEHP is negligible in terms of time. Therefore, people who donate platelets and plasma can avoid adverse reactions caused by DEHP. There are two groups of people who are at higher risk of taking DEHP after receiving blood transfusions, mainly infants undergoing blood replacement and adult patients undergoing extracorporeal membrane oxygenation. However, the number of patients who performed both treatments was relatively small, so the population of patients who ingested large amounts of DEHP due to blood exchange and extracorporeal circulation membrane oxygenation was small.

4. Hemodialysis and peritoneal dialysis
According to recent research data, the amount of DEHP in hemodialysis patients is very small and will not adversely affect patients. In addition, the amount of DEHP released into the peritoneal dialysate is also small, so the intake of DEHP in peritoneal dialysis patients has no adverse effects on the patient.

5. Gut nutrition and breastfeeding
Lipids in gut nutrition can precipitate a significant amount of DEHP from PVC bags and tubing, so these patients may be at high risk of DEHP-mediated adverse reactions. According to theoretical calculations, hemodialysis mothers may have high doses of DEHP, but the actual intake of these infants is difficult to determine. Due to the large degree of uncertainty in the evaluation, and in addition, hemodialysis women are often mostly infertile, so the infant population in this situation is also quite small. Breast milk storage bags through the milk pump are usually made of polyethylene or polyethylene coated nylon bags, so the baby does not have the possibility of ingesting DEHP through the milk pump and breast milk storage bag.

6. Children's intake of DEHP is higher than adults
A panel of experts from the US FDA Human Reproductive Toxicity Assessment Center concluded that children receiving medical device treatment are at higher risk of adverse reactions to DEHP. This conclusion is supported by three aspects: the amount of DEHP consumed by children in the treatment of medical devices is greater than that of adults; the difference in pharmacokinetics between children and adults makes children absorb more, DEHP is converted into MEHP more and MEHP Less excretion; children are more sensitive to pharmacokinetics than adult adverse reactions to DEHP.

Second, the drug compatibility of PVC infusion sets
The degree of adsorption and adsorption of PVC on drugs is a concern of clinical personnel.

(1) Adsorption of drugs
1. Adsorption of sedatives and analgesics
(1) Chlorpromazine: The adsorption of chlorpromazine on the surface of PVC, polypropylene (PP), high density polyethylene (HDPE), polyethylene (PE), vinyl acetate and glass was studied by fast chronoamperometry. influences. The results showed that the most adsorbed to chlorpromazine was PVC, followed by HDPE, while glass and PP had the least adsorption to chlorpromazine.
(2) Lorazepam: Lorazepam was added to a PVC bagged infusion containing 0.9% sodium chloride or lactated Ringer's solution, and its content decreased by 17% to 25% after storage for 24 hours at room temperature. When infused with polyethylene tube for 4 hours, the content of ********* is almost unchanged.
(3) Using a PVC bag and a PE bag to hold a mixed solution of 5% or 0.9% sodium chloride of citric acid and fluorouridine, observe the change in concentration, and the concentration in the PVC bag is reduced by 70% within 24 hours. No decrease in concentration was observed in the control PE bags. Comparing the effects of PVC bags and glass bottles on the concentration, it was found that the PVC bags reduced the concentration, while the glass bottles had no effect.

2. Adsorption of immunomodulators
(1) Cyclosporin A: In the drug concentration monitoring study of cyclosporine A, it was found that cyclosporin A lost almost 40% to 50% after 24 hours using PVC infusion tube, but under the same conditions, PE or polybutadiene (PB) infusion tubes do not cause a loss of cyclosporine A concentration, indicating the use of non-PVC infusion tubes to ensure drug concentration when intravenously injecting cyclosporine A.
(2) Macrocyclic meran: Macrocyclic meran (FK-506) was added to a 5% glucose solution and stored in a PVC bag, a polyolefin bag, and a glass bottle, respectively. At room temperature, the concentration of FK-506 in the PVC bag decreased by 15% in 6 hours, 19% in 24 hours, and 26% in 48 hours, while the concentration of the other two materials remained unchanged within 48 hours of observation. .

3. Adsorption of anticancer drugs
In low density polyethylene (LDPE) containers, glass bottles and PVC bags, respectively, for Carmustine, Carboplatin, Cytarabine, Dacarbazine,
The material adsorption properties of nine anticancer drugs, Fluorouracil, Gemcitabine, Melphalan, Methotrexate, and Vinorelbine, were compared. 0.9% sodium chloride was used as the infusion medium, and 5% glucose solution was used as the storage environment. It was found that the adsorption of Carmustine on PVC was obvious at room temperature, and its concentration decreased by about 25% in 5.5 hours. In LDPE containers and glass bottles, the drug concentration decreased by no more than 10% and 5%, respectively; at 4 °C At 72 hours of storage, the concentration of Carmustine decreased by 17%, while at the same time there was almost no loss of Carmustine in LDPE containers and glass bottles.

4. Adsorption of biological agents
(1) Urokinase: The concentration of urokinase in PBS filled with 5% glucose solution is reduced by 15% to 20% within 20~30 minutes, while the concentration of urokinase in PP bag and glass bottle is within 24 hours. No decline. In addition, the concentration of urokinase added to the 0.9% sodium chloride solution in PVC bags did not decrease. This indicates that the adsorption of urokinase by PVC is also affected by other factors.

(2) Insulin: insulin and many peptide drugs can be
PVC, PE and glass products are adsorbed, and the larger the contact area, the more adsorption. Among them, PVC has the highest adsorption capacity for insulin, and insulin can be adsorbed 55% within 15 seconds. In order to reduce the adsorption, an appropriate amount of potassium chloride (500 ml of insulin mixed with 10% potassium chloride 15 ml) can be added to the infusion.

5. Adsorption of cardiovascular drugs
(1) Nitroglycerin: It was added to a PVC bag and instilled with a PVC infusion device for 2 hours, and its concentration was reduced by 20.7%.
(2) Isosorbide dinitrate: Isosorbide dinitrate was added to a PVC bag and instilled with a PVC infusion device for 2 hours, and its concentration was reduced by 50%.

6. Adsorption of traditional Chinese medicine injections
(1) Ligustrazine: The researchers reduced the concentration of ligustrazine after adding the traditional Chinese medicine injection ligustrazine to the PVC peritoneal dialysis bag. Compared with the charging of PVC bags and glass bottles, the drug concentration was 40mg / L, the storage was 500mL, the storage was 8 hours, the drug concentration in the PVC bag decreased by 6.3%, and decreased by 9.6% in 24 hours; when the loading was 50mL, The concentration decreased by 26.1% in 8 hours, and decreased by 43.2% in 24 hours, while the drug concentration in the glass bottle was stable within 24 hours and was not affected by the loading.
(2) PVC containers and infusion sets for amiodarone amiodarone, lidocaine lidocaine, hydralazine Hydralazine, thiopental pentothal
Sodium, warfarin, nimodipine, calcitonin, tacrolimus and carmustine, isosorbide mononitrate (Isosorbide Mononitrate), chloroquine ( The adsorption of chloroquine)
Can have a greater impact on clinical treatment. It has a slight adsorption effect on phentolamine. At the same time, the data show that PVC on lactic acid ring, cifloxacin, left oxygen
Ofloxacin, ofloxacin, fluconazole, metronidazole, mannitol, ribavirin, sodium carbonate
Lidocaine 9 kinds of clinically used drugs have no adsorption and can be safely used in clinical practice.
(2) Factors affecting adsorption
1. The factors of the drug itself
PVC has an adsorption effect on certain drugs, while other drugs have no adsorption effect. For example, Beitz et al. used 9 anticancer drugs as adsorption experiments, only found that carmustine had strong adsorption in PVC materials, while other drugs did not find adsorption loss. Domestic scholars have pointed out that no change in concentration of puerarin injection was found within 3 hours after flowing through the PVC infusion set. At the same time, it has also been found that the adsorption of puerarin injection by different manufacturers of infusion sets does not cause significant changes in drug concentration. Other experts have studied the effect of PVC bags on mannitol and confirmed that PVC has no adsorption to mannitol.

2. Effect of solution pH
In general, pH affects the degree of dissociation of the drug, thereby affecting the fat solubility of the drug and affecting the adsorption effect. The fentanyl adsorption test reported by Sattler et al. uses four different pH values, and as the pH increases, the more the PVC adsorbs the drug. In the urokinase adsorption test, when urokinase was added to a PVC infusion bag containing 0.9% sodium chloride solution, no urokinase was found to be adsorbed, and the drug was added to a 5% glucose solution in a PVC bag, and the urokinase concentration decreased by 15%. 20%, while the glass bottle has no adsorption to urokinase and is not affected by the infusion medium.

3. The effect of temperature
The adsorption of carmustine by PVC, when the temperature is 4 ° C, its concentration only drops by 5% in 5.5 hours, and the concentration drops by 25% at room temperature. Another example is the adsorption of lorazepam by PVC. In 24 hours, its concentration drops by 8% to 9% at 4 °C, its concentration decreases by 14% at 24 °C, and its concentration decreases by 27% to 29% at 37 °C. It indicates that the higher the temperature, the easier it is to adsorb

4. The effect of drug concentration
In 5% glucose solution, the concentration of urokinase is 1.5×106 IU / L, PVC has adsorption effect (15%~20% reduction in drug concentration within 30min), and when the concentration of urokinase is changed to 5×106IU /L, PVC There is no adsorption effect on it. It indicates that the drug concentration will also seriously affect the adsorption effect.

Third, discussion
The addition of DEHP, a non-degradable toxic substance that stabilizes and softens it, has adversely affected the environment and human health.
PVC itself has certain limitations as an infusion set. Some countries in Europe and the United States have banned the use of disposable infusion sets made of PVC materials since January 2007. Due to the economic level, although the infusion bags of domestic PVC materials were discontinued in 1999, the infusion equipment for PVC materials in China is still the most widely used infusion equipment. Through DEHP safety assessment, the amount of DEHP released from PVC medical devices in most clinical use cases does not cause adverse reactions, but according to research data, it is indicated that the special population is mainly male fetus, male newborn and puberty male. There is a potential high risk risk. The adsorption of drugs by PVC infusion sets can have a great impact on the experimental research and clinical application of some drugs, and is considered to be poor or ineffective due to the decrease in effective concentration.

In summary, infusion set manufacturers should develop environmentally friendly, safe, non-adsorbing disposable infusion sets to replace PVC infusion sets; pharmaceutical manufacturers in the application of new drugs, to investigate the adsorption of PVC infusions on drugs, in the drug specifications Indicate whether PVC infusion sets are available; medical institutions should use PVC infusion sets according to the instructions in the instructions for drugs or infusion sets. For some drugs, it is not advisable to prepare the liquid storage in advance or avoid using PVC infusion sets to achieve safe and effective drug use. the goal of. In addition, the National Center for Adverse Drug Reaction Monitoring and the National Pharmacopoeia Committee should promptly issue monitoring and notification of the compatibility of drugs and infusion devices to facilitate the guidance and supervision of drug safety at the grassroots level.

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