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Comparison between Saline Solution Containing Heparin versus Saline Solution in the Lock of Totally Implantable Catheters
Accepted Manuscript Comparison Between Saline Solution Containing Heparin Versus Saline Solution in the Lock of Totally Implantable Catheters A.R.O. Brito, K. Nishinari, P.F. Saad, K.R. Saad, M.A.T. Pereira, S.C.D. Emídio, G. Yazbek, G.A.Z. Bomfim, R.N. Cavalcante, M. Krutman, M.P. Teivelis, B.S. Pignataro, I.Y.I. Fonseca, G. Centofanti, B.L.F. Soares PII:
S0890-5096(17)31011-7
DOI:
10.1016/j.avsg.2017.09.015
Reference:
AVSG 3597
To appear in:
Annals of Vascular Surgery
Received Date: 29 June 2017 Revised Date:
29 August 2017
Accepted Date: 7 September 2017
Please cite this article as: Brito A, Nishinari K, Saad P, Saad K, Pereira M, Emídio S, Yazbek G, Bomfim G, Cavalcante R, Krutman M, Teivelis M, Pignataro B, Fonseca I, Centofanti G, Soares B, Comparison Between Saline Solution Containing Heparin Versus Saline Solution in the Lock of Totally Implantable Catheters, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2017.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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COMPARISON BETWEEN SALINE SOLUTION CONTAINING HEPARIN
2
VERSUS SALINE SOLUTION IN THE LOCK OF TOTALLY IMPLANTABLE
3
CATHETERS
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BRITO ARO1; NISHINARI K2; SAAD PF3; SAAD KR4; PEREIRA MAT5;
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EMÍDIO SCD6; YAZBEK G7; BOMFIM GAZ8; CAVALCANTE RN9; KRUTMAN
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M10; TEIVELIS MP11; PIGNATARO BS12; FONSECA IYI13; CENTOFANTI G14;
8
SOARES BLF15.
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9
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1-
Antonio Rafael de Oliveira Brito, MD. Department of Vascular and Endovascular Sugery of San Francisco
2-
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Valley University Hospital.
Kenji Nishinari, MD, PhD, Head of Department of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
Paulo Fernandes Saad, PhD, San Francisco Valley Federal University Teacher.
4-
Karen Ruggeri Saad, PhD, San Francisco Valley Federal University Teacher.
5-
Monica Aparecida Tomé Pereira, PhD, San Francisco Valley Federal University Teacher.
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Suellen Cristina Dias Emidio, MSc Nurse. PhD Student in Unicamp University.
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Guilherme Yazbek, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
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Guilherme Andre Zottele Bomfim, MD, MSc, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
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Rafael Noronha Cavalcante, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo
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Cancer Center. 10- Mariana Krutman, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
11- Marcelo Passos Teivelis, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
Center.
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12- Bruno Soriano Pignataro, MD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer
13- Igor Yoshio Imagawa Fonseca, MD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
14- Guilherme Centofanti, MD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer
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Center.
15- Bruno Leonardo Freitas Soares, MD, MSc, Federal University of Alagoas Teacher.
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Corresponding author: Antonio Rafael de Oliveira Brito
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E-mail adress: [email protected]
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Adress: Beethoven street, 50 City: Petrolina, State: Pernambuco, Contry: Brazil
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Zip code: 56332-455
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Phone Number: +55 (87) 98115-5050
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ABSTRACT
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Introduction: there are only three studies comparing the efficacy of two
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different types of lock used in totally implantable catheters regarding occlusion
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or reflux dysfunction. The present study contains the largest published casuistry
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(862 patients) and is the only that analyzes three parameters: occlusion, reflux
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dysfunction and flow dysfunction. Method: it was a retrospective study of
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patients operated at a large oncology center and followed up in the outpatient
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clinic between 2007 and 2015. The patients were divided in two groups
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according to the type of lock: the Hep group, whose lock was composed of
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saline solution 0,9% with heparin (100 IU / ml) and the SS group, whose lock
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was composed of saline solution 0,9%. Results: the Hep group was composed
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of 270 patients (31%) and the SS group of 592 patients (69%). Regarding
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occlusion, there were eight cases in the Hep group (2,96%) and eight in the SS
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group (1,35%) (p = 0,11); in relation to reflux dysfunction, there were eight
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cases in the Hep group (2,96%) and eight in the SS group (1,35%) (p = 0,11); in
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relation to flow dysfunction there was one case in the Hep group (0,37%) and
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four cases in the SS group (0,68%) (p = 1). Conclusions: there was no
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statistically significant difference between the groups regarding occlusion, reflux
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dysfunction and flow dysfunction.
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INTRODUCTION
In 1982 there was a great innovation in the segment of central venous
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access, when Niederhuber1 described the first results of a fully implantable
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device (port). This device has revolutionized the treatment of patients with
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malignant neoplasias and is indicated mainly for intermittent access in the long
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term, with great practicality and comfort for the patients.2
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The ideal functioning of the device consists on fluid infusion without any
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kind of resistance (flow) and blood aspiration without resistance either (reflux).
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A catheter with reflux dysfunction shows normal flow and absence of reflux. A
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catheter with flow dysfunction shows a resistance during the inflow (usually
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possible with an infusion device) and usually presents an abnormal reflux too.
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The reflux dysfunction is the main mechanical complication of these devices. Reflux and flow dysfunctions are undesirable complications, since they
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prevent collection of blood samples, prolong the time of the chemotherapy
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session and can evolve to occlusion of the device.3 For this reason, their proper
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management between the chemotherapy sessions or during their outpatient
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maintenance is fundamental.4
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As in all central venous catheters, at the end of their use the port is filled
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with a solution (lock) up to a new handle.5 There is still no consensus regarding
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the ideal substance used in the lock, nor the time interval for changing the lock
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in the outpatient maintenance phase.
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There are only three studies comparing the efficacy of maintenance of
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ports with saline solution or saline solution containing heparin regarding
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occlusion or reflux dysfunction.6
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The present study contains the largest published casuistry (862 patients)
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and is the only that analyzes three parameters: occlusion, reflux dysfunction
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and flow dysfunction.
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OBJECTIVE
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The objective of this study was to compare two types of lock (saline
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solution 0,9% containing heparin versus saline solution 0,9%) in the
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maintenance of the ports regarding to: 1. occlusion (absence of flow and reflux),
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2. reflux dysfunction (normal flow without reflux) and 3. flow dysfunction
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(abnormal flow and abnormal reflux).
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PATIENTS AND METHODS
It was an observational retrospective study with data collection from the
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electronic charts (MV2000 system instituted in 2007) of patients treated at the
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AC Camargo Cancer Center in São Paulo from 2007 to 2015.
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The inclusion criteria were:
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. patients over 18 years of age who underwent port implantation at the AC Camargo Cancer Center.
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. non-valved devices with catheter 8,0 Fr
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. patients on outpatient follow-up receiving chemotherapy or performing
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maintenance after completion of chemotherapy (without any manipulation of the
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device for some weeks).
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The criteria for non-inclusion were:
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. patients with port dysfunction related to: deep venous thrombosis, fracture, kinking, migration or drug precipitation.
. patients submitted to any kind of anticoagulation therapy
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. hospitalized patients
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The patients were divided in two groups: Hep group, with patients
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attended between 2007 and 2009, whose lock was composed of saline solution
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0,9% containing heparin at a concentration of 100 IU / ml; and, SS group with
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patients attended between 2009 and 2015 whose lock was composed of saline
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solution 0,9%.
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The ports were filled with 1,5 mL of each solution (enough volume to fill
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the prime) and the locks were changed every four weeks or after the
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chemotherapy infusion.
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STATISTICAL ANALYSIS
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Data was presented by means of frequency tables and by the media when appropriate.
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Statistical analysis was performed using the R-Program software.
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Fischer's exact test was used to compare the groups in relation to the
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qualitative variables. In all the results obtained by the inferential analysis, the
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significance level of 5% was adopted.
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RESULTS
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A total of 862 patients were included, with the Hep group consisting of 270 patients (31%) and the SS group (592 patients) (69%).
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The distribution of sex between the two groups is shown in table 1.
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Table 1: distribution of patients in relation to sex.
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Regarding age, in the Hep group it ranged from 18 to 86 years with a
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median of 56 (mean 53) and in the SS group ranged from 19 to 85 years with a
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median of 56 (mean 54).The follow-up time was higher in the SS group, ranging
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from one to 1760 days (median 330 and average 363 days), whereas in the
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Hep group it ranged from ten to 900 days (median 240 and average 272 days).
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Regarding occlusion, there were eight cases (2,96%) in the Hep group
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and eight cases (1,35%) in the SS group. There was no statistical difference
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between the groups (p = 0,11) (Table 2).
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Table 2. Incidence of occlusion
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Eight patients (2,96%) in the Hep group presented dysfunction and eight
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patients (1,35%) in the SS group had dysfunction, and there were no statistical
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differences between the groups (p = 0,11) (Table 3).
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Table 3. Incidence of reflux dysfunction
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In relation to the flow, there was one case of dysfunction (0,37%) in the
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Hep Group and four (0,68%) cases in the SS Group, and there was no
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significant statistical difference between the groups (Table 4). Table 4. Incidence of flow dysfunction
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DISCUSSION
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Ports are essential in the treatment of many patients with malignant
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neoplasms. The instillation of saline solution before and after the use of the
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device, being complemented at the end with the lock aims to avoid
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accumulation and/or deposition of blood, fibrin and substances that can lead to
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its mechanical dysfunction or contamination.7
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For many years heparin diluted in saline solution is used as a central catheter lock to prevent occlusion.8
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The use of heparin is based on the fact that it is an anticoagulant
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substance, therefore it would minimize the indices of their mechanical
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complications like dysfunction and the occlusion. However, it has not yet been
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studied whether the heparin contained in the catheter lock remains with its
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anticoagulant properties, nor what is the duration of this effect. In many services, maintenance performed with heparin consists of
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adequate dilution of the heparin, implying greater handling and care in relation
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to a simple lock with saline solution.9
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Adverse reactions or side effects to heparin use are described when
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systemically employed as thrombocytopenia, iatrogenic overdose, drug
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incompatibility and microbial contamination.6 Instillation of central venous
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catheters with heparin seems to be a safe practice, but the possibility of
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heparin-induced thrombocytopenia, thrombocytopenia and thrombosis induced
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by heparin, allergic reactions, drug incompatibility and the possibility of
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iatrogenic hemorrhage arise as a threat in some patients. In addition, there are
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concerns regarding the cost of heparin versus saline 0,9%.10
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Garajová et al11 reported a patient with hypersensitivity reaction to
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heparin contained in the lock of a port characterized by facial and palmar
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erythema, rhinitis, lacrimation, nausea and vomiting. He was treated with
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systemic corticoid and antihistamine, with complete reversal of symptoms. In the case of short term central catheters, there are three meta-analises
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that analyze saline and saline containing heparin in the locks of these devices.
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The three studies did not show differences between these two types of
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locks for occlusion indices using heparin at concentrations ranging from 10 IU /
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ml to 5.000 IU / ml.
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In relation to long term central catheters, there are few published articles.
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In a prospective randomized study15 containing 102 patients undergoing
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peripheral insertion central catheter (PICC) implantation, the objective was to
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compare occlusion rates. In the group of 50 patients whose lock was composed
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of saline solution there were six occlusions (6%), whereas in the group of 52
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patients whose lock was composed of saline containing heparin (100 IU / ml)
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there was no occlusion, however without statistically difference between the
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groups.
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Lyons and colleagues16 published a prospective randomized study in
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patients with PICC who were divided into 3 groups with different types of lock:
ACCEPTED MANUSCRIPT group 1 (28 patients) with saline solution, group 2 (30 patients) with saline
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solution and heparin at the concentration of 10 IU / ml and group 3 (32 patients)
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with saline solution and heparin at a concentration of 100 IU / ml. The analyzed
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parameters were: flow dysfunction, occlusion, catheter replacement, additional
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nursing visits and use of alteplase. Each of the study groups had patients who
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experienced one or more patency-related complications. Additional factors that
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may affect catheter function, including age, gender, diagnosis, type of therapy,
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catheter use frequency, catheter size, catheter diameter, catheter lumens,
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concomitant use of anticoagulants, and the catheter was used for routine
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laboratory exams, were analyzed, and no statistical significance was
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determined. Duration of catheter use was statistically significant (p = 0,003,
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confidence interval: 95%) and confirmed that the longer the time of implantation
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and use of the catheter in the patient in home care, the more complications will
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occur. There were no cases of allergic reaction to heparin, heparin-induced
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thrombocytopenia, or infection of the catheter. The data provide some evidence
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to eliminate heparin in the lock of patients in home care with PICC.
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Beigi and colleagues17 published a prospective randomized study of 96
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patients who underwent implantation of semi-implantable catheters for
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hemodialysis. In a group of 47 patients the lock was composed of saline
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solution with heparin (1.000 IU / mL) and in another group of 49 patients the
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lock was composed of saline solution. The patients were followed up for 24
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hours, and the objectives were to compare the occlusion indexes and the
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maneuvers necessary to maintain the patency. There was no catheter occlusion
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in both groups. Two patients (4,2%) in the heparin group and three patients
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(6,1%) in the saline group required manipulation (lavage or mobilization of the
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catheter) to maintain patency (p = 0,520), therefore the saline solution was as
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effective as the serum containing heparin in the maintenance of these
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catheters.
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Regarding the ports, there are only three studies comparing maintenance
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with saline and saline containing heparin, however, none of them addresses the
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three parameters analyzed in our study.
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The retrospective study by Bertoglio et al18 included 610 patients and the
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objective was to compare the occlusion index between two groups. The
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maintenance of group A (297 patients) was done with saline containing heparin
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(50 IU / ml) and group B (313 patients) with saline solution. The mean follow-up
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time was 413 days for group A and 386 days for group B. Occlusion was
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observed in 20 patients in group A (3,2%) and 18 (2,9%) in group B, without
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statistical difference (p = 0,907). The difference between our study and that of Bertoglio is that we used a
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higher concentration of heparin (100 IU / ml), however there was also no
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statistical difference in occlusion indices between the groups.
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The randomized study by Goossens et al6 contained 765 patients and
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the objective was to compare the reflux dysfunction index between two groups.
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In a group of 383 patients the lock was composed of saline with heparin (100 IU
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/ ml) and in the other group of 382 patients the lock was composed of saline
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solution. Seventy eight patients (20,4%) from the saline group and 73 patients
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(19,1%) from the heparin group had at least one episode of reflux dysfunction.
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Considering the total number of accesses to the ports in the groups, the reflux
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dysfunction indexes were 3,92% in the heparin group and 3,70% in the saline
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group, with no statistically significant difference between the groups.
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In our study, in relation to reflux dysfunction we also did not find significant difference between the groups, using the same dilution of heparin. Finally, the study by Dal Molin et al19 aimed to determine the non-
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inferiority of the saline solution lock compared to the saline solution with heparin
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lock (50 IU / ml) for reflux dusfunction and occlusion indexes. A total of 415
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patients were randomly assigned to two groups: 203 patients in the saline group
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and 212 in the heparin group. The median follow-up was 204 days in the saline
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group and 294 days in the heparin group. The reflux dysfunction occurred in ten
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patients in the heparin group (4,71%) and 14 (6,90%) in the saline group, there
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was only one occlusion (0,49%) occurring in the saline group. It was not
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possible to prove the non-inferiority of the saline solution lock in this study.
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CONCLUSION
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When comparing the occlusion, reflux dysfunction and flow dysfunction
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indexes between two groups of patients with fully implantable catheters using
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two types of lock (saline or saline containing heparin), we did not find any
280
differences between the groups.
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REFERENCES 1) NIEDERHUBER JE, et al. Totally implanted venous and arterial access
285
system to replace external catheters in cancer treatment. Surgery. 1982;
286
92:706-712.
RI PT
284
287
2) BOMFIM GAZ, et al. Comparative Study of Valved and Nonvalved Fully
288
Implantable Catheters Inserted Via Ultrasound-Guided Puncture for
289
Chemotherapy. Ann Vasc Surg. 2014 Feb; 28(2):351-7.
3) GREGORY NADOLSKI, RICHARD D. SHLANSKY-GOLDBERG, S.
291
WILLIAM STAVROPOULOS et. al. Chest Radiograph–based Algorithm
292
for Managing Malfunctioning Ports. J Vasc Interv Radiol 2013; 24:1337–
293
1342.
M AN U
SC
290
294
4) R. BIFFI, S. POZZI, A. AGAZZI et al; Use of totally implantable central
295
venous access ports for high-dose chemotherapy and peripheral blood
296
stem cell transplantation: results of a monocentre series of 376 patients.
297
Annals of Oncology 2004; 15: 296–300.
299
5) DAL MOLIN A. et al. Flushing the central venous catheter: is heparin necessary? Journal Vascular Acess, 2014; v. 15, n. 4, p. 241-248.
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298
6) GOOSSENS GA et al. Comparing normal saline versus diluted heparin
301
to lock non-valved totally implantable venous access devices in cancer
302
patients: a randomized, non-inferiority, open trial. Annals of Oncology.
303
2013 v. 24, p. 1892-1899.
EP
300
7) GOOSSENS GA et al. Management of functional complications of totally
305
implantable venous access devices by an advanced practice nursing
306 307 308
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304
team: 5 years of clinical experience. Eur J Oncol Nurs, 2012; v. 16, p.465-471.
8) KIMBERLY PETERSON, MARY D. GORDON. The Development of
309
Central Venous Access Device Flushing Guidelines Utilizing an
310
Evidence-Based Practice Process. Journal of Pediatric Nursing (2013)
311
28, 85–88.
312
9) GOODE CJ ET AL. A META-ANALYSIS OF EFFECTS OF HEPARIN
313
FLUSH AND SALINE FLUSH: QUALITY AND COST IMPLICATIONS.
314
NURS RES, 1991 V. 40, P.324-330.
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10) MARK A. JONKER, KURT R. OSTERBY, LEE C. VERMEULEN et al.
316
Does Low-Dose Heparin Maintain Central Venous Access Device
317
Patency? A Comparison of Heparin Versus Saline During a Period of
318
Heparin Shortage. Journal of Parenteral and Enteral Nutrition. 2010,
319
July; Volume 34 Number 4 p. 444-449. 11) GARAJOVÁ I. et al. Port-a-Cath related complications in 252 patients
321
with solid issue tumors and the first report of heparin-induced delayed
322
hypersensitivity after Port-a-Cath heparinisation. European Journal of
323
Cancer Care, 2013, 22, 125-132.
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12) LÓPEZ-BRIZ E, RUIZ GARCIA V, CABELLO JB, BORT-MARTI S,
325
CARBONELL SANCHIS R, BURLS A.Cochrane Database Syst Rev.
326
2014 Oct 8;(10):CD008462.
SC
324
13) SANTOS EJ, NUNES MM, CARDOSO DF, APÓSTOLO JL, QUEIRÓS
328
PJ, RODRIGUES MA.Effectiveness of heparin versus 0.9% saline
329
solution in maintaining the permeability of central venous catheters: a
330
systematic review]. Rev Esc Enferm USP. 2015 Dec; 49(6):999-1007.
331
14) ZHONG L, WANG HL, XU B, YUAN Y, WANG X, ZHANG YY, JI L, PAN
332
ZM, HU ZS. Normal saline versus heparin for patency of central venous
333
catheters in adult patients - a systematic review and meta-analysis. Crit
334
Care. 2017 Jan 8; 21(1): 5.
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335
M AN U
327
15) BOWERS L, SPERONI KG, JONES L, ATHERTON M. Comparison of occlusion
337
inserted central catheters with positive pressure Luer-activated devices.
338
J Infus Nurs. 2008 Jan-Feb; 31(1):22-7.
340 341 342 343
16) LYONS
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rates
by
flushing
solutions
for
peripherally
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336
MG,
PHALEN
AG.
A randomized controlled comparison of flushing protocols in home care p atient with peripherally inserted central catheters. J Infus Nurs. 2014 JulAug; 37(4):270-81.
17) BEIGI AA1, HADIZADEH
MS1, SALIMI
F1, GHAHERI
H1.
Heparin
344
compared with normal saline to maintain patency of permanent double
345
lumen hemodialysis catheters: A randomized controlled trial. Adv Biomed
346
Res. 2014 May 28; 3: 121.
347
18) SERGIO BERTOGLIO, NICOLA SOLARI, PAOLO MESZAROS, ET AL.
348
Efficacy of Normal Saline Versus Heparinized Saline Solution for Locking
ACCEPTED MANUSCRIPT 349
Catheters of Totally Implantable Long-Term Central Vascular Access
350
Devices in Adult Cancer Patients. Cancer Nursing TM, 2012. Vol. 35, No.
351
4.
352
19) DAL
MOLIN
A, CLERICO
M, BACCINI
M, GUERRETTA
B, RASERO
L.
L, SARTORELLO
354
Normal saline versus heparin solution to lock totally implanted venous ac
355
cess devices: Results from a multicenter randomized trial. Eur J Oncol
356
Nurs. 2015 Dec;19(6):638-43.
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ACCEPTED MANUSCRIPT Sex
Hep Group
SS Group
Male
151 (55.93%)
273 (46.11%)
Female
119 (44.07%)
319 (53.89%)
Total
270 (100%)
592 (100%)
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Table 1: distribution of patients in relation to sex.
ACCEPTED MANUSCRIPT Oclusion
Hep Group
SS Group
p-value*
Yes
8 (2.96%)
8 (1.35%)
0.11
No
262 (97.04%)
584 (98.65%)
*Fischer
exact
test
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Table 2. Incidence of occlusion
ACCEPTED MANUSCRIPT Reflux dysfunction
Hep Group
SS Group
p-value*
Yes
8 (2.96%)
8 (1.35%)
0.11
No
262 (97.04%)
584 (98.65%)
* Fischer exact test
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Table 3. Incidence of reflux dysfunction
ACCEPTED MANUSCRIPT Flow dysfunction
Hep Group
SS Group
p-value*
Yes
1 (0.37%)
4 (0.68%)
1
No
269 (99.63%)
588 (99.32%)
* Fischer exact test
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Table 4. Incidence of flow dysfunction
S0890-5096(17)31011-7
DOI:
10.1016/j.avsg.2017.09.015
Reference:
AVSG 3597
To appear in:
Annals of Vascular Surgery
Received Date: 29 June 2017 Revised Date:
29 August 2017
Accepted Date: 7 September 2017
Please cite this article as: Brito A, Nishinari K, Saad P, Saad K, Pereira M, Emídio S, Yazbek G, Bomfim G, Cavalcante R, Krutman M, Teivelis M, Pignataro B, Fonseca I, Centofanti G, Soares B, Comparison Between Saline Solution Containing Heparin Versus Saline Solution in the Lock of Totally Implantable Catheters, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2017.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
COMPARISON BETWEEN SALINE SOLUTION CONTAINING HEPARIN
2
VERSUS SALINE SOLUTION IN THE LOCK OF TOTALLY IMPLANTABLE
3
CATHETERS
4
BRITO ARO1; NISHINARI K2; SAAD PF3; SAAD KR4; PEREIRA MAT5;
6
EMÍDIO SCD6; YAZBEK G7; BOMFIM GAZ8; CAVALCANTE RN9; KRUTMAN
7
M10; TEIVELIS MP11; PIGNATARO BS12; FONSECA IYI13; CENTOFANTI G14;
8
SOARES BLF15.
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5
9
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Antonio Rafael de Oliveira Brito, MD. Department of Vascular and Endovascular Sugery of San Francisco
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Valley University Hospital.
Kenji Nishinari, MD, PhD, Head of Department of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
Paulo Fernandes Saad, PhD, San Francisco Valley Federal University Teacher.
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Karen Ruggeri Saad, PhD, San Francisco Valley Federal University Teacher.
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Monica Aparecida Tomé Pereira, PhD, San Francisco Valley Federal University Teacher.
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Suellen Cristina Dias Emidio, MSc Nurse. PhD Student in Unicamp University.
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Guilherme Yazbek, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
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Guilherme Andre Zottele Bomfim, MD, MSc, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
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Rafael Noronha Cavalcante, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo
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Cancer Center. 10- Mariana Krutman, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
11- Marcelo Passos Teivelis, MD, PhD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
Center.
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12- Bruno Soriano Pignataro, MD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer
13- Igor Yoshio Imagawa Fonseca, MD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer Center.
14- Guilherme Centofanti, MD, Departament of Vascular and Endovascular Surgery - AC Camargo Cancer
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Center.
15- Bruno Leonardo Freitas Soares, MD, MSc, Federal University of Alagoas Teacher.
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Corresponding author: Antonio Rafael de Oliveira Brito
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E-mail adress: [email protected]
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Adress: Beethoven street, 50 City: Petrolina, State: Pernambuco, Contry: Brazil
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Zip code: 56332-455
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Phone Number: +55 (87) 98115-5050
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ABSTRACT
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Introduction: there are only three studies comparing the efficacy of two
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different types of lock used in totally implantable catheters regarding occlusion
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or reflux dysfunction. The present study contains the largest published casuistry
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(862 patients) and is the only that analyzes three parameters: occlusion, reflux
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dysfunction and flow dysfunction. Method: it was a retrospective study of
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patients operated at a large oncology center and followed up in the outpatient
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clinic between 2007 and 2015. The patients were divided in two groups
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according to the type of lock: the Hep group, whose lock was composed of
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saline solution 0,9% with heparin (100 IU / ml) and the SS group, whose lock
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was composed of saline solution 0,9%. Results: the Hep group was composed
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of 270 patients (31%) and the SS group of 592 patients (69%). Regarding
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occlusion, there were eight cases in the Hep group (2,96%) and eight in the SS
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group (1,35%) (p = 0,11); in relation to reflux dysfunction, there were eight
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cases in the Hep group (2,96%) and eight in the SS group (1,35%) (p = 0,11); in
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relation to flow dysfunction there was one case in the Hep group (0,37%) and
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four cases in the SS group (0,68%) (p = 1). Conclusions: there was no
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statistically significant difference between the groups regarding occlusion, reflux
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dysfunction and flow dysfunction.
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INTRODUCTION
In 1982 there was a great innovation in the segment of central venous
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access, when Niederhuber1 described the first results of a fully implantable
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device (port). This device has revolutionized the treatment of patients with
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malignant neoplasias and is indicated mainly for intermittent access in the long
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term, with great practicality and comfort for the patients.2
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The ideal functioning of the device consists on fluid infusion without any
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kind of resistance (flow) and blood aspiration without resistance either (reflux).
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A catheter with reflux dysfunction shows normal flow and absence of reflux. A
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catheter with flow dysfunction shows a resistance during the inflow (usually
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possible with an infusion device) and usually presents an abnormal reflux too.
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The reflux dysfunction is the main mechanical complication of these devices. Reflux and flow dysfunctions are undesirable complications, since they
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prevent collection of blood samples, prolong the time of the chemotherapy
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session and can evolve to occlusion of the device.3 For this reason, their proper
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management between the chemotherapy sessions or during their outpatient
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maintenance is fundamental.4
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As in all central venous catheters, at the end of their use the port is filled
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with a solution (lock) up to a new handle.5 There is still no consensus regarding
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the ideal substance used in the lock, nor the time interval for changing the lock
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in the outpatient maintenance phase.
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There are only three studies comparing the efficacy of maintenance of
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ports with saline solution or saline solution containing heparin regarding
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occlusion or reflux dysfunction.6
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The present study contains the largest published casuistry (862 patients)
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and is the only that analyzes three parameters: occlusion, reflux dysfunction
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and flow dysfunction.
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OBJECTIVE
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The objective of this study was to compare two types of lock (saline
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solution 0,9% containing heparin versus saline solution 0,9%) in the
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maintenance of the ports regarding to: 1. occlusion (absence of flow and reflux),
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2. reflux dysfunction (normal flow without reflux) and 3. flow dysfunction
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(abnormal flow and abnormal reflux).
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PATIENTS AND METHODS
It was an observational retrospective study with data collection from the
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electronic charts (MV2000 system instituted in 2007) of patients treated at the
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AC Camargo Cancer Center in São Paulo from 2007 to 2015.
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The inclusion criteria were:
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. patients over 18 years of age who underwent port implantation at the AC Camargo Cancer Center.
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. non-valved devices with catheter 8,0 Fr
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. patients on outpatient follow-up receiving chemotherapy or performing
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maintenance after completion of chemotherapy (without any manipulation of the
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device for some weeks).
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The criteria for non-inclusion were:
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. patients with port dysfunction related to: deep venous thrombosis, fracture, kinking, migration or drug precipitation.
. patients submitted to any kind of anticoagulation therapy
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. hospitalized patients
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The patients were divided in two groups: Hep group, with patients
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attended between 2007 and 2009, whose lock was composed of saline solution
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0,9% containing heparin at a concentration of 100 IU / ml; and, SS group with
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patients attended between 2009 and 2015 whose lock was composed of saline
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solution 0,9%.
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The ports were filled with 1,5 mL of each solution (enough volume to fill
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the prime) and the locks were changed every four weeks or after the
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chemotherapy infusion.
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STATISTICAL ANALYSIS
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Data was presented by means of frequency tables and by the media when appropriate.
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Statistical analysis was performed using the R-Program software.
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Fischer's exact test was used to compare the groups in relation to the
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qualitative variables. In all the results obtained by the inferential analysis, the
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significance level of 5% was adopted.
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RESULTS
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A total of 862 patients were included, with the Hep group consisting of 270 patients (31%) and the SS group (592 patients) (69%).
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The distribution of sex between the two groups is shown in table 1.
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Table 1: distribution of patients in relation to sex.
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Regarding age, in the Hep group it ranged from 18 to 86 years with a
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median of 56 (mean 53) and in the SS group ranged from 19 to 85 years with a
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median of 56 (mean 54).The follow-up time was higher in the SS group, ranging
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from one to 1760 days (median 330 and average 363 days), whereas in the
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Hep group it ranged from ten to 900 days (median 240 and average 272 days).
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Regarding occlusion, there were eight cases (2,96%) in the Hep group
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and eight cases (1,35%) in the SS group. There was no statistical difference
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between the groups (p = 0,11) (Table 2).
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Table 2. Incidence of occlusion
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Eight patients (2,96%) in the Hep group presented dysfunction and eight
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patients (1,35%) in the SS group had dysfunction, and there were no statistical
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differences between the groups (p = 0,11) (Table 3).
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Table 3. Incidence of reflux dysfunction
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In relation to the flow, there was one case of dysfunction (0,37%) in the
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Hep Group and four (0,68%) cases in the SS Group, and there was no
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significant statistical difference between the groups (Table 4). Table 4. Incidence of flow dysfunction
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DISCUSSION
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Ports are essential in the treatment of many patients with malignant
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neoplasms. The instillation of saline solution before and after the use of the
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device, being complemented at the end with the lock aims to avoid
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accumulation and/or deposition of blood, fibrin and substances that can lead to
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its mechanical dysfunction or contamination.7
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For many years heparin diluted in saline solution is used as a central catheter lock to prevent occlusion.8
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The use of heparin is based on the fact that it is an anticoagulant
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substance, therefore it would minimize the indices of their mechanical
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complications like dysfunction and the occlusion. However, it has not yet been
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studied whether the heparin contained in the catheter lock remains with its
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anticoagulant properties, nor what is the duration of this effect. In many services, maintenance performed with heparin consists of
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adequate dilution of the heparin, implying greater handling and care in relation
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to a simple lock with saline solution.9
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Adverse reactions or side effects to heparin use are described when
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systemically employed as thrombocytopenia, iatrogenic overdose, drug
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incompatibility and microbial contamination.6 Instillation of central venous
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catheters with heparin seems to be a safe practice, but the possibility of
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heparin-induced thrombocytopenia, thrombocytopenia and thrombosis induced
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by heparin, allergic reactions, drug incompatibility and the possibility of
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iatrogenic hemorrhage arise as a threat in some patients. In addition, there are
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concerns regarding the cost of heparin versus saline 0,9%.10
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Garajová et al11 reported a patient with hypersensitivity reaction to
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heparin contained in the lock of a port characterized by facial and palmar
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erythema, rhinitis, lacrimation, nausea and vomiting. He was treated with
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systemic corticoid and antihistamine, with complete reversal of symptoms. In the case of short term central catheters, there are three meta-analises
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that analyze saline and saline containing heparin in the locks of these devices.
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The three studies did not show differences between these two types of
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locks for occlusion indices using heparin at concentrations ranging from 10 IU /
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ml to 5.000 IU / ml.
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In relation to long term central catheters, there are few published articles.
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In a prospective randomized study15 containing 102 patients undergoing
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peripheral insertion central catheter (PICC) implantation, the objective was to
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compare occlusion rates. In the group of 50 patients whose lock was composed
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of saline solution there were six occlusions (6%), whereas in the group of 52
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patients whose lock was composed of saline containing heparin (100 IU / ml)
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there was no occlusion, however without statistically difference between the
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groups.
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Lyons and colleagues16 published a prospective randomized study in
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patients with PICC who were divided into 3 groups with different types of lock:
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solution and heparin at the concentration of 10 IU / ml and group 3 (32 patients)
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with saline solution and heparin at a concentration of 100 IU / ml. The analyzed
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parameters were: flow dysfunction, occlusion, catheter replacement, additional
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nursing visits and use of alteplase. Each of the study groups had patients who
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experienced one or more patency-related complications. Additional factors that
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may affect catheter function, including age, gender, diagnosis, type of therapy,
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catheter use frequency, catheter size, catheter diameter, catheter lumens,
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concomitant use of anticoagulants, and the catheter was used for routine
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laboratory exams, were analyzed, and no statistical significance was
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determined. Duration of catheter use was statistically significant (p = 0,003,
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confidence interval: 95%) and confirmed that the longer the time of implantation
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and use of the catheter in the patient in home care, the more complications will
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occur. There were no cases of allergic reaction to heparin, heparin-induced
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thrombocytopenia, or infection of the catheter. The data provide some evidence
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to eliminate heparin in the lock of patients in home care with PICC.
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Beigi and colleagues17 published a prospective randomized study of 96
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patients who underwent implantation of semi-implantable catheters for
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hemodialysis. In a group of 47 patients the lock was composed of saline
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solution with heparin (1.000 IU / mL) and in another group of 49 patients the
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lock was composed of saline solution. The patients were followed up for 24
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hours, and the objectives were to compare the occlusion indexes and the
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maneuvers necessary to maintain the patency. There was no catheter occlusion
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in both groups. Two patients (4,2%) in the heparin group and three patients
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(6,1%) in the saline group required manipulation (lavage or mobilization of the
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catheter) to maintain patency (p = 0,520), therefore the saline solution was as
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effective as the serum containing heparin in the maintenance of these
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catheters.
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Regarding the ports, there are only three studies comparing maintenance
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with saline and saline containing heparin, however, none of them addresses the
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three parameters analyzed in our study.
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The retrospective study by Bertoglio et al18 included 610 patients and the
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objective was to compare the occlusion index between two groups. The
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maintenance of group A (297 patients) was done with saline containing heparin
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(50 IU / ml) and group B (313 patients) with saline solution. The mean follow-up
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time was 413 days for group A and 386 days for group B. Occlusion was
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observed in 20 patients in group A (3,2%) and 18 (2,9%) in group B, without
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statistical difference (p = 0,907). The difference between our study and that of Bertoglio is that we used a
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higher concentration of heparin (100 IU / ml), however there was also no
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statistical difference in occlusion indices between the groups.
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The randomized study by Goossens et al6 contained 765 patients and
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the objective was to compare the reflux dysfunction index between two groups.
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In a group of 383 patients the lock was composed of saline with heparin (100 IU
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/ ml) and in the other group of 382 patients the lock was composed of saline
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solution. Seventy eight patients (20,4%) from the saline group and 73 patients
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(19,1%) from the heparin group had at least one episode of reflux dysfunction.
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Considering the total number of accesses to the ports in the groups, the reflux
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dysfunction indexes were 3,92% in the heparin group and 3,70% in the saline
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group, with no statistically significant difference between the groups.
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In our study, in relation to reflux dysfunction we also did not find significant difference between the groups, using the same dilution of heparin. Finally, the study by Dal Molin et al19 aimed to determine the non-
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inferiority of the saline solution lock compared to the saline solution with heparin
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lock (50 IU / ml) for reflux dusfunction and occlusion indexes. A total of 415
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patients were randomly assigned to two groups: 203 patients in the saline group
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and 212 in the heparin group. The median follow-up was 204 days in the saline
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group and 294 days in the heparin group. The reflux dysfunction occurred in ten
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patients in the heparin group (4,71%) and 14 (6,90%) in the saline group, there
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was only one occlusion (0,49%) occurring in the saline group. It was not
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possible to prove the non-inferiority of the saline solution lock in this study.
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CONCLUSION
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When comparing the occlusion, reflux dysfunction and flow dysfunction
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indexes between two groups of patients with fully implantable catheters using
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two types of lock (saline or saline containing heparin), we did not find any
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differences between the groups.
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REFERENCES 1) NIEDERHUBER JE, et al. Totally implanted venous and arterial access
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system to replace external catheters in cancer treatment. Surgery. 1982;
286
92:706-712.
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2) BOMFIM GAZ, et al. Comparative Study of Valved and Nonvalved Fully
288
Implantable Catheters Inserted Via Ultrasound-Guided Puncture for
289
Chemotherapy. Ann Vasc Surg. 2014 Feb; 28(2):351-7.
3) GREGORY NADOLSKI, RICHARD D. SHLANSKY-GOLDBERG, S.
291
WILLIAM STAVROPOULOS et. al. Chest Radiograph–based Algorithm
292
for Managing Malfunctioning Ports. J Vasc Interv Radiol 2013; 24:1337–
293
1342.
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SC
290
294
4) R. BIFFI, S. POZZI, A. AGAZZI et al; Use of totally implantable central
295
venous access ports for high-dose chemotherapy and peripheral blood
296
stem cell transplantation: results of a monocentre series of 376 patients.
297
Annals of Oncology 2004; 15: 296–300.
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5) DAL MOLIN A. et al. Flushing the central venous catheter: is heparin necessary? Journal Vascular Acess, 2014; v. 15, n. 4, p. 241-248.
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6) GOOSSENS GA et al. Comparing normal saline versus diluted heparin
301
to lock non-valved totally implantable venous access devices in cancer
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patients: a randomized, non-inferiority, open trial. Annals of Oncology.
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2013 v. 24, p. 1892-1899.
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7) GOOSSENS GA et al. Management of functional complications of totally
305
implantable venous access devices by an advanced practice nursing
306 307 308
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team: 5 years of clinical experience. Eur J Oncol Nurs, 2012; v. 16, p.465-471.
8) KIMBERLY PETERSON, MARY D. GORDON. The Development of
309
Central Venous Access Device Flushing Guidelines Utilizing an
310
Evidence-Based Practice Process. Journal of Pediatric Nursing (2013)
311
28, 85–88.
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9) GOODE CJ ET AL. A META-ANALYSIS OF EFFECTS OF HEPARIN
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FLUSH AND SALINE FLUSH: QUALITY AND COST IMPLICATIONS.
314
NURS RES, 1991 V. 40, P.324-330.
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10) MARK A. JONKER, KURT R. OSTERBY, LEE C. VERMEULEN et al.
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Does Low-Dose Heparin Maintain Central Venous Access Device
317
Patency? A Comparison of Heparin Versus Saline During a Period of
318
Heparin Shortage. Journal of Parenteral and Enteral Nutrition. 2010,
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July; Volume 34 Number 4 p. 444-449. 11) GARAJOVÁ I. et al. Port-a-Cath related complications in 252 patients
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with solid issue tumors and the first report of heparin-induced delayed
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hypersensitivity after Port-a-Cath heparinisation. European Journal of
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Cancer Care, 2013, 22, 125-132.
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12) LÓPEZ-BRIZ E, RUIZ GARCIA V, CABELLO JB, BORT-MARTI S,
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CARBONELL SANCHIS R, BURLS A.Cochrane Database Syst Rev.
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2014 Oct 8;(10):CD008462.
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13) SANTOS EJ, NUNES MM, CARDOSO DF, APÓSTOLO JL, QUEIRÓS
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PJ, RODRIGUES MA.Effectiveness of heparin versus 0.9% saline
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solution in maintaining the permeability of central venous catheters: a
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systematic review]. Rev Esc Enferm USP. 2015 Dec; 49(6):999-1007.
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14) ZHONG L, WANG HL, XU B, YUAN Y, WANG X, ZHANG YY, JI L, PAN
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ZM, HU ZS. Normal saline versus heparin for patency of central venous
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catheters in adult patients - a systematic review and meta-analysis. Crit
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Care. 2017 Jan 8; 21(1): 5.
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15) BOWERS L, SPERONI KG, JONES L, ATHERTON M. Comparison of occlusion
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inserted central catheters with positive pressure Luer-activated devices.
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J Infus Nurs. 2008 Jan-Feb; 31(1):22-7.
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16) LYONS
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rates
by
flushing
solutions
for
peripherally
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MG,
PHALEN
AG.
A randomized controlled comparison of flushing protocols in home care p atient with peripherally inserted central catheters. J Infus Nurs. 2014 JulAug; 37(4):270-81.
17) BEIGI AA1, HADIZADEH
MS1, SALIMI
F1, GHAHERI
H1.
Heparin
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compared with normal saline to maintain patency of permanent double
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lumen hemodialysis catheters: A randomized controlled trial. Adv Biomed
346
Res. 2014 May 28; 3: 121.
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18) SERGIO BERTOGLIO, NICOLA SOLARI, PAOLO MESZAROS, ET AL.
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Efficacy of Normal Saline Versus Heparinized Saline Solution for Locking
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Catheters of Totally Implantable Long-Term Central Vascular Access
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Devices in Adult Cancer Patients. Cancer Nursing TM, 2012. Vol. 35, No.
351
4.
352
19) DAL
MOLIN
A, CLERICO
M, BACCINI
M, GUERRETTA
B, RASERO
L.
L, SARTORELLO
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Normal saline versus heparin solution to lock totally implanted venous ac
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cess devices: Results from a multicenter randomized trial. Eur J Oncol
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Nurs. 2015 Dec;19(6):638-43.
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ACCEPTED MANUSCRIPT Sex
Hep Group
SS Group
Male
151 (55.93%)
273 (46.11%)
Female
119 (44.07%)
319 (53.89%)
Total
270 (100%)
592 (100%)
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Table 1: distribution of patients in relation to sex.
ACCEPTED MANUSCRIPT Oclusion
Hep Group
SS Group
p-value*
Yes
8 (2.96%)
8 (1.35%)
0.11
No
262 (97.04%)
584 (98.65%)
*Fischer
exact
test
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Table 2. Incidence of occlusion
ACCEPTED MANUSCRIPT Reflux dysfunction
Hep Group
SS Group
p-value*
Yes
8 (2.96%)
8 (1.35%)
0.11
No
262 (97.04%)
584 (98.65%)
* Fischer exact test
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Table 3. Incidence of reflux dysfunction
ACCEPTED MANUSCRIPT Flow dysfunction
Hep Group
SS Group
p-value*
Yes
1 (0.37%)
4 (0.68%)
1
No
269 (99.63%)
588 (99.32%)
* Fischer exact test
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Table 4. Incidence of flow dysfunction