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

Oliveira, Francisca Jane Gomes de; Rodrigues, Andrea Bezerra; Ramos, Islane Costa; Caetano, Joselany Áfio

doi:10.1590/1518-8345.3326.3304

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Revista Latino-Americana de Enfermagem

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Review Article • Rev. Latino-Am. Enfermagem 28 • 2020 • https://doi.org/10.1590/1518-8345.3326.3304 copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Descriptors:
Vascular Access Devices; Central Venous Catheters; Catheters, Indwelling; Heparin; Heparin Lock; Catheter Obstruction

Study code/Author(s)/ Year	Title	Evidence level	Methodological quality
E01. Girda E; Phaeton R; Nevadunsky N; Huang G; Smith Ho; Smotkin D; Goldberg G; Kuo D, 2013⁽¹1 Girda E, Phaeton R, Goldberg GL, Kuo D. Extending the interval for port-a-cath maintenance. Modern Chemother. 2013 Oct;2(2):15-8. doi: 10.4236/mc.2013.22003 https://doi.org/10.4236/mc.2013.22003... ⁾.	Extending the interval for port-a-cath maintenance	2B^* * 2B = cohort studies;	Category A^§ § Category A = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) of the Assessment of Multiple Systematic Reviews (AMSTAR) and that met more than 80% of the established criteria;
E02. Dal Molin A, Clerico M, Baccini M, Guerretta L, Sartorello B, Rasero L, 2015⁽²²22 Dal Molin A, Clerico M, Baccini M, Guerretta L, Sartorello B, Rasero L. Normal saline versus heparin solution to lock totally implanted venous access devices: results from a multicenter randomized trial. Eur J Oncol Nurs. [Internet]. 2015[cited Oct 10, 2018];19(6):638-43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25933709 https://www.ncbi.nlm.nih.gov/pubmed/2593... ⁾.	Normal saline versus heparin solution to lock totally implanted venous access devices: Results from a multicenter randomized trial	1B^† † 1B = studies of controlled and randomized clinical trial with a narrow confidence interval;	High quality
E03. Brito, 2018⁽²³23 Brito ARO, Nishinari K, Saad PF, Saad KR, Pereira MAT, Emídio SCD, et al. Comparison between saline solution containing heparin versus saline solution in the lock of totally implantable catheters. Ann Vasc Surg. [Internet]. 2018 Feb[cited Aug 03, 2018];47:85-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28947219 https://www.ncbi.nlm.nih.gov/pubmed/2894... ⁾.	Comparison between Saline Solution Containing Heparin versus Saline Solution in the Lock of Totally Implantable Catheters	2B^* * 2B = cohort studies;	Category A^§ § Category A = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) of the Assessment of Multiple Systematic Reviews (AMSTAR) and that met more than 80% of the established criteria;
E04. Goossens GA; Jérôme M; Janssens C; Peetermans WE; Fieuws S; Moons P; Verschakelen J; Peerlinck K; Jacquemin M; Stas M, 2013⁽²⁴24 Goossens GA. Flushing and locking of venous catheters: available evidence and evidence deficit. Nurs Res Pract. [Internet]. 2015 [cited Oct 10, 2018];2015:985686. Available from: https://www.hindawi.com/journals/nrp/2015/985686 https://www.hindawi.com/journals/nrp/201... ⁾.	Comparing normal saline versus diluted heparin to lock non-valved totally implantable venous access devices in cancer patients: a randomised, non-inferiority, open trial	1B ^† † 1B = studies of controlled and randomized clinical trial with a narrow confidence interval;	High quality
E05. Bertoglio S, Solari N, Meszaros P, Vassallo F, Bonvento M, Pastorino S, Bruzzi P, 2012⁽²⁵25 Bertoglio S, Solari N, Meszaros P, Vassallo F, Bonvento M, Pastorino S, et al. Efficacy of normal saline versus heparinized saline solution for locking catheters of totally implantable long-term central vascular access devices in adult cancer patients. Cancer Nurs. [Internet]. 2012 Jul-Ago[cited Aug 03, 2018];35(4):E35-42. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22228390 https://www.ncbi.nlm.nih.gov/pubmed/2222... ⁾.	Efficacy of normal saline versus heparinized saline solution for locking catheters of totally implantable long-term central vascular access devices in adult cancer patients	2B^* * 2B = cohort studies;	Category A^§ § Category A = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) of the Assessment of Multiple Systematic Reviews (AMSTAR) and that met more than 80% of the established criteria;
E06.Kuo YS; Schwartz B; Santiago J; Anderson PS; Fields AL; Goldberg GL, 2005⁽²⁶26 Kuo YS, Schwartz B, J Santiago, Anderson PS, Campos AL, Goldberg GL. How often should a port-A-cath be flushed? Cancer Invest. [Internet]. 2005 [cited Nov 05, 2018];23(7):582-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16305984 https://www.ncbi.nlm.nih.gov/pubmed/1630... ⁾.	How Often Should a Port-A-Cath be Flushed?	2B^* * 2B = cohort studies;	Category B^\|\| \|\| Category B = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) or the Assessment of Multiple Systematic Reviews (AMSTAR) and that met 50% to 80% of these criteria
E07. Baram A, Majeed G, Abdullah H, Subhi A, 2014⁽²⁷27 Baram A, Majeed G, Abdullah H, Subhi A. Heparin versus saline solution for locking of totally implantable venous access port (TIVAP): cohort study of the first Kurdistan series of TIVAP. Adv Lung Cancer. [Internet]. Dec 2014 [cited Aug 03, 2018];3(4):67-74. Available from: https://www.scirp.org/journal/PaperInformation.aspx?PaperID=51365 https://www.scirp.org/journal/PaperInfor... ⁾.	Heparin versus Saline Solution for Locking of Totally Implantable Venous Access Port (TIVAP): Cohort Study of the First Kurdistan Series of TIVAP	2B^* * 2B = cohort studies;	Category A^§ § Category A = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) of the Assessment of Multiple Systematic Reviews (AMSTAR) and that met more than 80% of the established criteria;
E08. Goossens GA, 2014⁽²⁸28 Goossens GA, Jérôme M, Janssens C, Peetermans WE, Fieuws S, Moons P, et al. Comparing normal saline versus diluted heparin to lock non-valved totally implantable venous access devices in cancer patients: a randomised, non-inferiority, open trial. Ann Oncol. [Internet]. 2013 Jul [cited Nov 05, 2018];24(7):1892-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23553060 https://www.ncbi.nlm.nih.gov/pubmed/2355... ⁾.	Flushing and Locking of Venous Catheters: Available Evidence and Evidence Deficit	1A^‡ ‡ 1st= systematic review studies (with homogeneity) of controlled and randomized clinical trials. Evaluation of the methodological quality:	Medium quality
E09. López-Briz E, Ruiz GV, Cabello JB, Bort-Marti S, Carbonell SR, Burls A, 2014⁽²⁹29 López-Briz E, Ruiz GV, Cabello JB, Bort-Marti S, Carbonell SR, Burls A. Heparin versus 0.9% sodium chloride intermittent flushing for prevention of occlusion in central venous catheters in adults. Cochrane Database Syst Rev. [Internet]. 2014 Oct [cited Aug 03, 2018];(10):CD008462. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25300172 https://www.ncbi.nlm.nih.gov/pubmed/2530... ⁾.	Heparin versus 0.9% sodium chloride intermittent flushing for prevention of occlusion in central venous catheters in adults	1A^‡ ‡ 1st= systematic review studies (with homogeneity) of controlled and randomized clinical trials. Evaluation of the methodological quality:	High quality
E10. Palese A, Baldassar D, Rupil A et al. 2014⁽³3 Palese A, Baldassar D, Rupil A, Bonanni G, Capellari Maria T, Contessi D, et al. Maintaining patency in totally implantable venous access devices (TIVAD): a time-to-event analysis of different lock irrigation intervals. Eur J Oncol Nurs. 2014 Feb;18(1):66-71. doi: 10.1016/j.ejon.2013.09.002 https://doi.org/10.1016/j.ejon.2013.09.0... ⁾.	Maintaining patency in totally implantable venous access devices (TIVAD): A time-to-event analysis of different lock irrigation intervals	2B^* * 2B = cohort studies;	Category A^§ § Category A = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) of the Assessment of Multiple Systematic Reviews (AMSTAR) and that met more than 80% of the established criteria;
E11. Johansson E, Björkholm M, Björvell H et al. 2004⁽³⁰30 Johansson E, Björkholm H, Björvell H, Acaso R, Takolander R, Olofsson P, et al. Totally implantable subcutaneous port system versus central venous catheter placed before induction chemotherapy in patients with acute leukaemia - a randomized study. Support Care Cancer. [Internet]. 2004 Feb [cited Oct 03, 2018];12(2):99-105. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14648310 https://www.ncbi.nlm.nih.gov/pubmed/1464... ⁾.	Totally implantable subcutaneous port system versus central venous catheter placed before induction chemotherapy in patients with acute leukaemia-a randomized study	1B^† † 1B = studies of controlled and randomized clinical trial with a narrow confidence interval;	High quality
E12. Kefeli U, Dane F, Yumuk PF, et al. 2009⁽³¹31 Kefeli U, Dane F, Yumuk PF, Karamanoglu A, Iyikesici S, Basaran G, et al. Prolonged interval in prophylactic heparin flushing for maintenance of subcutaneous implanted port care in patients with cancer. Eur J Cancer Care. [Internet]. 2009 Mar [cited Oct 10, 2018];18(2):191-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19267736 https://www.ncbi.nlm.nih.gov/pubmed/1926... ⁾.	Prolonged interval in prophylactic heparin flushing for maintenance of subcutaneous implanted port care in patients with cancer	2B^* * 2B = cohort studies;	Category A^§ § Category A = studies evaluated according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) of the Assessment of Multiple Systematic Reviews (AMSTAR) and that met more than 80% of the established criteria;
E13. Biffi R, Braud F, Orsi F et al. 2001⁽³²32 Biffi R, De Braud F, Orsi F, Pozzi S, Arnaldi P, Rotmensz N, et al. A randomized, prospective trial of central venous ports connected to standard open-ended or Groshong catheters in adult oncology patients. Cancer. [Internet]. 2001 Sep [cited Aug 03, 2018];1;92(5):1204-12. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11571734 https://www.ncbi.nlm.nih.gov/pubmed/1157... ⁾.	A randomized, prospective trial of central venous ports connected to standard open-ended or Groshong catheters in adult oncology patients	1B^† † 1B = studies of controlled and randomized clinical trial with a narrow confidence interval;	High quality

Objective	Intervention/Maintenance	Result
E01. To standardize a safe and adequate interval to maintain CVC-TI patency^* * CVC-TI = Totally Implanted Central Venous Catheter; .	The protocol used a 10 ml flush^† † ml = Milliliters; < of physiological serum followed by a 5 ml heparin lock (100 IU/ml^‡ ‡ International units per milliliter; ). 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^† † ml = Milliliters; < saline solution, followed by a block with 5 ml^† † ml = Milliliters; < saline solution, using positive pressure. Heparin Group (212 patients): wash with 10 ml^† † ml = Milliliters; < saline solution followed by a block with 5 ml^† † ml = Milliliters; < heparin (10 IU/ml^‡ ‡ International units per milliliter; ).	CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; 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^* * CVC-TI = Totally Implanted Central Venous Catheter; .	Heparin Group (270 patients): maintenance consisting of 1.5 ml^† † ml = Milliliters; < of 0.9% saline solution with heparin content (100 IU/ml^‡ ‡ International units per milliliter; ). Saline Solution Group (592 patients): maintenance with 1.5 ml^† † ml = Milliliters; < of 0.9% saline solution.	Regarding CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; 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^† † ml = Milliliters; < saline solution before and after blood collection and drug administration, every 8 weeks, when the device was not in use and with 20 ml^† † ml = Milliliters; < saline solution after administration of blood (components) or parenteral nutrition. Heparin Group (398 patients): block with 3 ml^† † ml = Milliliters; < 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.
E05. To evaluate the efficacy and safety of the normal saline solution for CVC-TI blocking procedures^* * CVC-TI = Totally Implanted Central Venous Catheter; .	Heparin Group (297 patients): wash with heparinized solution (500 IU/10 ml^‡ ‡ International units per milliliter; ) Saline Solution Group (313 patients): 10 ml^† † ml = Milliliters; < normal saline solution.	The results do not show statistically significant differences with regard to catheter obstruction.
E06. To demonstrate that a longer maintenance interval for CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; can be safe, convenient, and more efficient.	Washing the catheter with 10 ml^† † ml = Milliliters; < saline solution followed by a block with 5 ml^† † ml = Milliliters; < heparin (100 IU/ml^‡ ‡ International units per milliliter; ). 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.
E07. To evaluate the efficacy and safety of the normal saline solution in the practice of maintaining CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; in cancer patients	Heparin Group (194 patients): wash twice a month with heparinized solution (20 ml^† † ml = Milliliters; < normal saline solution and 5,000 IU/ml^‡ ‡ International units per milliliter; unfractionated heparin). Saline Solution Group (190 patients): wash the catheter with 20 ml^† † ml = Milliliters; < saline solution twice a month.	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^* * CVC-TI = Totally Implanted Central Venous Catheter; 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^† † ml = Milliliters; < saline solution is sufficient. Regarding the block, volumes should be minimal and based on the prime of the catheter. A maximum of 1 ml^† † ml = Milliliters; < 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^§ § CVC = Central Venous Catheter occlusion rate maintained with heparin compared to CVC^§ § CVC = Central Venous Catheter 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^* * CVC-TI = Totally Implanted Central Venous Catheter; devices every eight weeks, instead of every four weeks, to maintain the patency of the device.	A wash with 20 ml^† † ml = Milliliters; < normal saline solution, followed by a block with 3 ml^† † ml = Milliliters; < sodium heparin (250 IU/5 ml^‡ ‡ International units per milliliter; ) 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^* * CVC-TI = Totally Implanted Central Venous Catheter; irrigated every four weeks, instead of every eight weeks.
E11. To compare the survival time, function, and complication rates of double lumen CVC^§ § CVC = Central Venous Catheter use versus CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; for chemotherapy in patients with leukemia.	CVC-TI Group^* * CVC-TI = Totally Implanted Central Venous Catheter; (19 patients): wash with 5 ml^† † ml = Milliliters; < heparinized saline solution (100 IU/ml^‡ ‡ International units per milliliter; ) after each use or at least once a month. Double lumen CVC^§ § CVC = Central Venous Catheter (24 patients): wash with 5 ml^† † ml = Milliliters; < heparinized saline solution (12.5 IU/ml^‡ ‡ International units per milliliter; ) after use and at least twice a week.	There was no significant difference between the two groups regarding the catheter survival time. CVC^§ § CVC = Central Venous Catheter occlusion was noted on 14 occasions in seven patients; and CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; occlusion, in 3 patients.
E12. To compare the safety and efficacy of administering a larger dose of heparin (1,000 IU/ml^‡ ‡ International units per milliliter; ) and flushes every 6 weeks, versus standard dose and schedule (500 IU/ml^‡ ‡ International units per milliliter; every 4 weeks), to reduce the incidence of CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; -related infections and thrombosis.	For catheter maintenance after chemotherapy. Group 1 (59 patients): they received 1,000 IU/ml^‡ ‡ International units per milliliter; heparin in 3 ml^† † ml = Milliliters; < normal saline solution every 6 weeks. Group 2 (30 patients): they received 500 IU/ml^‡ ‡ International units per milliliter; heparin in 3.5 ml^† † ml = Milliliters; < normal saline solution every 4 weeks.	Maintaining catheter patency with 1,000 IU/ml^‡ ‡ International units per milliliter; 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^* * CVC-TI = Totally Implanted Central Venous Catheter; in cancer patients undergoing chemotherapy.	Both the control (152 patients with Groshong catheter) and the intervention (152 patients with CVC-TI^* * CVC-TI = Totally Implanted Central Venous Catheter; ) groups received 5 ml^† † ml = Milliliters; < heparin (50 IU/ml^‡ ‡ International units per milliliter; ) for catheter maintenance every 28 days.	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^* * CVC-TI = Totally Implanted Central Venous Catheter; in terms of early and late complications. With regard to catheter obstruction, there was no difference between the two.

Studies	Heparin concentration (IU/ml^* * IU/ml = International units per milliliter; )	Heparin volume	Total heparin concentration	Maintenance interval
E 01	100 IU/ml^* * IU/ml = International units per milliliter;	5 ml^† † ml = Milliliters;	500 IU^§ § IU = International units	90 days
E 02	10 IU/ml^* * IU/ml = International units per milliliter;	5 ml^† † ml = Milliliters;	50 IU^§ § IU = International units	20 days
E 03	100 IU/ml^* * IU/ml = International units per milliliter;	1.5 ml^† † ml = Milliliters;	150 IU^§ § IU = International units	28 days
E 04	100 IU/ml^* * IU/ml = International units per milliliter;	3 ml^† † ml = Milliliters;	300 IU^§ § IU = International units	56 days
E 05	500 IU/ml^* * IU/ml = International units per milliliter;	10 ml^† † ml = Milliliters; of the solution^‡ ‡ solution = Solution composed of the heparin concentration reported in the table, combined with this quoted volume of saline solution;	500 IU^§ § IU = International units	28 days
E 06	100 IU/ml^* * IU/ml = International units per milliliter;	5 ml^† † ml = Milliliters;	500 IU^§ § IU = International units	38 days
E 07	5000 IU/ml^* * IU/ml = International units per milliliter;	20 ml^† † ml = Milliliters; of the solution^‡ ‡ solution = Solution composed of the heparin concentration reported in the table, combined with this quoted volume of saline solution;	5000 IU^§ § IU = International units	15 days
E 08	100 IU/ml^* * IU/ml = International units per milliliter;	2.5 ml^† † ml = Milliliters;	250 IU^§ § IU = International units	42-56 days
E 09	100 IU/ml^* * IU/ml = International units per milliliter;	3 ml^† † ml = Milliliters;	300 IU^§ § IU = International units	28 days
E 10	250 IU/5 ml^* * IU/ml = International units per milliliter;	3 ml^† † ml = Milliliters;	750 IU^§ § IU = International units	28-56 days
E 11	100 IU/ml^* * IU/ml = International units per milliliter;	5 ml^† † ml = Milliliters;	500 IU^§ § IU = International units	28 days
E 12	1,000 IU/ml^* * IU/ml = International units per milliliter; and 500 IU/ml^* * IU/ml = International units per milliliter;	3 ml^† † ml = Milliliters; and 3.5 ml^† † ml = Milliliters;	3000 IU^§ § IU = International units and 1,750 IU^§ § IU = International units	28 and 42 days
E 13	50 IU/ml^* * IU/ml = International units per milliliter;	5 ml^† † ml = Milliliters;	250 IU^§ § IU = International units	28 days

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[1] Corresponding author: Francisca Jane Gomes de Oliveira E-mail: jane3876@gmail.com https://orcid.org/0000-0002-4401-2009