Chemical phlebitis (CP) is a sterile inflammatory reaction caused by the infusion of low pH, high osmotic pressure, high concentration of drugs, and produces chemical stimulation of the intima, vascular endothelial damage and phlebitis as well [1] [2] [3] . Clinical manifestations are local venous redness, fever, pain, swelling, and/or palpable induration [2] . The incidence of CP exceeds is 57.6% [2] [4] . The high incidence of CP inevitably leads to the removal of the catheter and shortens the indwelling time [2] [4] .

Researches on the CP have become a hot topic at home and abroad, and have been getting more results. In particular, more achievements have been made in animal experimental research. Application of clinically used stimulant drugs to the veins of animals can establish a CP animal model, and prevent and treat drugs before or after modeling [1] [5] [6] . The method of infusion is reproduced below (Figure 1). The data and results of these experimental studies have greatly contributed to the clinical prevention and treatment of CP.

Currently, the veins of rabbit ear and mouse tail are usually used for puncture modeling. However, the veins of these animal models are susceptible to factors, such as the dose, concentration, speed, and timing of the drug, causing local adverse reaction. As a result, this paper reviews recent advances in modeling drugs for animal models of CP.

In order to accurately apply the modeled drugs, the animal model of CP was effectively established. The current status of application of CP animal model drugs was searched. The databases searched were Cochrane Library, ProQuest Academic Journal Library, PubMed, Web of Science, Ovid, Embase, CINAHL complete (EESCO), being the limits articles published since the establishment of the databas, and studies in English, Chinese. “chemical” OR “chemotherapy” OR “chemotherapeutic” OR “infusion” AND “phlebitis” phlebitis, “intravenous” OR “vein” OR “blood vessel” AND “damage” AND “animal” OR “rabbit” OR “mouse” OR “dog”, “model” OR “drug” and other keywords are searched. A total of 1463 related articles were retrieved. By reading the titles and abstracts of the literature, articles such as non-animal experimental research and application of drug modeling were excluded. 55 articles were initially screened, 33 articles were excluded by reading the full text, and 22 articles were rescreened (Figure 2).

A number of studies have established animal models of CP and then given different interventions to prevent and treat phlebitis. The success of CP directly affects the subsequent experimental results.

There are also many models for CP research. Currently, the types of animals are mainly rabbits and mice. Other animals have rarely been reported. Common rabbit species include Japanese white rabbits, New Zealand rabbits, and rabbits, weighing about 2.0 - 3.0 Kg (Table 2). Some researchers select male rabbits [20] [27] , while the other part is not limited to males and females [18] [22] [25] . Because female rabbits not only have light weight, blood vessels are fine, but also secreted estrogen affects blood vessels. It is recommended that rabbits in the CP model be easy to select males in the future. The mouse model is also a small animal that is often selected. The use of standard inbred C57 mice increased the reliability of the experimental data relative to normal mice [14] [15] . However, the tail vein of the mouse is difficult to puncture. If the dose and concentration are too high, the mortality of the mice is increased. Shen et al. [15] injected VNR at the same concentration and speed into the tail vein of mice, and the dose varied from low to high of 18.8, 28.1, 37.5, 56.3 and 75 mg/Kg, respectively. The results showed that the higher dose of the drug, the higher incidence of sinusitis (P = 0.006), and the mortality of the high-dose group (56.3 and 75 mg/Kg) was 25.0%. 50.0%. In addition, they also found that the incidence of phlebitis in the three groups was 100%, no mice died in the high-concentration group, and the mortality rates in the middle and low-concentration groups were 50.0% and 62.5% respectively. The reason for explain that the size of mouse is smaller than the rabbit model, so the circulating blood volume is small. The one-time infusion amount cannot be effectively metabolized in the body, because too much accumulation is likely to result in poisoning death. Therefore, it is important for us to focus on maintaining the gradient and total amount of the while modeling the mice, which can help prevent the high mortality rate of the mice from affecting analysis results.

The drugs commonly used in modeling drugs are chemotherapeutic drugs such as VNR, DXR, etc., hypertonic drugs such as mannitol. The common feature of these drugs is that they are more irritating and easily damage blood vessels, making it easier to establish a CP model. Shen et al. [15] found that when the mice were injected with VNR at a dose of 37.5 mg/Kg and a concentration of 10 mg/mL, the incidence of phlebitis was 100% and no mice died; when the speed was 0.3 μl/s, the incidence of phlebitis was higher than in other speed groups (75% vs 33.3%, 25%), and no mice died. Therefore, it can conclude that the appropriate dose of VNR in mice is 37.5 mg/Kg, or 25 mg/m², the concentration is 10 mg/mL, and the speed is 0.3 μl/s [13] [15] . In addition, Shen et al. [10] simulated clinical chemotherapy courses, used a dose of 20 mg/m², a rate of 90 mL/h intravenous infusion of DXR which administered at the first, third, and fifth weeks to establish a model. This modeling mode is in line with the actual clinical use of drugs, and can provide a more accurate reference for the prevention of patients with CP. Mannitol is a commonly used dehydrating agent for brain damage. Because of high permeability, it is often used as a model drug for CP. However, some researchers injected 10 mL intravenously into the ear of each rabbit [17] [19] (Table 2). The weight of each rabbit is different, but the medication is the same, which will lead to inconsistent modeling effects and affect the experimental results. Therefore, the dose of the animal is recommended to use the body weight or surface area to convert the calculation, rather than counting the number of medications.

There are references using a single factor to compare the effects of different levels of parameters on the establishment of CP [13] [18] [25] (Table 3). A number of factors were combined to compare the effects of the model establishment, such as the combination of dose, concentration and speed, the combination of speed and number of days of administration [15] [22] (Table 3). There are even simulated clinical rinsing and before and after infusion to observe the impact on the CP model [20] .

At present, the researchers agree that factors such as dose, concentration and time of administration are positively correlated with vascular endothelial injury. Therefore, the higher the dose, the higher the incidence of CP. But, researchers at home and abroad hold opposing views on the effects of drug rates on CP. One view is that low-speed medication is easy to cause CP, the other is that high-speed medication is easy to cause CP. Kuwahara et al. [27] injected AF into the rabbit ear vein at low-speed (5 mL/Kg/h) and high-speed (15 mL/Kg/h), and found that the low speed group is more prone to phlebitis than the high speed group (P < 0.05). Shen et al. [19] found that the incidence of CP in the high speed group (0.75 μl/s), medium-speed group (0.3 μl/s) and low speed group (0.15 μl/s) of VNR in the tail vein of mice is 33.3%, 75.0% and 25% respectively. The incidence of phlebitis in the moderate speed group was higher than the low speed group (P < 0.05). What’s more, there is no mouse died in the middle and low speed groups, while 5 mice died in the high speed group. The reason explained for the results may be the differences in animal models, the different anatomical locations of the mouse tail and the rabbit ear vein, the thickness of the wall and the ability to tolerate stimulating drugs, which may require further research in the future.

Not only will accurate use of animal models pave the way for further prevention and treatment of CP, but also provide a reference for the clinical rational use of drugs. It can be viewed on this review that rabbits are mainly modeled animals, followed by rodents, and other large animals are rarely reported in the experimental studies. The size of rabbits and mice is very small compared to humans, so their circulatory and vascular conditions are quite different from those of clinical patients. In the future, studied animals should be closer to human body types, and also can add animal models simulating clinical patients, such as various types of cancer, diabetes, and cerebral edema. In the current research, the drug dose is calculated by the body weight or body surface area of the animal, and only a few researchers use the amount of modeling drugs as the units according to the number of animals. Although this method is simple, it will have a negative effect on the research result. Therefore, it is not recommended to use drugs based on the number of animals. Besides, in terms of the speed effects on CP, altered animal models present different results and conclusions, which need further research and discussion. Recently, despite the fact that there are many types of drugs for modeling phlebitis, the drugs used in the specific experiments are relatively simple, and they are not fully compatible with the actual clinical combination. In the future research, modeling drugs can be diversified and more in line with clinical practice.

This study is supported by the Hubei Medical and Health Science and Technology Plan Project (2017-97). And the third batch of joint fund project of Hubei Provincial Health and Family Planning Commission (WJ2018H231).

The authors declare no conflicts of interest regarding the publication of this paper.

Tong, C.L., Zhou, H. and Geng, J. (2019) Application of Modeling Drugs in Animal Models of Chemical Phlebitis: Review. Yangtze Medicine, 3, 19-31. https://doi.org/10.4236/ym.2019.31003