Confounding Factors & Patency

Common language facilitates communication between professional and organisations, the translation of evidence into clinical practice, data sharing, and research. CNSA, eviQ and eviQ Education are leading vascular access management and education in cancer care in Australia utilizing common, contemporary terminology (Table 1).

Table 1: CVAD terminology

Cancer and anticancer treatments potentially increase the risk of Central Venous Access Devices (CVAD) complications (1). The pathophysiology of cancer alone may increase the risk of complications as it involves complex processes. This includes the inflammatory process (2) and coagulopathies, which may result in an increased risk of bleeding, thromboses or both, for example disseminated intravascular coagulation and thrombotic microangiopathy (1,3). Thrombotic microangiopathy is a process in which platelets adhere to the endothelium causing blood vessel narrowing or obstruction at a capillary level which also results in a consumptive thrombcytopaenia (1).

Adverse effects of systemic anticancer therapies including chemotherapy and immunotherapy provide an additional risk for patients with cancer, for example mitomycin-C, cyclosporin A, l-asparaginase, platinum-based chemotherapy (gemcitabine), hormonal manipulates, vascular endothelial growth factor pathway inhibitors, thalidomide and proteasome inhibitors (bortexomib) (1). This is related to the damage of endothelial cells associated with these medications. Also antiangiogenic agents and in combination with high dose chemotherapy considerably increase the risk of endothelial damage (1). Furthermore, anticancer therapies in recent years have become more intense, for example the myeloablative regimes for stem cell transplants resulting in more frequent thrombotic and thrombotic microangiopathy complications (1).

Added to the potential endothelial damage caused by the pathophysiology of cancer and anticancer therapies is the damage caused by the insertion of vascular access devices. This may result in an increased risk of infection, bleeding, thrombosis, skin impairment and delayed healing of CVAD wounds, for example totally implantable venous access device suture lines or catheter exit sites. The surface of CVADs also provides an additional surface for thrombosis to occur (1).

A combination of any of these factors potentially impacts CVAD insertion and maintenance practices in order to attempt to reduce the risk of complications leading to premature removal. This question identifies three groups of factors form the literature that potentially impact CVAD occlusion rates for patients with cancer including:

1. Patient related factors
   • Types of cancer
   • Comorbidities
   • Age
   • Body Mass Index
   • Pathology
2. Device related factors
   • Type of CVAD
   • Left or right side
   • Number of lumens or size of catheter
   • Insertion vein
   • Valve or non-valved catheters
   • Angle of catheter attachment onto TIVAD body
   • CVAD dwell time
3. Therapy related factors
   • Type of infusate
   • Blood sampling
   • Inpatient admissions

The majority of studies that identify factors that potentially impacted occlusion rates were observational or incidental findings in retrospective studies which primarily documented incidence rates of CVAD complications. Furthermore, the vast majority of factors were non-modifiable so could not be changed e.g. diagnosis, comorbidity or age. Some factors are potentially modifiable e.g. left or right side insertions, insertion vein, diametre of accessed vessel, angle of catheter attachment on Totally Implantable Venous Access Device (TIVAD) body. These factors are identified in the recommendations below.

CNSA recommends a comprehensive patient assessment is completed prior to the selection and insertion of the most appropriate vascular access device for the individual patient with cancer, including patient, treatment, and device related factors. Assessment includes the patient, family/carer and healthcare team (4).

CNSA recommends reducing the potential risk of occlusion of central venous access devices for adult and paediatric patients with cancer:

Preinsertion

• to insert the smallest diameter or fewest number of lumens for the prescribed therapy (5-9,10-13,14)
• to complete a risk benefit analysis prior to CVAD insertion for those with a body mass index > 25 (15,16)
• to consider the insertion of TIVADs with non-valved catheters: compared to valved catheters (17)
• to consider the insertion of TIVADs: potentially superior to PICCs and CICCs for long-term vascular access needs in adults (18) and potentially superior to tc-CICC in paediatric patients (13,19)
• to consider the insertion of tunnelled centrally inserted central catheters (t-CICC): potentially superior to peripherally inserted central catheters (PICCs) for administration of parenteral nutrition in the home in adults (20)

Insertion

• to insert CVADs on right side (8,21-23)
• to insert TIVAD: catheter is in a straight line and not at a sharp angle where it attaches to the TIVAD body (24)

Maintenance

• to comply with flushing practices post blood sampling every time (25)
• to maintain the catheter tip position: at the distal third of the superior vena cava (SVC), cavoatrial junction to the upper half of the right atrium (26)

Removal

• to remove the CVAD when no longer required: shortest duration time for prescribed therapy because the longer the CVAD is insitu, increases the risk of complications (27)

The pathophysiology of cancer and side effects of systemic anticancer therapies impact the insertion and management of central venous access devices. This can be influenced by patient factors including the type of cancer, comorbidities, age, body mass index and race of the individual patient.

Summary of evidence:

2.1 TYPE OF CVAD

The type of CVAD, particularly long term CVADs are noted in observational or incidental findings as having an increased risk of occlusion within 1-2 years of insertion (8). In adult patients, t-CICCs were identified to be superior to PICCs in relation to mechanical complications for the administration of parenteral nutrition in the home for adult participants with cancer in a systematic review (20). TIVADs had significantly longer life span (p= <0.001) according to all types of removal reasons or complications compared to CICCs in the subclavian vein or PICCs. Also PICCs had significantly more frequent thrombotic occlusions and catheter tip migration or malposition (p<0.001) in a prospective observational study of 116 paediatric and adult participants and 179 CVADs (18).

In paediatric patients, evidence was varied. TIVADs were 1.8 times and tc-CICC were 2.3 times higher risk for occlusion compared to PICCs in a prospective data registry study investigating risk factors for thrombotic complications of 423 CVADs in 262 paediatric participants for 76,540 catheter days. It was also noted this possibly could be related to the shorter dwell time of PICCs and different catheter tip location by an interventional radiology insertion team. Occlusion accounted for 5% of CVAD removals in this study (19). This contrasted with a retrospective study of 330 paediatric patients, in which 25.8% participants experienced 123 occlusions, more frequently with tunnelled CICCs (41.5%), PICCs (37%) and TIVAD (19.4%) (13). Also occlusions were associated more with patients with acute myeloid leukaemia who received a double lumen tc-CICC in a 15 year retrospective study of 358 paediatric participants (12).

2.2 LEFT OR RIGHT SIDE

In adult patients, left side CVAD insertions were associated with a higher incidence of occlusions. Catheter tip position was an important factor in CVAD survival with a higher number of tip malposition’s with left side insertions in a cohort study of 235 adult participants (26). Left side insertion were 1.5 times more likely to develop occlusions compared to right side insertions according to a retrospective observational cohort study of 610 adult participants (21).

In paediatric patients, left side PICCs (22.9%) compared to right side PICCs (9.2%) were significantly associated (p=0.044) with PICC removals due to complications, with occlusion and infection being the most frequent complications in a retrospective population-based cohort study of 87 paediatric participants over 14 years (22). Also, insertion of CVADs on the right side was a recommendation to reduce the risk of thrombus formation by the Italian Association of Paediatric Hematology and Oncology. A significant association of thrombosis and occlusion, and infection occlusion and thrombosis were identified. This was expert consensus of the literature for the management of CVAD occlusion and thrombosis for paediatric patients with haematological malignancies (23). Left side CVADs, due to the longer distance a catheter travels in the veins, had a fivefold increased risk of thrombosis compared to the right side, according to expert opinion (8).

Comparatively, no association was found between left and right side insertion’s for occlusion complications in a retrospective cohort study of 51 paediatric participants with tunnelled cuffed centrally inserted central catheters (10) and a prospective cohort study of 477 adult participants (16).

2.3 NUMBER OF LUMENS OR SIZE OF CATHETER

In adult patients, the size and number of CVAD lumens were noted as risk factors associated with occlusions in a meta-analysis of interventions for occluded long-term CVADs in cancer patients (5). Overall failure of 4 French (FR) was 9.59 % compared to 5 Fr PICCs, 16.97 % in the analysis of numerous potential influential factors in a prospective cohort study, investigating incidence of complications and failures of 291 adult participants (6). It was noted, all PICCs were inserted with the recommended catheter to vein ratio of 1:3. According to expert opinion, large or multiple lumen catheters have a higher risk of occlusion (7). Also, triple lumen compared to single lumen CVADs have a higher incidence of thrombosis which can be associated with occlusions according to expert opinion (8).

Double lumen compared to single lumen CVADs are associated with an increased risk of occlusion in several studies of paediatric patients. In a randomised controlled trial of 203 paediatric participants with double lumen tc-CICCs associated with any complications, it was observed that occlusion the most frequent complication (9). Double lumen tc-CICC and TIVADs had a statistically significant risk for occlusion (p=0.023) in a 10 year prospective surveillance study of 919 paediatric participants (11). Double lumen compared to single lumen CVADs were at significantly higher risk of occlusion in a retrospective observational study of 330 paediatric participants (13). Also double lumen TIVADs were associated with an increased risk of occlusion in a retrospective cohort study of 488 paediatric participants (14). Paediatric participants with acute myeloid leukeamia routinely had double lumen tc-CICC inserted which were noted to have higher rates of dysfunction than younger patients with single lumens in a 15 year retrospective study of 358 paediatric participants (12). However, lumen diameter of ≤4.2 Fr compared to > 4.2 Fr French had a statistically significant association with occlusion in a paediatric cohort study of 51 participants (10).

2.4 INSERTION VEIN

One study noted the insertion of PICCs into the basilic vein versus axillary or brachial veins were associated (p=0.074) with higher failure in a prospective cohort study investigating incidence of complications and failures of 291 adult participants (6).

2.5 VALVE VS NON-VALVED CATHETERS

All episodes of partial occlusion and the only episode of complete occlusion occurred in TIVADs with valved catheters compared to TIVADs with non-valved catheters in a retrospective study of 100 adult participants (17).

2.6 ANGLE OF CATHETER ATTACHMENT TO TIVAD BODY

The angle where the catheter attaches to the TIVAD body, specifically the sharper the angle was the only significant risk factor for malfunction complication in 1508 TIVAD insertion procedures in a retrospective study of adult participants (24).

Figure 1: Angle between the locking nut and the catheter (24)

2.7 CVAD DWELL TIME

Patients with PICCs in place for longer time had more complications in a retrospective observational study of 212 adult participants (27).

3.1 TYPE OF INFUSATE

Infusates (solutions, medications, and fluids) infused through a CVAD that are associated with an increased risk of CVAD occlusion include:

Chemotherapy

In adult patients, a systematic review investigating the treatment of CVAD occlusion noted chemotherapy was a risk factor for thrombotic occlusions in TIVADs (5). Chemotherapy, and specifically fluorouracil, oxaliplatin and bevacizumab based regimes had over three times increased risk of PICC failure in a prospective cohort study investigating incidence of complications and failures of 291 adult participants (6). Also, it was noted partial occlusions were significantly more frequent with chemotherapy compared to other treatments in a prospective cohort study with 198 participants and 4111 observations of TIVAD access and flushing post use. Furthermore, partial occlusion was more likely with weekly or fortnightly chemotherapy compared to every 3-4 weeks (25).

In paediatric patients, chemotherapy was the most common reason for TIVAD insertion (93%) in a retrospective study of 182 participants over 10 years. It was discussed that the type of infusion played a key role in thrombotic occlusions (28). The administration of chemotherapy and parenteral nutrition were associated with a 4 fold increased risk of occlusion compared to chemotherapy alone in a retrospective observational cohort study of 610 participants with TIVADs (21). In regard to chemotherapy dosage, a prospective observational study of 155 paediatric and adolescent participants noted different dose intensities of chemotherapy for osteosarcoma and Ewing sarcoma had no significant impact on occlusion rates (15)

Calcium, phosphate in parenteral nutrition, lipids and incompatible solutions were a high risk of occlusions according to expert opinion (7).

Procoagulant medications

In paediatric patients, procoagulant drugs for example prednisolone, dexamethasone or L-asparaginase used in the treatment of leukaemia and lymphoma were noted to nearly double the risk of the formation of fibrin within the CVAD lumen or on the catheter tip in a 10 year prospective surveillance study of 919 paediatric participants (11). Nearly 25% of occlusive events followed an L’asparaginase infusion in an observational study of 124 paediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphomas and tc-CICCs. The participants were also concurrently on steroids as per the standard treatment protocols. However, in the group of participants who had L’asparaginase (n=74), there were less frequent L’asparaginase related thrombotic complications compared to those not related to L’asparaginase (30). Also, L’asparaginase given intramuscularly was not associated with occlusion, in a retrospective paediatric cohort study of 51 participants with tc-CICCs for Acute Lymphoblastic Leukaemia, Acute Myeloid Leukaemia, neuroblastoma, Hodgkins disease and optic nerve glioma (10).

Mannitol and packed cells

It was noted in a small observational study of 12 adult participants investigating TIVAD occlusion, occlusions occurred during the infusion in 83% of cases of mannitol 20% (25% of the cases) and packed cells (8%). Also, 50% of cases were associated with the TIVADs not flushed post infusion. Infusion of mannitol 20%, blood transfusion and parenteral nutrition in the month prior to occlusions occurring was also noted (33)

Heparin

Patients treated with Bevacizumab have an increased risk of thrombosis, however the pathophysiology remains unknown. A small observational study investigated the serum levels of heparin of participants with TIVADs post heparin flush compared to serum levels healthy participants. This was in response to a previous study by the same researchers where it was noted heparin greatly enhanced platelet activation in mice. Significantly increased serum levels of heparin were noted and it was proposed this may contribute to thrombosis associated with bevacizumab. (34). Further investigations are required.

Tissue plasminogen Activator (tPA)

A small retrospective observational study of 53 paediatric patients with leukemia noted tPA used to treat CVAD occlusion was associated with the development of symptomatic venous thromboembolism. All participants who developed a symptomatic VTE had received TPA prior and 22% of participants who received tPA developed a symptomatic VTE. (35)

Ethanol

An expert review of current literature identified an increased risk of occlusion with the use of ethanol lock therapy to prevent and treat CVAD associated infection (36)

3.2 BLOOD SAMPLING

Blood sampling was significantly associated (p<0.0001) with partial occlusion in a prospective cohort study of 198 adult participants. However, there were more partial occlusions when no blood sampling was performed with short time intervals between treatment cycles. It was suggested this may be related to nurses awareness of blood sampling related occlusions and due diligence to flushing prior to and post blood sampling (25).

3.3 INPATIENT ADMISSIONS

A higher risk of CVAD complications with patients who had at least one inpatient admission was noted in a retrospective observational study of 212 adult participants (27).

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