Abstract
Keywords
Introduction
PICC lines have been increasingly used as an important intravenous access, which could effectively avoid repeated venipuncture and transfuse stimulant or even toxic medications safely. The top of the catheter is positioned on the superior vena cava or subclavian vein. Chemotherapy medications can directly reach the central vein that has high blood flow. Because the osmotic pressure and concentration of the medications could be reduced immediately, the occurrence of the destruction of peripheral blood vessels and the stimulation of local skin could be much lower [1]. Therefore, PICC lines have been widely applied in the chemotherapy of tumor patients.
However, after the placement of PICC, the formation of fibrin sheaths begins. Fibrin sheaths consist of cellular and non-cellular components. The cellular components refer to endothelial cells and smooth muscle cells, while the non-cellular components refer to collagen. A number of studies [11, 29] indicate that all kinds of venous access devices have fibrin sheaths on their surfaces, such as PICC lines, implantable venous access ports, and non-tunneled central venous catheters and so on.
The fibrin sheaths will lead a large amount of catheter complications [2, 3], and significantly decrease the fluid flow, and even enhance the thrombosis, infection and persistent bacteremia and so on.
Cancer patients could release tumor necrosis factor (TNF), some of which conduct as procoagulant substance that affecting exogenous coagulation system and lead the increasing of fibrous protein, fibrinogen and fibrin degradation products in the blood. Due to the above, the tumor patients are usually in a state of hyper coagulation and hyper viscosity, which may result in thrombosis and embolism that is life-threatening [24]. Other researches revealed that the disorder in hemorheology may facilitate metastasis and spread to other adjacent organs [28]. Therefore, regular monitoring of the hemorheological parameters of the cancer patients plays an important role in diagnosis, treatment and prognosis.
Oliver [16] examined that the fibrin sheaths were discovered in 70% of all the participants on maintenance hemodialysis who suffered the end-stage renal disease. Whigham [29] examined the 50 patients with venous port access that had catheter dysfunction and found that nearly all the surface of the catheters were covered with fibrin sheaths when the patients were performed venography.
As time went by, catheter dysfunctions began to appear at about the fifteen week after the placement of the catheters, such as plugging, exudation in puncture site, thrombosis, etc. At the puncture site, fibrin sheath were connected very close to the blood tissues. Even if the catheter was removed, it’s still not easy to be eliminated. It was indicated that the hemodialysis catheters had poor catheter flow on account of the presence of the sheath. Therefore, it fails to maintain the ideal flow to allow effective dialysis in these end-stage renal disease patients. Schon [20] and Santilli [21] demonstrated that the fibrin sheath generally make a significant contribution to catheter dysfunction of the patients with end-stage renal disease which were equipped with dialysis catheter. The two researches revealed that the incidences of catheter dysfunctions were 38% and 50% respectively. Starkhammar [22] examined the 16 tumor patients who were equipped with central venous catheters and found that all of the catheters were got rid of due to the catheter malfunction caused by fibrin sheath.
Acetylsalicylic acid could inhabit the synthesis of cyclooxygenase, which acts as one of the important substances related to platelet aggregation. Therefore, aspirin could inhabit platelet aggregation [17, 19]. While the common side effects are digestive tract symptoms such as nausea, vomiting and so on. The side reaction of long-term daily use high doses aspirin is bleeding tendency. A small dose (usually 50–100 mg) of acetylsalicylic acid could effectively inhibit the aggregation of platelet and prevent thrombogenesis [12]. Zhou Chunling [34] and Wang Wulong [26] respectively found that taking enteric-coated acetylsalicylic acid orally 50 mg every day for 5 to 6 months could efficiently prevent lung cancer patients from thrombus. Gunnar [9] reported that acetylsalicylic acid might inhibit the formation of fibrin sheath, but similar researches haven’t been reported in Chinese literature yet.
Objective
We conduct this study to explore the influences of oral acetylsalicylic acid on hemorheology and infusion speed related to fibrin sheaths in cancer patients who were inserted with PICC lines.
Methods
Ethics principles
Permission was acquired from Ethics Committee of the second Hospital of Xiangya, Central South University. The license number of the study is (2013) 
(09). The researchers interpreted the objective and contents of the research to the patients, and then the patients signed the informed consent forms if they want to join the research.
Study design
The study design of this research is randomized, controlled and repeated. The participants were chosen from the Cancer Center of the second Hospital of Xiangya. The sample size of each group was 48, and the sample size altogether was 96. The selection criteria were shown below: more than 18 years old; no serious diseases or vital organs impairment and Karnofsky performance score (KPS)⪢60 points [25], patients with PICC lines who were provided with the solid pathology evidences had the normal blood coagulation. The exclusion standards were indicated as participants who had gastric and duodenal ulcer or high platelet, or who had gone through an important surgical operation lately. 96 eligible subjects were allocated to the experimental or the control group at random. Every individual of the study was offered a figure ranging from 1–96, and then we selected 96 three-digit numbers from a certain procession of the random digits table. The 96 three-digit numbers should be correspondence with the patients’ number. Then we ranked the 96 three-digit numbers. Individuals with numbers correspondence with the first 48 three-digit numbers were assigned to the experimental group, and individuals correspondence with the last 48 three-digit numbers were assigned to the control group. Participants in the experimental group were conducted oral acetylsalicylic acid100 mg per night half an hour after supper, while the control group received the route care of cancer patients only.
Interventions
Oral acetylsalicylic acid
Each participant in the experimental group received a small dose of acetylsalicylic acid, which was given orally, 100 mg per night half to one hour after supper. These participants had been taking acetylsalicylic acid for four months. The doctor prescribed acetylsalicylic acid to the eligible patients and the start time of the medication was the next day after the implantation of PICC.
Text message education
Text message education was developed to every experimental participant for four months. The education involved the reminding of taking medicine, the functions of acetylsalicylic acid, the newly research progress of acetylsalicylic acid applied to cancer patients, the basic general knowledge of using medicines, the route nursing care of patients during radiotherapy and chemotherapy, some knowledge of PICC lines with respect to maintenance and prevention of complication, some useful information about diet, exercise and sleep were also included. The short messages were sent by the researcher’s mobile phone every evening half to one hour after supper. Several steps were to take to control the quality of this study. The family members were stimulated to remind the patients to take their medicine on time every evening. Besides, the researchers carried out telephone follow-ups every week at fixed time so that they could verify the pill boxes, exchange each other’s ideas with the patients and guarantee their medication compliance.
Research instruments
General information of the patients such as gender, age, medical history, diagnosis, chemotherapy options, tumor staging and so on was totally brought into a questionnaire. This research used SA-5600 automatic hemorheology detector to investigate systematical changes of hemorheology of all the participants. The blood samples were taken before breakfast early in the morning. We used heparin anticoagulant tubes as the sampling tubes and we obtained blood from other vein rather than PICC. Firstly, we took the tube that contained blood sample into the inspection hole and turned on the computer that combined with the automatic hemorheology detector. Then we opened the operating software that controlled by the detector and the blood sample could be tested automatically. The rotational viscometer was used to test viscosity. An object, which could rotate actively with a changeable velocity, had the interaction with the blood sample and drive the other object rotated passively that have the same axes. The object rotated passively could generate a certain size of torque. We could calculate the viscosity of the blood sample if we know the velocity of the actively rotated object and the torque of the passively rotated object. The red blood cell aggregation index and deformability index could be calculated by the viscosity detected by the automatic hemorheology detector [33].
The process of data collection
At first, the main researcher of this study carried out a period of training to the other researchers of the study team in order to guarantee the reliability of the measurement. The patients were included according to the inclusion criteria and exclusion criteria. Every qualified participant would be informed about the study details and content. The baseline information of hemorheology and infusion speed of the patients before the research was acquired firstly. Hemorheology, which identified through a blood test, and infusion speed testified by observation were measured again at the end of the 2nd and 4th months of the study. Besides, some drug safety indexes such as coagulation function, liver and renal function, blood test, cardiac function, routine urine test and bleeding tendency were also monitored during the whole research.
Statistical analysis
We used SPSS 17.0 to conduct data processing. The patients’ general condition was specified by descriptive statistics. The general information, hemorheology and infusion speed before study between the two groups were compared by Mann-Whitney U test, chi-square test and t-test. The effects of oral acetylsalicylic acid on hemorheology and infusion speed of the two groups were explored by repeated measures analysis of variance. P≤0.05 was considered to be significant differences.
Research results
General condition of the subjects
Ninety-six subjects were allocated to the two groups. Four patients of the experimental group and four patients of the control group didn’t accomplish the research on account of discharging from hospital or death. There were no significant differences between the two groups for all the general condition, catheter and disease characteristics, and hemorheology and infusion speed related to fibrin sheath before the research (P > 0.05), as shown in Table 1.
The effect of acetylsalicylic acid on hemorheology parameters of the cancer patientswith PICC
The values of hemorheology parameters of the two groups were indicated in Table 2. Repeated measures analysis of variance was used in this part. Table 3 indicated that time had significant main effect as well as interaction effect with oral acetylsalicylic acid on low shear blood viscosity and red blood cell aggregation index (P < 0.05), showing that the participants’ low shear blood viscosity and red blood cell aggregation index decreased over time. It also revealed that taking acetylsalicylic acid orally had significant main effect on high shear blood viscosity and red blood cell deformability index (P < 0.05), indicating that acetylsalicylic acid is effective in decreasing the participants’ high shear blood viscosity and red blood cell deformability index. Besides, taking acetylsalicylic acid had significant main effect as well as time effect on plasma viscosity (P < 0.05), revealing that acetylsalicylic acid is valid in decreasing or inhabiting the increasing of the patients’ plasma viscosity and the effect enhanced as time passed.
The effect of acetylsalicylic acid on infusion speed of the cancer patients with PICC
After a period of intervention, the drop numbers (are used to evaluate infusion speed) of the experimental group increased a little compared with the data before study, while they decreased a lot in the patients of the control group. The data was displayed in Table 4. Table 5 indicated that taking acetylsalicylic acid orally had significant main effect, time effect and interaction effect on infusion speed (P < 0.01), displaying that taking acetylsalicylic acid 100 mg orally per day is valid in increasing the patients’ infusion speed and the effect enhanced as time passed.
Adverse drug reactions
Bleeding tendency and coagulation disorder of these study population were not observed. No abnormality in routine urine function examinations was found. There was only one case of electrocardiogram abnormality (first-degree atrioventricular block) in the control group, which might be related to primary heart disease. No unusual cases were found in experimental group. In the whole process, ten cases of routine blood abnormalities (reduction in the number of white blood cells) of the test group and fourteen cases of the control group were found. Fourteen cases of liver function abnormalities (abnormalities in liver enzymes) of the experimental group and thirteen cases in the control group were observed. The incidences of drug adverse reactions between the groups were not statistically significant (P > 0.05).
Discussion
Whole blood viscosity 5 s–1 is the blood viscosity of low shear rate, reflecting the ability of erythrocyte aggregation. The higher the low shear blood viscosity is, the stronger the erythrocyte aggregation ability would be. Red blood cell aggregation index is an objective indicator, which also effectively reflects the ability of erythrocyte aggregation. Increased whole blood viscosity has been attributed to erythrocyte aggregation which in turn is greatly influenced by other rheological parameters, including its membrane surface charge and plasma fibrinogen concentration [10]. Microcirculation resistance and blood viscosity increase when red blood cell aggregation increases. It may lead to the blockage of capillary, the decrease of blood perfusion, the lack of oxygen and the formation of thrombus, which are severe complications of cancer patients. Due to the placement of PICC, the risk of thrombus increases a lot. Therefore, some effective measures should be taken to reduce the red blood cells’ aggregation ability and blood viscosity. This study revealed that red blood cell aggregation index and the low shear blood viscosity of the control group and experimental group were all decreasing over time, but there was no difference between groups. The results were in accord with the reported conducted by SU HH [23]. SU HH believed that whole blood viscosity, whole blood reduced viscosity and red blood cell aggregation index of the high blood viscosity patients, who took acetylsalicylic acid for a long time, were a little lower than those who did not took. However, there was no significant difference. Whole blood viscosity 200 s–1 is the blood viscosity of high shear rate, reflecting the deformability of red blood cell. The effective microcirculation perfusion, the normal erythrocyte life span and regular blood flow are closely related to erythrocyte deformability, which is the ability of changing its shape to adapt to the conditions of blood flow. When erythrocyte deformability decreases, the calthrop begins to appear in the surface of erythrocyte, which could lead to lipid accumulation, accelerating the atherosclerotic process and slowing down the blood circulation [14]. Our findings revealed that the high shear blood viscosity of experimental group reduced obviously than control group, while the red blood cell deformability index was higher significantly than control group. Acetylsalicylic acid could inhabit the synthesis of cyclooxygenase, which acts as one of the important substances related to platelet aggregation. Therefore, aspirin could inhabit platelet aggregation and decrease the blood viscosity. These results indicated that acetylsalicylic acid could effectively decrease high shear blood viscosity, increase erythrocyte deformability and improve blood rheological characteristics of the cancer patients [27]. The results above were similar to the research carried out by MA XQ [15]. The research results showed that acetylsalicylic acid can significantly enhance the erythrocyte deformability of elderly patients with hyperlipidemia and improve the flowing ofblood.
The plasma viscosity, which mainly depends on the concentration of plasma protein, fibrinogen, lipoprotein and globulin, is one of the important factors that affect the whole blood viscosity. The whole blood viscosity increases when the plasma viscosity increases. As the medium of red blood cells, plasma not only affects the whole blood viscosity, but also affects the erythrocyte deformability and aggregation. The placement of PICC catheter may lead to the breakage of vascular endothelial cell and start the endogenous blood coagulation system, and then the formation of local micro thrombus might lead to the high blood coagulation state. The damage of vessel wall activates platelets, which could increase platelet aggregation, adhesion and release, and then cause the increasing of blood viscosity. In addition, in the process of tumor proliferation, several kinds of coagulation factors are released to the blood. At the same time, the rapid development of tumor tissue causes the relative insufficient blood supplies and oxygen deficiency, and then would lead to the accumulation of acid metabolites and the increasing of fibrinogen generated and released by the liver [6]. From the above, the plasma viscosity of the cancer patients are usually high than normal population. This study indicated that the plasma viscosity of the control group and the experimental group were both increased gradually over time and the increasing extent of the experimental group is much less than the control group. It revealed that acetylsalicylic acid could inhibit the increasing of plasma viscosity. The increasing trend of both groups in our study might related to the sustainable increasing of plasma proteins and cancer procoagulant substance generated by the growth of tumor tissues. Taking acetylsalicylic acid 100 mg per day for four months could decrease the platelet aggregation ability and adhesion to some extent. Consequently, the aggregation ability of platelets and fibrinogen decreased. It revealed that acetylsalicylic acid is valid in decreasing or inhabiting the increasing of the patients’ plasma viscosity. These findings were similar to Yu GQ [32], but not consistent with the results conducted by SJ Qu [18], which might have something to do with the dose and duration.
The infusion speed could directly affect the quantity and concentration of the drugs that infused into the body. Therefore, it is the key problem in PICC intravenous therapy that effectively controlling the infusion speed and maximizing the drug effects. In the process of chemotherapy, drugs are usually required to be infused within the prescribed time. As a result, the low infusion speed of patients would affect the effect of the treatment. The research [30] showed that, the liquid infusion speed of hemodialysis catheter in the end-stage renal disease patients would lower than normal population, which would eventually cause the slow pace, a substantial reduction in dialysis amount and the dialysis effect is significantly weaken. After the placement of PICC, the formation of fibrin sheaths, which consist of cellular and non-cellular components, may begin at the puncture point and connect firmly with venous wall and could not be removed even if the catheter was taken off from the body [4]. Because of the presence of the fibrin sheaths on the catheter surface, it creates a one-way valve mechanism, and the PICC catheter occupies the lumen volume, which might cause local blood stasis and the decrease of infusion speed. It’s important that the decrease of the infusion speed is a catheter dysfunction related to the formation of fibrin sheath, which is a key clinical clue [8]. As we know, acetylsalicylic acid conducts a major role in inhibiting the aggregation of fibrinogen and platelet; and might effectively inhibit the formation of fibrin sheath at the early stage. We could conclude that acetylsalicylic acid might suppress the growth of fibrin sheath that adhere to the surface of PICC lines. What’s more, aspirin decrease the whole blood viscosity and red blood cell aggression index, so it might low the blood resistance of the patients, guarantee the circulation unobstructed, increase the fluidity of blood and in this way may improve the infusion speed. These study population in experimental group had taken acetylsalicylic acid for a long time from the second day after the insertion, so the drop numbers of infusion in the experimental group kept stable or a little higher, while as the insertion time went by, the drop numbers of the control group gradually decreased which might be related to the lack of prevention provided by acetylsalicylic acid and the continuous growth of fibrin sheath along the catheter.
Coagulation disorders of the study population were not observed in this study. That is to say, it is safe to apply acetylsalicylic acid to the cancer patients with PICC. This finding was similar to the study conducted by SHUJUN QU [18]. During the research, routine blood function, routine urine function, electrocardiogram, liver and kidney function of both groups were all observed for four months. At the end of our study, even if the incidences of several abnormal cases were higher than before, serious adverse reactions were not found in our study yet and there was not statistically significance between the two groups. In other words, the patients’ problems cannot be interpreted as anything to do with acetylsalicylic acid. This study believes it may be related to the treatment. Cisplatin, methotrexate, 5-fluorouracil and mitomycin are toxic to the kidneys; adriamycin, pharmorubicin and paclitaxel are toxic to the heart; cyclophosphamide and vincristine could cause myelosuppression and so on. The side effects of chemotherapy may be the reasons of abnormities we mentioned above.
Conclusion
The study revealed that oral acetylsalicylic acid could improve hemrheology parameters and increase or keep the infusion speed from decreasing in the cancer patients.
Relevance to clinical practice
PICC lines are increasingly being used in the patients who need long-term intravenous therapy. They are primarily applied for chemotherapy and parenteral nutrition. The study [7] had explored the kinds and occurrence rate of the complications related to PICC lines. The previous measures dealing with the complications have been carried out after the occurrence of these complications. On the contrary, this study focuses on preventions before the complications take place. Acetylsalicylic acid is not only cheap, but also has little side effects. A lot of literatures have provided many important evidences that the efficient effects of acetylsalicylic acid on the improvement of hemorheology parameters. What’s more, text message acted as a reminder to remind these participants to take acetylsalicylic acid on time in order to enhance their medication compliance.
The advantages and limitations of this study
Several advantages have been summarized as shown below. In the first place, previous studies have concentrated on the interventions after complications have occurred. In contrast, our study focuses on preventions before the complications take place. Second, the text message education not only acted as a reminder to remind these participants to take acetylsalicylic acid on time in order to enhance their compliance, but also provided relevant knowledge including catheter maintenance, sleep, diet and exercise. In spite of these advantages, the limitations of the study are inevitable. Due to time limit, the sample size was small and the types of cancer were a little simple. The majority of the types consist of lung cancer and intestinal cancer. The future research should expand the sample size and collect more types of cancer patients.
Footnotes
Acknowledgments
This study was funded by the Innovation Project for Graduates of Central South University (2013zzts304). We hereby thank all the tumor patients who participated in this research for their cooperation. Thanks for the great supports of the Directors of Cancer Center, Professor Chunhong Hu, Professor Xianling Liu and Professor Jinan Ma. Thanks for the selfless assistances of head nurses, Miss Chunfang Xia and Miss Jing Li. Thanks for the honest help of sincere nurses, Miss Yulan Zuo, Miss Ling Li, Miss Juyang Chen, Miss Haiyan Li and Miss Li Huang and so on.