NHS England (2016) reported that over 150 000 people in the UK were receiving some form of systemic anti-cancer therapy (SACT). The increasing effectiveness of drug regimens has resulted in patients now being able to receive multiple courses of SACT over a number of years. However, it is well documented that repeated peripheral administration of intravenous (IV) anti-cancer therapies has the potential to cause significant debilitating chemical phlebitis, which can ultimately compromise a patient's treatment schedule (Moureau et al, 2012; Flynn et al, 2014; Kelly et al, 2015; Marshall-McKenna et al, 2015). As a result, various types of long-term central venous access devices (CVADs) are now routinely inserted to allow the safe and timely administration of IV SACT (Bertoglio et al, 2016; Harrold et al, 2016; Kelly, 2017; Ryan et al, 2018; Campagna et al, 2019). These include: cuffed tunnelled central catheters (Hickman lines), peripherally inserted central catheters (PICCs) and totally implanted CVADs (ports).
Although there are acknowledged complications associated with all CVADs, the incidence and management strategies reported in the literature tend to focus on the potentially life-threatening complications of catheter-related bloodstream infection (CR-BSI) and upper extremity venous thrombus (UEVT) (Loveday et al, 2014; Bertoglio et al, 2016; Noyes and Dickey, 2018; Al-Asadi et al, 2019; Krein et al, 2019). However, other thrombotic complications, such as the development of a fibrin tail attached to the distal tip of the catheter, a fibrin sheath extending around the catheter encompassing the distal tip, or clotted blood in the internal catheter lumen (Gabriel, 2013; Kumwenda et al, 2018a) can result in the dysfunction of a long-term CVAD (Table 1).
| Type of occlusion | Symptom | Possible cause | Graphic descriptor |
|---|---|---|---|
| Persistent withdrawal occlusion | Able to infuse fluids/medications with ease but no blood return (ie inability to aspirate blood) |
1. Fibrin tail formation
Externally at the distal tip of the catheter |
|
| Total occlusion | No blood return (eg inability to aspirate blood), plus inability to, or resistance felt when attempting to infuse fluids/medications | Intraluminal blood clot completely occluding the fluid pathway inside the catheter |
Removal and replacement of the dysfunctional catheter can interrupt the treatment schedule or result in a potential loss of venous access, compromising the treatment plan; which for some cancer patients can adversely affect their outcome (Young et al, 2009; Wyatt et al, 2015). It is therefore essential that any catheter dysfunction caused by an intraluminal clot, fibrin sheath or tail is managed quickly and effectively (Kumwenda et al, 2018a).
Although the most commonly accepted management strategy for a partially or totally occluded CVADs is by use of a thrombolytic agent, such as urokinase (Dougherty, 2014; Royal College of Nursing, 2016; da Costa et al, 2019), there appears to be a lack of national or international best practice guidelines with evidence as to its efficacy, the optimum dose, method or duration of administration when using it (Van Miert et al, 2012; da Costa et al, 2019).
Aim
The aim of this audit was to evaluate safety and outcome following use of urokinase (Syner-Kinase®) using a push lock or dwell lock technique; followed by high-dose infusion if the lock was unsuccessful. The data were drawn from a larger, national, multi-centre, prospective audit and contribute to the development of an evidence-based, standardised, best practice recommendation protocol (PASSPORT (Prospective Audit to Study Syner-Kinase use to restore Patency in Occluded Central Venous CaTheters) (Kumwenda et al, 2018b; Kumwenda et al, 2018c). Data presented are from one of the eight participating oncology centres. (Syner-Kinase mode of action is shown in Figure 1).
Participating site
The cancer centre treats non-surgical oncology patients from a catchment population of almost 2 million people. The majority of patients receiving IV anti-cancer therapies are treated in the chemotherapy day unit, which has a throughput of approximately 150 patients a week. Data show that in 2017, 583 patients had a CVAD placed for administration of their SACT (Figure 2).
Method
This was a non-interventional prospective audit; therefore, research ethics committee approval was not required. However, the audit was approved by the local NHS hospital audit committee. Once approval was granted, prospective data were collected from all patients identified as having an occluded CVAD that required use of Syner-Kinase to manage a persistent withdrawal occlusion (PWO) or total occlusion (TO) from 11 September 2017 to 9 March 2018. Data were collected from patients medical and nursing records incorporating details on background demographics, clinical history, type and site of catheter, cause of catheter dysfunction, remedial action and outcome.
Data were recorded anonymously using a REDCap (Research Electronic Data Capture) tool. REDCap is a secure, web-based application designed to support data capture for research studies; providing an intuitive interface for validated data entry, audit trails for tracking data manipulation and export procedures, automated export procedures for seamless data downloads to common statistical packages and procedures for importing data from external sources (Harris et al, 2019).
Data from all participating centres were analysed collectively by the study steering committee, with each participating centre having access to their individual data.
Protocol for use of Syner-Kinase
The dose and protocol for use of Syner-Kinase (Table 2) was as per the protocol guidelines in use at the study site during the time of data collection.
| Cause of dysfunction | Dose | Protocol |
|---|---|---|
| Persistent withdrawal occlusion | 10000-25000 lU Syner-Kinase instilled into each lumen of CVAD using push lock technique |
PICC: Reconstitute 10000 lU of Syner-Kinase in 2ml sodium chloride 0.9% |
| Persistent withdrawal occlusion | Infusion of up to 25000 lU Syner-Kinase into each lumen of CVAD | Reconstitute 25000 lU of Syner-Kinase in 2ml sodium chloride 0.9% |
| Total occlusion | 5000-25000 lU Syner-Kinase instilled into each lumen of CVAD using 3-way tap technique | Protocol as per Dougherty and Lister (2015) |
Baseline data
Twenty-two patients were identified as having an occluded CVAD that required use of Syner-Kinase to manage a persistent withdrawal occlusion (PWO) or total occlusion (TO) during the data collection period. Of these 22 patients, 11 were male and 11 were female. There was a median age of 63 years.
Table 3 presents a brief summary of clinical history, CVAD type and rationale for placement in patients (n=22) identified as having catheter dysfunction during the 6 month audit period. Compared with routine annual audit data, which indicated that of 327 PICCs placed by nursing staff in 2017, 156 were dual lumen (5 Fr) and 171 were single lumen (4 Fr), these data shows a distinct disparity in the incidence of PWO or TO between single and dual lumen catheters; with the greatest incidence of catheter dysfunction in dual lumen 5 Fr PICCs (n= 14).
| Diagnosis | SACT regimen | Rational for placement | CVAD type | Size (Fr) and number of lumens |
|---|---|---|---|---|
| Male | ||||
| GI cancer | Folfirinox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfirinox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfiri | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfiri | Infusional 5FU | PICC 5 | Fr dual lumen (EV) |
| GI cancer | Folfiri | Infusional 5FU | PICC 5 | Fr dual lumen (EV) |
| GI cancer | Folfiri | Infusional 5FU | PICC 5 | Fr dual lumen (EV) |
| GI cancer | Folfoxiri | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| H&N cancer | 5FU/cetuximab | Infusional 5FU | PICC | 4 Fr single lumen (EV) |
| Female | ||||
| GI cancer | Folfirinox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfiri | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfoxiri | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| GI cancer | Folfox | Infusional 5FU | PICC | 5 Fr dual lumen (EV) |
| Breast cancer | EC/T | Vesicant drug | PICC | 4 Fr single lumen (OEC) |
| Breast cancer | AC/T | Vesicant drug | PICC | 4 Fr single lumen (EV) |
| Breast cancer | Paclitaxel | Ongoing palliative | Port | 6.6 Fr single |
| Breast | Herceptin/pertuzumab | 18 months chemo | Port | 6.6 Fr single |
| Ovarian | Carboplatin/Caelyx | Ongoing palliative | Port | 6.6 Fr single |
| Ovarian | Paclitaxel | Ongoing palliative | Port | 6.6 Fr single |
| Melanoma | Pembrolizumab | Ongoing palliative | Port | 6.6 Fr single |
GI = gastrointestinal, EV = externally valved, H&N = head and neck, OEC = open ended/clamped
The majority of CVADs included in the audit were right-sided placements (Figure 3). The internal jugular vein was the route of access for all implanted ports (n=5). The insertion site for PICCs was either via the basilic vein (n=12) or brachial vein (n=5).
Irrespective of catheter type or site of placement, the main cause of catheter dysfunction was due to PWO (77%) with no difference in the incidence of PWO and TO between single or dual lumen PICCs (Figure 4).
Outcome measure
A positive outcome (successful intervention) was judged as an ability to attain blood return and able to administer treatment or flush 250 ml through the CVAD.
A negative outcome (unsuccessful intervention) was judged as an inability to attain blood return and unable to administer treatment or flush 250 ml through the CVAD.
Results from interventional data
Persistent withdrawal occlusion Interventions and outcomes
Of the 22 patients, 17 presented with PWO, 5 patients with an implanted port in situ and 12 with a PICC (Figure 4). However, one patient with a PICC in situ presented with PWO on two separate occasions and one patient with an implanted port also presented with PWO on two separate occasions, resulting in a total of 24 individual cases of PWO.
PICCs
For all 13 cases of PWO, urokinase 10 000 IU was administered, using push lock technique (Table 3). Although outside the summary of product characteristics, in two cases, the final 0.5 ml of the thrombolytic was left locked in the catheter overnight. The intervention was successful in all 13 cases (100% success rate).
Ports
Administration of Syner-Kinase using push lock technique, was successful in 5 of the 6 cases of PWO (84% success rate) using a dose range of 10 000–25 000 IU. The procedure was unsuccessful in one case, despite repeated administration of Syner-Kinase on five separate occasions using various techniques. It was administered as push lock over 30 minutes on one occasion, left locked in the catheter overnight on two occasions, left over the weekend on one occasion and administered as a slow infusion on one occasion. Although outside the summary of product characteristics, Syner-Kinase was locked in the catheter overnight and/or over the weekend. This resulted in the port finally being removed and replaced.
Total occlusion interventions and outcomes
Five patients presented with a totally occluded PICC (Figure 4). Administration of Syner-Kinase (5 000 IU in 1 ml sodium chloride 0.9%) using three-way tap technique (Dougherty and Lister, 2015) was successful in 4 of 5 cases (80% success rate). The one case where use of Syner-Kinase proved unsuccessful was the single lumen, open-ended, clamped PICC, which subsequently had to be removed and replaced.
No adverse events were reported during or after administration of Syner-Kinase.
Discussion
CVADs increasingly have an essential role in the safe and timely administration of intravenous therapy for patients with chronic disease, cancer and other critical illness. Consequently, catheter dysfunction can significantly impact a patient's treatment schedule and has the potential to negatively affect outcome. It is therefore essential that an occluded catheter is managed appropriately and effectively. Reflecting findings from van Miert et al (2012) Syner-Kinase was found to be well tolerated, with no adverse events recorded.
Combined data for PWO and TO demonstrate a single administration of Syner-Kinase for catheter occlusion clearance to be effective in 92% of cases (n=22). Results showed that when 10 000 IU was administered, using push lock technique, for PICC dysfunction caused by PWO it was successful in 100% of cases (n=13), with an 84% success rate for PWO in implanted ports (n=5). This reflects findings from da Costa et al (2019) where the results from a meta-analysis of 14 studies also showed an overall restoration rate of 84%.
These data did, however, reveal a marked difference in the percentage of TO versus PWOs in comparison with the combined data from all eight non-renal sites in the PASSPORT study (Kumwenda et al, 2018b). Results from the single study site revealed a 79% PWO rate and 21% TO rate (n=24) in contrast to 55% PWO and 45% TO (n=138) reported in the combined, non-renal, data set (Kumwenda et al, 2018b). It is impossible to determine the reasons for this from the original data, due to the multiple variables across the data sets. These include: variation in participating sites (eg specialist unit or district general hospital), knowledge and experience of staff, timing of the intervention, type of catheter used (eg externally or internally valved, open-ended and clamped, power injectable or not) and catheter material (eg silicone, polyurethane, integral polymer coating, chlorhexidine coating). All of which could impact on the incidence of catheter dysfunction.
Another finding from the single site data, which was not investigated in the main audit, was the prevalence of dysfunction in 5 Fr dual lumen PICCs, which accounted for 75% of the PICC audit data (n=14). One possible explanation for this could be the catheter:vein ratio. Future clinical studies may be able to address both of these issues.
Limitations
The limitations of these findings are acknowledged due to the small sample size reducing the ability to draw strong conclusions. The SACT regimens were primarily fluoropyridamines for gastrointestinal cancers, and potentially influenced the results. The SACT regimens were primarily those including fluoropyridamines (infusional 5FU) for patients with gastrointestinal cancers. This may introduce an element of bias and consequently skew the data, as it did not include a variety of anticancer drugs or patients with different tumour sites. Therefore, the impact of consistent success of Syner-Kinase in PWO may be underestimated and likely to have wider impact than demonstrated.
Conclusion
Results from this single site prospective audit suggest that use of the thrombolytic agent Syner-Kinase at doses ranging from 5 000 to 25 000IU is well tolerated and an effective means of restoring patency for long-term CVADs in cancer patients. Combined data for PWO and TO demonstrates a single administration of Syner-Kinase for catheter occlusion clearance to be effective in 92% of cases.
There remains a need for further multicentre studies to expand and validate these findings. However, as part of the larger, national, multi-centre, prospective audit (PASSPORT) these findings contribute to the developing evidence-base for a standardised, best practice recommendation protocol.
It is recommended that studies should also be designed to address the multiple variables associated with factors such as the type, gauge and material of catheter.