Heparin solution in the prevention of occlusions in Hickman® catheters a randomized clinical trial*

Objective: to evaluate the effectiveness of the 50 IU/mL heparin solution compared to the 0.9% isotonic saline solution in preventing occlusion of the double lumen Hickman® catheter, 7 and 9 French, in patients undergoing hematopoietic stem cell transplantation. Method: a triple-blind randomized clinical trial. 17 double-lumen catheters (heparin group: n=7 and 0.9% isotonic saline group: n=10) were analyzed in which the two catheter routes were evaluated separately, totaling 34 lumens. The outcome variables were occlusion without reflux and complete occlusion. Descriptive analyses were performed using the Chi-square test and, of survival, according to the Kaplan-Meier test. Results: the mean number of days until the occlusion outcome was 52 in the heparin group and 13.46 in the 0.9% isotonic saline group in the white catheter route (p<0.001). In the red route, the mean follow-up days in the heparin group were 35.29, with no occlusion and 22.30 in the 0.9% isotonic saline group until the first occlusion (p=0.030). Conclusion: blocking with 50 IU/mL heparin solution is more effective than 0.9% isotonic saline in preventing occlusion of the Hickman® catheter. Brazilian Registry of Clinical Trials: RBR-3ht499.


Introduction
The Central Venous Catheter (CVC) is a device used for intravenous fluid infusion and blood extraction, the tip of which is positioned in the superior or inferior vena cava (1) . This type of catheter should be selected from the assessment of the patient's needs, such as the condition of the venous network, the treatment regime and time, in addition to the technical capacity of the team that handles the device (2) .
CVC are classified as short-and long-term.
Short-term CVC are those who are inserted by direct venipuncture, with a permanence time of less than one month. Long-term ones are used for patients with an indication for treatment longer than 21 days (2)(3) . These are divided into totally implanted central venous catheter (CVC-TI) and semi-implanted central venous catheter (CVC-SI) and are indicated for cancer patients, and for those with hydroelectrolytic disorders, malnutrition, renal failure and acquired immunodeficiency syndrome. Among them, the Hickman ® catheter (3) , characterized as a CVC-SI, has benefited patients undergoing Hematopoietic Stem Cell Transplantation (HSCT).
HSCT is a therapy used for malignant and nonmalignant hematological diseases, which aims to replace the deficient bone marrow with a healthy one (4) . The use of the CVC-SI in this population is mainly due to the intense and continuous infusion of hydration, drugs, blood components and parenteral nutrition, necessary for this therapy. However, although the use of CVC-SI in HSCT is extremely favorable, it is not without complications (5) .
In a study that investigated incidents related to CVC-SI in patients undergoing HSCT, it was concluded that occlusion was the preponderant event in relation to other possible complications with the Hickman ® catheter (6) . The occlusion of a CVC is a worrying event and it frequently requires the interruption of therapy or, still, the patient's exposure to a new invasive procedure (1) .
Permeability is the ideal condition of a CVC that consists of the act of infusing fluids and collecting blood from this device without resistance. Occlusion is characterized by the permeability dysfunction of this device and can be classified into three degrees: partial, without reflux, and complete. The first is defined as resistance to infusion or slow reflux. Occlusion without reflux presents an inability to obtain blood reflux, but in a condition of infusion without resistance (2) and complete occlusion is defined as the impossibility of infusion and reflux in the CVC.
The causes can be mechanical, chemical or thrombotic (1) . Chemical and thrombotic occlusions are preventable, as long as the recommended techniques for flush and blocking the device (1) are maintained, in addition to the appropriate blocking solution for preventing occlusion, that is, for guaranteeing permeability (2,7) .
Regarding the maintenance of venous devices in general, there is already a consensus on the use of 0.9% Isotonic Saline Solution (ISS) for flush. However, for the long-term solution of CVC blockade, there is no strong clinical evidence for the ISS recommendation on the heparin solution in reducing the incidence of occlusion (5,(7)(8)(9) .
It is highlighted that, in the available studies, there is heterogeneity both due to the different types of catheter and research protocol, as well as to the basic pathology of the patient, in addition to the variation in the nursing practice, when comparing the frequency of flush, the concentration of heparin and the volume to be administered in the different services.
A number of studies recommend the development of clinical trials comparing different concentrations of heparin with ISS in more homogeneous samples (7)(8)10) .  After inserting the Hickman ® catheter in the Surgical Center, the surgeon and the nursing team in the sector forwarded the cut end of the catheter to the BMTS, for the measurement and definition of an adequate volume for the block, using the following adapted formula: priming volume = reduced length (cm) ÷ total length (cm) x total priming volume (+20%) (2) .
The randomization process was carried out by a nurse external to the research, PhD in Nursing from the Federal University of Paraná, who used the Random computerized system to generate a list of random order of solution allocations (11) . Each coded card was stored in sequential opaque envelopes that were sealed. These envelopes were then handed over to the main researcher. Each envelope was opened as the participants were included in the survey, ensuring that the increasing order of opening of the envelopes was maintained.
The contact to communicate the inclusion of the participant and the code of the solution to be prepared was made through the WhatsApp ® application between the main researcher and the pharmaceutical company. The participants who met the inclusion criteria were randomLy divided into blocks of six between the two research groups: three for the intervention group and three for the control group. As included in the research, the participants received a code for the solution to be used and the syringes were coded.
The syringes were filled with blocking solutions at the hospital's pharmacy service and four 10 mL syringes per participant/day were filled and coded (according to randomization) with 3 mL of solution in each.
These syringes were delivered to the service daily and Prior to data collection, the nursing team responsible for blocking the catheter, using heparin 50 IU/mL and ISS solutions, was instructed on the recommended actions for maintaining the catheter permeability (flush that precedes the block and the block properly). This allowed for the standardization of procedures related to blocking and opening the lumens of the Hickman ® catheter.
The catheter was released for use first by confirming the correct position of the catheter tip after chest X-ray, followed by a positive catheter permeability test, which consists of blood aspiration and ISS infusion without resistance. In catheters permeable to this first assessment, control and recording of the catheter's performance was initiated until the outcomes.   2) asking the patient to inhale and hold the air (up to five attempts); 3) hyperextending the patient's neck and asking him to place the corresponding hand next to the catheter insertion in the occipital region (up to five attempts) (Figure 2).
In cases in which blood return was not successful, after the four steps described, the catheter was flushed without forcing. And, when there was no difficulty in infusing ISS into the catheter, it was called occlusion without reflux, characterized by the inability to draw blood, but in an infusion condition without resistance (2) .
Occlusion without reflux was also considered when blood reflux was positive only after flush with ISS.
When flushing the route, after the four attempts, there was resistance to infuse ISS, it was called complete occlusion, characterized by the impossibility of infusion or aspiration in the CVC (2) .
In both cases, monitoring of the occluded catheter route by the research team was terminated. In complete occlusion, the clearance procedure established in the service was carried out.

Results
A total of 25 CVC-SI were eligible for the research (Figure 3). Of these, four were Leonard ® CVC-SI and one, a Broviac ® CVC-SI, which were excluded from the analysis. There were also three follow-up breaks: two in the heparin group and one in the ISS group. The reasons for follow-up failure were the following: insertion of the catheter for infusion of total parenteral nutrition, for follow-up in another unit; a follow-up was interrupted due to lack of chemotherapy to start treatment and a catheter was no longer followed-up due to difficulties with the donor, which resulted in early discharge in these three situations. Thus, 17 catheters were analyzed, ten from the ISS group and seven from the heparin group. The two catheter routes were evaluated separately, totaling 34 lumens.

White Route
Follow-up loss (n=1)  The catheter routes were analyzed separately (white route and red route), with a view to infusing different solutions in both. The red route, of larger caliber, is used for blood collection or infusion of blood components.

Inclusion
Among the outcomes of the white catheter route, in the heparin group there was complete occlusion (14.28%).
In the ISS group, there were nine occlusions, three complete (30%) and six without reflux (60%), showing a significant difference between the groups (p=0.006).
Among the outcomes of the red catheter route, there was no occlusion in the heparin group. In the ISS group, five occlusions occurred: one complete (10%) and four without reflux (40%).

Discussion
When assessing permeability, this study considered blockade as the condition of a closed catheter with solution inside the lumen (2) and the analysis of the permeability of the catheter lumens occurred at its opening. This research allowed us to identify that the mean number of days until the occlusion outcome was greater in the heparin group in the two catheter routes (white and red), with p<0.001 and p=0.030, respectively.
Other studies show similar results, despite the difference in the concentration of heparin, which ranged from 10 to 5,000 IU/mL, used for blocking, over time to assess the permeability and type of the catheter. This heterogeneity is confirmed in a systematic review, which verified this variety of actions (8) .
German researchers performed triple-lumen CVC blocking with 5000 IU/mL heparin solution, a concentration that exceeds current recommendations, versus ISS flush www.eerp.usp.br/rlae 8 Rev. Latino-Am. Enfermagem 2021;29:e3385. and 200 mg/mL vitamin C flush and considered occlusion without reflux as the primary outcome, concluding there is a difference between the use of heparin and ISS (p <0.04), choosing the heparin solution, more effective than ISS in maintaining the permeability of the analyzed CVC (13) . Regarding the use of heparin solution to block the catheter, when used in high concentration, although this practice has benefits in maintaining CVC permeability, it is important to remember that it is a drug and, as such, it deserves attention in its use. There are also concerns about the cost of heparin versus ISS (14) .
Another study, when comparing the 200 IU/mL heparin flush versus ISS in Broviac-Hickman CVC, defined partial, without reflux and complete occlusion as the outcome. The results show that the incidence of occlusion was significantly higher in the ISS group (82.17%) compared to the heparin group (40.19%) (p=0.0002) (15) .
The 100 IU/mL heparin solution in 5 mL was compared to ISS to maintain the permeability of CVC in another study and no difference was identified between the use of the solutions (p=0.744) (16) . It is worth highlighting that the heparin concentration of 100 IU/ mL is the maximum recommended concentration (7) and that the volume of 5 mL far exceeds what is necessary to fill the priming of a CVC. This result differs from the present study, especially in relation to the blocking solution, which used ISS versus 50 IU/mL heparin, with a volume variation between 0.4 to 1 mL to fill the priming, respecting the international recommendation for the heparin concentration and that of the manufacturer for the lumen filling volume (7) , which minimizes the risk of the heparin solution contacting the patient's bloodstream, ensuring greater safety for this practice.
Other studies with different concentrations of heparin solution (10 IU/mL and 100 IU/mL), which were also compared with ISS, found no difference between the solutions in maintaining the permeability of short-term CVC, in adults (16)(17) .
An Iranian study evaluated complete occlusion and occlusion without reflux. Flush was compared with 10 mL of ISS versus 10 IU/mL heparin flush, using 3 mL of the solutions after the injection of each medication.
Researchers claim to have found no significant difference in relation to the two types of occlusion assessed between the use of ISS and heparin (18) . The use of the heparin solution after each injection of a drug should be carefully evaluated, considering that a patient may have several drugs in a 24-hour period, such as, for example, those undergoing complex treatments like HSCT.
In the case of a long-term catheter, a retrospective study compared the efficacy of ISS with a 100 IU/mL heparin solution in CVC-TIs and the three types of occlusion were analyzed. The results show that there is no significant difference between the groups regarding the three types of occlusion (p=0.11) (14) . Another study, which also evaluated CVC-TI and aimed to assess occlusion without reflux, compared flush with 10 mL of ISS to flush with 10 mL of ISS + 300 IU heparin (3 mL).
The results do not show significant differences in catheter-free survival (19) , as well as the study that evaluated complete occlusion with ISS block versus block with 500 IU/10 mL heparin solution (20) .
There is limited evidence regarding the comparison of using ISS and heparin in terms of efficacy or safety (7)(8)(9)(10)21) .
The importance of the CVC blocking practice with an adequate solution is justified by the risk of infection due to the formation of a fibrin network and to the adherence of bacteria and fungi with loss of permeability (22) . In addition to the risk of infection, the occlusion of the catheter can lead to its early withdrawal, exposing the patient to the risk of a new surgical procedure (6) plus the risk to his safety, since a second catheter is certainly inserted at a more unfavorable moment, within the HSCT process.
The results found in this study, that is, the better to the impossibility of recruiting all the eligible patients.
There was also a reduction in the number of active beds in the BMTS, in April 2017, from 13 to 10.
Another limitation for the execution is related to the lack of important inputs to carry out the research, such as the Hickman ® catheter and 10 mL syringe, the latter defined as the first choice for flushes with ISS before blocking and for blocking solutions. In the absence of this input, 20 mL syringes with ISS were used for flush before blocking, seeking to respect the recommendation of using syringes that promote less positive pressure in the catheter (2) . For the blocking solution, due to the reduced volume, the 5 mL syringe was used.
In relation to the limitations for analysis and discussion, the following are highlighted: the withdrawal of five catheters for analysis, as they present some characteristics that differ from the ones of the Hickman ® catheter, which reduced the sample size; the difference in the outcomes listed in other studies, considering that the occlusion outcome, classified as partial occlusion, occlusion without reflux and complete occlusion, was present in various studies, but that each considered one, two or the three types of occlusion for its outcome.
The present study considered occlusion without reflux and complete occlusion as the outcome. In addition, in the studies found there is no homogeneity of heparin concentration, volume of solution, type of CVC and frequency of the permeability test.

Conclusion
The catheters allocated for blocking with heparin solution showed better performance compared to those allocated for blocking with ISS. Therefore, the hypothesis was accepted that blocking with a 50 IU/mL heparin solution is more effective than ISS in preventing occlusion of the Hickman ® catheter in patients undergoing HSCT.
Further clinical trials are recommended to investigate the effectiveness of heparin in maintaining the permeability of the Hickman ® catheter, using the same methodological design in other populations.