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Dosage of heparin for patency of the totally implanted central venous catheter in cancer patients

Objective: to analyze the evidence available in the literature about the lowest necessary dose of heparin to maintain the patency of the totally implanted central venous catheter in adult cancer patients. Method: an integrative literature review, carried out in the following databases: Literatura Latino-Americana e do Caribe em Ciências de Saúde, Sciverse Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, including thirteen studies. Results: the evidence showed that the dose of heparin (300 IU/ml) is the most used in maintaining the patency of the totally implanted central venous catheter. Conclusion: according to the selected studies, the lowest dose of heparin found in maintaining the patency of the totally implanted central venous catheter in cancer patients was 10 UN/ml with a volume of 5 ml of the heparin solution.


Introduction
Among the options of devices used for the longterm administration of chemotherapy in cancer patients is the totally implanted central venous catheter (CVC-TI), such as the port-a-cath ® , a siliconized rubber device, surgically implanted, which has a reservoir located at the distal end, which remains below the skin in the thoracic region, on a bone surface (1) .
The CVC-TI offers greater comfort to the patient and a lower infection rate, reduces the risk of thrombosis, allows for outpatient treatment, does not interfere in the patient's daily activities, and preserves the peripheral venous system, in addition to reducing the suffering and stress of the patients by avoiding repeated unsuccessful venous punctures, when compared to other available catheters (2) .
Although widely used, this device is not exempt from complications, such as hematomas, gas embolism, complications resulting from the anesthetic act, cardiac tamponade, and intolerance to the catheter. And because it is a long-term catheter, late complications are also added, such as: thrombosis, infection, catheter migration, rupture or fracture of the system, and catheter occlusion, among others (3) .
Occlusion of a CVC-TI is defined as the inability to infuse and/or draw blood from it, which can be classified as thrombotic, mechanical or chemical, being an event of concern for the health team, as it is mostly related to suspension of therapy or even exposure of the patient to a new invasive procedure (4)(5) .

The
Occlusion Management Guideline for Central Venous Access Devices (CVADs) guideline, whose purpose is to standardize the care related to the clinical practice in order to obtain positive results with a CVC-TI, considers the health professional fundamental for the management, prevention, and treatment of the occlusion, as this is the main responsible for its direct handling (6) .
Thus, in order to reduce complications related to this device, its handling, maintenance and optimization can be understood as a set of practices in which the nurse must gather knowledge, skills and attitudes that enable him to ensure an appropriate handling of them.
To guarantee CVC-TI patency, some precautions are necessary such as using the appropriate solution and performing the correct washing and blocking technique of this device, according to available protocols and guidelines, thus preventing its occlusion (4,7) .  (8)(9)(10) .
Over the years, the heparinized solution has been the most used method to maintain the patency of the catheter; however, the routine of this technique seems to hide the iatrogenic effects of the drug itself, such as thrombocytopenia, which occurs due to its connection with an inhibitor of serine protease, antithrombin (AT), causing conformational change in the AT molecule, resulting in increased inhibition of thrombin (factor IIa) and of other serine proteases involved in the coagulation cascade. As thrombin stimulates the conversion of fibrinogen to fibrin, being inhibited, consequently, it generates a decrease in the formation of fibrin (11) .
Because it is an anticoagulant that acts at the level of the coagulation cascade and contributes to the development of adverse events, even if used in small quantities, such as washing (flush) of central venous catheters, it affects up to 20 to 30% of the patients who are exposed to the drug (12)(13) . In this context, the objective of this study is to analyze scientific evidence in the literature on the lowest necessary dose of heparin to maintain the patency of the totally implanted central venous catheter in adult cancer patients.

Method
This is an integrative literature review study, which allows for research studies already carried out to be summarized and conclusions to be established based on the critical evaluation of different methodological approaches, aiming to synthesize and analyze the data to develop a more comprehensive explanation of a specific phenomenon from the synthesis or analysis of study findings, with theoretical and/or interventionist purposes (14) .
Thus, six stages were adopted for the elaboration of this review: selection of the research question; definition of study inclusion criteria and sample selection; representation of the selected studies in table format, considering all the characteristics in common; critical analysis of the findings, identifying differences and conflicts; interpretation of the results, and clearly reporting the evidence found (15) .
For the elaboration of the guiding question, the PICOS strategy was used, with P for Population, Patient identified and used with the use of the OR Boolean operator (MESH): "catheters, indwelling" OR "vascular access devices" OR "port catheters" OR "port a cath" OR "catheters, port" OR "port, vascular access" OR "vascular access port" OR "central venous catheters" OR "totally implantable venous device" OR "totally implantable central venous access port" OR heparin OR "heparin lock" OR "heparin flush" OR "obstruction catheter" OR "catheter obstruction". Most of the descriptors were enclosed in quotation marks because they are compound terms.  (18) was used.
This scale consists of five criteria and varies from 0 to 5 points, where each item receives 1 point for the "yes" answer, or zero points for the "no" answer, in which a score below 3 indicates that the study has a low methodological quality and that its results can hardly be extrapolated to other scenarios.
The systematic reviews were assessed according to the Assessment of Multiple Systematic Reviews (AMSTAR).
AMSTAR was built from the analysis and updating of other empirically validated instruments (19) . The items that comprise the checklist present minimum requirements for a systematic review: The review design was presented not. For each "yes" answer, one point (20) is applied. The more items in accordance with the checklist, the better the methodological quality of the study. The calculation of the final score was converted into a percentage and the quality of the manuscripts was assessed in three categories for both criteria: A for studies that meet more than 80% of the criteria established by Strengthening the Reporting of Observational Studies in Epidemiology (STROBE); B for studies that meet 50% to 80% of these criteria; and C for studies that meet less than 50% of the criteria (21) .
The STROBE guidelines were used to assess the observational studies, in which a score of 0 means "does not meet" and a score of 1 means "meets", being used for each of the 22 items of the STROBE guidelines. As well as in AMSTAR, the calculation of the final score was converted into a percentage and the quality of the manuscripts was assessed in three categories for both criteria: A for studies that meet more than 80% of the criteria established by STROBE; B for studies that meet 50% to 80% of these criteria; and C for studies that meet less than 50% of the criteria (21) .
Independently, two researchers carried out the selection of studies: first, studies were excluded from the reading of their titles (first analysis), then abstracts (second analysis) and, finally, after reading the full texts (third analysis). In case of disagreement or doubt, a third experienced researcher was consulted.
The discussion of the obtained data was carried out in a descriptive way, allowing the reader to evaluate the applicability of the integrative review elaborated, in order to achieve the objective of this method, that is, to facilitate the incorporation of evidence and build knowledge in the area of higher education in Nursing.

Results
At the end of the article search process, the sample of the integrative review was composed of 13 primary studies, as shown in Figure 1.    (32) .   Rev. Latino-Am. Enfermagem 2020;28:e3304.

Objective Intervention/Maintenance Result
E01. To standardize a safe and adequate interval to maintain CVC-TI patency*.
The protocol used a 10 ml flush † of physiological serum followed by a 5 ml heparin lock (100 IU/ml ‡ ). Total number of patients included: 201.
When compared to 90-day maintenance versus those more than 90 days apart (mean of 112 days), there was no difference in occlusion rates between the groups.
E02. To determine the effectiveness of the saline solution compared to heparin in maintaining totally implanted venous access devices.
Saline Solution Group (203 patients): flush with 20 ml † saline solution, followed by a block with 5 ml † saline solution, using positive pressure. Heparin Group (212 patients): wash with 10 ml † saline solution followed by a block with 5 ml † heparin (10 IU/ml ‡ ).
CVC-TI* occlusions were observed in 24 patients: 10 (4.71%) in heparin and 14 (6.90%) in the normal saline group, with no significant difference in the results.
E03. To compare the heparinized saline solution versus 0.9% saline solution for the maintenance of CVC-TI*.
Regarding CVC-TI* occlusion, there were 8 cases in the Heparin group and 8 cases in the Saline Solution group, with no statistical difference between the groups.
E04. To evaluate the effectiveness of heparin compared to the saline solution.
Saline Solution Group (404 patients): wash with 10 ml † saline solution before and after blood collection and drug administration, every 8 weeks, when the device was not in use and with 20 ml † saline solution after administration of blood (components) or parenteral nutrition. Heparin Group (398 patients): block with 3 ml † heparin before the needle is removed.
No significant complications were found when using saline solution instead of heparin as a blocking solution for catheter maintenance. The results do not show statistically significant differences with regard to catheter obstruction.
E06. To demonstrate that a longer maintenance interval for CVC-TI* can be safe, convenient, and more efficient.
Washing the catheter with 10 ml † saline solution followed by a block with 5 ml † heparin (100 IU/ml ‡ ). Total number of patients included: 82.
The mean intervals for catheter maintenance ranged from 38 to 244 days, with a mean interval between patients without complications associated with catheter obstruction of 63 days. The incidence of catheter-related occlusion was quite low for both groups, with no significant differences between the two groups.
E08. To clarify issues related to washing and blocking the CVC-TIs* and to describe the available evidence regarding the benefits of the interventions in relation to occlusion.
Washing and blocking venous catheters.
For washing the catheter a volume of 10 ml † saline solution is sufficient. Regarding the block, volumes should be minimal and based on the prime of the catheter. A maximum of 1 ml † excess volume for the block is adequate to safely fill the catheter and any complements.
E09. To evaluate the effectiveness of washing with heparin versus saline solution in adults with central venous catheters.
Heparin x saline solution.
The review found no convincing evidence of a reduction in the CVC § occlusion rate maintained with heparin compared to CVC § maintained with sterile saline solution. As heparin is more expensive, the results of this review do not support its use, except in future clinical trials.
E10. To evaluate the efficacy of irrigating CVC-TI* devices every eight weeks, instead of every four weeks, to maintain the patency of the device.
A wash with 20 ml † normal saline solution, followed by a block with 3 ml † sodium heparin (250 IU/5 ml ‡ ) for a total of 150 units of heparin was performed with two homogeneous groups with catheter maintenance every 4 weeks (17 patients) and 8 weeks (20 patients).
There were no differences in the occurrence of occlusion between CVC-TIs* irrigated every four weeks, instead of every eight weeks.
E11. To compare the survival time, function, and complication rates of double lumen CVC § use versus CVC-TI* for chemotherapy in patients with leukemia.
CVC-TI Group* (19 patients): wash with 5 ml † heparinized saline solution (100 IU/ml ‡ ) after each use or at least once a month. Double lumen CVC § (24 patients): wash with 5 ml † heparinized saline solution (12.5 IU/ml ‡ ) after use and at least twice a week.
There was no significant difference between the two groups regarding the catheter survival time. CVC § occlusion was noted on 14 occasions in seven patients; and CVC-TI* occlusion, in 3 patients.
E12. To compare the safety and efficacy of administering a larger dose of heparin (1,000 IU/ml ‡ ) and flushes every 6 weeks, versus standard dose and schedule (500 IU/ ml ‡ every 4 weeks), to reduce the incidence of CVC-TI*-related infections and thrombosis.
Maintaining catheter patency with 1,000 IU/ ml ‡ heparin every 6 weeks may be a safer, easier, more economical, comfortable and effective alternative when compared to standard 4-week administration to prevent thrombosis and infections.
E13. To compare the associated complications in patients with Groshong catheter and CVC-TI* in cancer patients undergoing chemotherapy.
It has been shown that the Groshong central venous catheter (at least when used for the administration of long-term chemotherapy) is not superior to CVC-TI* in terms of early and late complications. With regard to catheter obstruction, there was no difference between the two.  Figure 4 shows the concentrations and volume of heparin used in studies for maintaining CVC-TI and the interval between the applications.

Discussion
Obstruction of the CVC-TI results in suspension of treatment, increased risks and related costs, making it a relevant concern for the health professionals.
Therefore, measures to reduce this problem are of crucial importance, especially with regard to the choice of the solution and the dose to be used to maintain the patency of the device (9) .
Most of the studies (E02, E03, E04, E05, and E07) The dose of heparin required to maintain CVC-TI patency can vary from 10 to 1,000 IU/ml, with the concentration of 100 IU/ml in a volume of 3 ml being the most commonly used (2,31,22,34) . thus avoiding incomplete filling which, consequently, would increase the risk of obstruction (31,22,35) .
In spite of the variation in the solution dose, the CVC-TI reservoir should be considered, which has a dead space and an internal volume larger than a standard catheter. Thus, a volume of 2.5 ml to 3 ml is used to perform the catheter block, so that the amount is slightly higher than the prime of the catheter, considering that the adherence of lipids, fibrin, and other drug deposits to the reservoir wall can result in the colonization of microorganisms and subsequently in bloodstream infection related to the catheter (2,28) . When using a concentration of 100 IU/ml (3 ml), seeking to extend the CVC-TI wash interval to 56 to 90 days, there were no changes in relation to catheter obstruction, regarding the maintenance performed every 28 days, presenting an occlusion rate of up to 3% (24,42) .
The maintenance of a CVC-TI has a mean cost of US$ 160.00, including time and nursing equipment.
Thus, reducing the number of washes from 12 to 4 times a year would reduce the annual cost from US$ 1,920.00 to US$ 640.00. This is without considering time off work, transportation costs, and other logistical expenses incurred by the patient. The considerable reduction in individual costs for patients has an even more significant economic impact when considered at a population level (36) .
The Centers for Disease Control and Prevention (CDCs) and the Oncology Nurse Society guidelines provide some evidence of flexibility for the flush, when recommending a heparin solution of 100 IU/ml, 5 ml every month or every 6 to 8 weeks, and after each use of the device, but no recommendation regarding the ideal range (26,(43)(44) .
With regard to the limitation of this study, a lack of studies within this perspective was identified. This

Conclusion
This study allowed us to conclude that the dose of heparin most used to maintain the patency of the totally implanted central venous catheter in cancer patients was 100 UN/ml, with a volume ranging from 5 ml to 3 ml of the heparin solution, being the dose of 10 UN/ml the lowest dose found in maintenance, with an interval of 28 days between maintenance instances.
However, it was possible to identify that there is an interest in extending the device's heparinization interval, in addition to the use of saline solution to maintain this type of catheter.
As a contribution to the care practice, it is believed that this study presents evidence that lower doses of heparin are sufficient to maintain the previous CVC-TI, showing that doses higher than 300 UN/ml are unnecessary, in addition to being able to contribute to the development complications associated with its use, as previously mentioned.
It is important to note that clinical trials have been carried out in order to compare the effectiveness of heparin in relation to the physiological solution for maintaining CVC-TI patency, and have shown similar effects with regard to its obstruction rate, evidencing a field to be explored through new studies that seek to prove the effectiveness of the physiological solution.