Abstract
Introduction:
Persistent withdrawal occlusion (PWO) is a specific catheter malfunction characterized by the inability to withdraw blood through the device. The most common cause of PWO in ports is the presence of a fibroblastic sleeve (FS). If malfunction occurs, medication can be applied incorrectly with the increased risk of complications.
Methods:
One hundred seventy-seven cases of PWO in venous ports were managed. We focused on evaluating the cause of PWO, the frequency of occurrence of FS, and the options to address the malfunction. The patients underwent fluoroscopy with a contrast agent administration. Mechanical disruption (MD) with a syringe of saline using the flush method was used; in case of its failure, subsequent administration of a lock solution with taurolidine and urokinase, or low-dose thrombolysis with alteplase was indicated. Demographic data were compared with a control group.
Results:
A significantly higher proportion of female patients was found in the cohort of patients with PWO (80.3% vs 66.3%, p = 0.004), dominantly patients with ovarian cancer (12.8% vs 4.8%, p = 0.022). No effect of the cannulated vein or the type of treatment on the incidence of PWO was demonstrated. The presence of FS was verified in 70% of cases. MD with a syringe was successful in 53.5% of cases. A significantly shorter time to referral (3 weeks) was demonstrated with successful management. The overall success rate of achieving desobliteration by MD alone or in combination with a thrombolytic (urokinase or alteplase) administration was 97.4%.
Conclusion:
We created a method for resolving PWO using MD +/- application of thrombolytics with 97.4% success rate. Current evidence showed that FS is not likely to be affected by thrombolytic drugs; however, we have ascertained an effect of these drugs, proposing a hypothesis of microthrombotic events at the tip of the catheter if fibroblastic sleeve is present.
Keywords
Introduction
Persistent withdrawal occlusion (PWO) is a specific catheter malfunction characterized by the inability to withdraw blood through the device while infusion remains possible. After excluding a mechanical cause of the occlusion, the most common cause of difficult aspiration from the port is the presence of a fibroblastic sleeve (FS). FS probably occurs often, but it is usually just a harmless phenomenon without any clinical significance. 1 If clinical manifestation does occur, it is usually at a later point, when the connective sleeve has enwrapped the tip of the catheter. In the presence of FS and malfunction of the catheter, medication can be applied incorrectly. Applied solution may be pushed back into the cleavage between the catheter and the inner surface of the FS. Thus, the medication is not applied to cavoatrial junction, but enters the venous system at the end of FS and usually enters the blood stream in the upper parts of the superior vena cava or brachiocephalic veins. Further, there is also the risk of extravasation at the exit site. The material of the sleeve has been already well described, demonstrating that FS is cellular tissue made of smooth muscle cells, fibroblasts, endothelial cells and collagen.2–7
In case of absent blood return, it is necessary to verify correct tip location. For many years, fluoroscopy with contrast medium examination was the only technique available. Over the last two decades, intra-cavitary electrocardiography has become a standard for assessing the correct location of the tip during implantation.8–10 Echo ‘bubble test’ (BT) is available to verify the correct tip location in the superior vena cava.11–14 The drugs can be administered safely in case of PWO and the positivity of the BT, but the port cannot be used for drawing blood. The main goal of the BT is not really to establish the diagnosis of the cause of the PWO, but more generally to be reassured that the port can be safely used, especially in case of administration of vesicant drugs. As the saline injection appears rapidly in the right atrium, we know that also chemotherapy will be delivered to the same location.
If the cause of PWO is not addressed further, there is a risk the patient will have to be retested with each subsequent administration of chemotherapy where blood return is not detected. Ignoring an initially small FS may lead to further growth of tissue enveloping the catheter with the risk of further complications. For precise evaluation of the aetiology of PWO and its management, fluoroscopy using a contrast agent was used. In previous years, we have recorded successful restoration of the port patency with catheter flushing alone; in other cases, the occlusion was resolved by using thrombolytics. Clear recommendations for the management of PWO, including the most appropriate procedures to restore venous return from the port, have been lacking. That is why we focused on this issue in our project.
Methods
Over the course of 28 months (September 2020–January 2023), 177 cases of PWO in venous ports were managed in 117 patients in the Vascular Access Center of Agel Nový Jičín Hospital, Czech Republic. The aim of this prospective study was to evaluate the cause of PWO, the frequency of occurrence of FS, and the options to address the port malfunction in a non-invasive way. We sought to identify the causes leading to the higher incidence of PWO. For this purpose, the following data were recorded: age, sex, cancer diagnosis, type of treatment, cannulated vein and side of insertion, physician undertaking the implantation, time from insertion to malfunction in weeks, and time from detection of malfunction to referral for management. We evaluated the demographic data of the study group, and these were compared with those of the control group, consisted of 398 patients cannulated in the same period who did not develop PWO.
We were assessing the success rate of occlusion release by mechanical disruption (MD) of the FS at the tip of the catheter using the flush method. We decided to confirm the hypothesis that early management of the PWO phenomenon could result in a higher efficiency of MD, as the FS is not yet too mature, making the flush method potentially more effective. In case of failure of this method, we would subsequently assess the effectiveness of thrombolytic administration, which proves effective. Patients were mostly referred from oncology outpatient clinics located within 50 km from the hospital; inclusion criteria included adult cancer patients with venous port and PWO and signed informed consent. Patients with an expected survival of less than 2 months (according to the expert opinion and prognostic nomogram), 15 impaired renal function with GFR under 0.5 ml/s according to the MDRD GFR equation (Modification of Diet in Renal Disease) or unable to sign informed consent were excluded (5 patients in total).
The protocol was approved by the Local Ethics Committee Nemocnice Nový Jičín a.s. (approval number 071020) and respected the Helsinki Protocol.
The patients were subsequently indicated for a fluoroscopy to assess the relation of catheteŕs tip to the cavoatrial junction and to exclude mechanical causes of occlusions from different possible reasons. 2 After administering the contrast agent (if possible), one of three possible situations occurred—the contrast agent flowed from the distal portion of the catheter in a usual undisrupted flow jet, or the contrast stream exited in a disrupted manner (typical is cloud-like pooling, spraying, or a sideways-oriented stream due to the presence of an occlusion in the distal part of the catheter), or the catheter was found to be thickened at the site where it was wrapped with FS (Figure 1), sometimes a ‘false route’ could be visualized with contrast agent leakage at the upper edge of the FS (Figure 2). MD was first attempted. This procedure consists in a flush of saline using a syringe of a smaller volume in order to clear the occlusion at the distal end of the catheter, as already described in a recent study of Yang et al. 16
Fluoroscopy. After the administration of a contrast agent, an increase in the catheter width is evident, caused by the fibroblastic sleeve that extends from the distal tip of the catheter in a retrograde fashion (as indicated by arrows).
Fluoroscopy–fibroblastic sleeve with false route. The contrast agent is administered through the catheter (blue arrows), but it does not flow from the distal portion of the catheter into the cavoatrial junction due to catheter occlusion (marked by a yellow asterisk) and returns in a retrograde fashion through the space between the outer wall of the catheter and the inner surface of the sleeve (red arrows). It enters the venous system at the end of FS in the upper part of the superior vena cava, where cloud-like opacities can be seen. FS: fibroblastic sleeve.
In our study, a 10 ml syringe was used initially, followed by 5 ml where blood return was not restored, and subsequently 2 ml as necessary, with higher pressure applied. Port patency could be verified by echocardiography with a BT to rule out port damage. The procedure did not lead to any port damage. Where blood return was restored, the catheter was adequately flushed with saline, and the port needle was removed.
Where this procedure was unsuccessful, the patient was indicated for the administration of thrombolytics. Naturally, active bleeding was excluded by clinical examination, no patient had a platelet count below 100 × 10e9/l, no coagulopathy / full anticoagulation therapy was present.
Taurolidine with urokinase (TU) was administered in case the blood return after MD was only temporary and PWO occurred repeatedly, or blood return was weak and intermittent. After the administration of the TU lock solution, the patient was observed for 15 min. If no adverse reactions occurred, he/she was sent to home care and the port was inspected 48–72 h later. Where the blood return was restored, adequate saline flushing was performed. Low-dose thrombolysis with alteplase was indicated in patients in whom MD did not restore port patency. The drug was administered as a 120 min continuous infusion of alteplase 2 mg in 48 ml of saline.
Statistical analysis
IBM SPSS Statistics software, version 23 (Armonk, NY: IBM Corp.) was used to analyse the data. The quantitative parameters were compared using the Mann–Whitney U test, while the chi-square test and Fisher's exact test were used to compare the qualitative parameters. The normality of the data was evaluated using the Shapiro–Wilk test. All the tests were performed at a significance level of 0.05.
Results
The cohort of 117 patients with a mean age of 58.3 years (min–max: 21–79 years old) consisted of 23 males with an average age of 61.4 years, and 94 females with an average age of 57.5 years, at a percentage ratio of 19.7% and 80.3%, respectively. Our centre has been inserting ports since 2011, with a total of 3448 ports inserted by the end of the period under review. A significantly higher proportion of female patients was found in the cohort of patients with PWO (80.3% vs 66.3% without PWO, p = 0.004). Their odds of developing PWO were 2.1 times higher than in males (OR = 2.074; 95% CI: 1.257–3.424). Results of the comparison between the PWO group and the control group without PWO are shown in Table 1. There was no significant effect of the cannulated vein (p = 0103) or the side of cannulation (p = 0372) on the incidence of PWO. A significantly higher proportion of patients with a diagnosis of ovarian cancer was found in the cohort of patients with PWO (12.8% vs 4.8%, p = 0.022). Both groups did not differ significantly in distribution by therapeutic type, the majority of the therapy administered were 5-fluorouracil-based cytostatic regimens (30.8%) and paclitaxel (51.3%). The mean catheter length was 23.1 cm (range 18–35 cm); the FS was several centimetres longer in shorter catheters (under the overall average) compared to longer catheters. There were seven physicians undertaking implantations, none of whom had a higher incidence of port occlusion compared with the others. All ports were inserted according to the recommended protocols. 17
Results of the comparison between the PWO group and the control group without PWO.
PWO: persistent withdrawal occlusion.
The median time of first occurrence of PWO from implantation was 27 weeks (min–max 2–329 weeks); the median time to referral was 2 weeks (min–max 0–104 weeks). Only one-third of patients were referred on the day when the PWO was ascertained, and another approximately one-third were, on the contrary, referred after more than one month.
Fluoroscopy with a contrast agent was performed in 87.1% of patients. Where contrast fluoroscopy could not be used (usually due to a history of allergies, or to respect the patient's wishes, or due to renal insufficiency, we were unable to find the reason for not administering the contrast agent in three cases), we performed an echo BT (to confirm the presence of the distal portion of the catheter in the superior vena cava) or a simple fluoroscopy with limited yield (usually in case of a negative BT to exclude secondary malposition).
No specific diagnosis showed a higher tendency for FS creation on the catheter. The average volume of contrast agent used was 8.58 ml (2–20 ml), the mean FS length was 5.57 cm (1–15 cm).
A total of 114 patients were indicated at their first occurrence of PWO to MD. This method resulted in restoration of blood return in 53.5% of cases (61 out of 114 patients). It has already been proven in earlier studies, that mechanical injection of saline is a safe and effective way of restoring patency in ports.16,18 Results of the comparison of the group of patients with successful and unsuccessful MDs are shown in Table 2. The success rate of MD did not depend on the patients’ age (p = 0134) or sex (p = 0084), type of malignancy (p = 0881), cannulated vein (p = 0519), time to 1st PWO from port insertion (p = 0273), length of the catheter or the distance of the tip from CAJ (p = 0517).
Results of the comparison of the group of patients with successful and unsuccessful MDs.
PWO: persistent withdrawal occlusion; MD: mechanical disruption.
In 22 patients (18.8%), a suboptimal position of the distal portion of the catheter (outside the area of 2.5 vertebral bodies below the level of the tracheal carina +/- 1 cm) was found during injection. In 10.3% of all cases, the catheter was inserted deep (more than three vertebral bodies below the carina), in 8.5% of cases was high (less than two vertebral bodies from the carina). When we retrospectively assessed the position of the tip of the catheters immediately after insertion, we found that the port had been initially inserted suboptimally only in six cases—in one case three vertebral bodies below the carina, in five cases high (only 1–1.75 vertebral bodies below the carina).
In more than a quarter of cases (32 events, 28.8%), the obstruction recurred (17 cases with one recurrence, 10 cases with two recurrences, 4 cases with three recurrences, 1 case with four recurrences). The incidence of PWO recurrence was independent of sex (p = 0.221), diagnosis (p = 0.140), vein (p = 0.373), cannulation side (p = 0.664), catheter length (p = 0.291), time to 1st PWO detection (p = 0.151) or time to referral (p = 0.378). A correlation between the incidence of recurrences and the age of the patients has been demonstrated. In the group with recurrent PWO, 93.8% of patients were in the age group over 50 years, compared to 72.2% in the group with no recurrence (p = 0.012). In 30% of recurrent cases, the MD was as successful as it was in the first occurrence of PWO. In 30% of patients, the MD method was used initially, but thrombolysis was necessary upon recurrence. On the other hand, in 20% of cases, thrombolysis was necessary at the beginning, but MD was sufficient for subsequent restoration of port patency. In 20% of cases, thrombolysis was used both initially and upon recurrence. We demonstrated that in the group with recurrences, attempted MD was often unsuccessful and low-dose thrombolysis with alteplase had to be used immediately (34.4% vs 20.3%, p = 0.037). Where the MD was not initially successful and only thrombolytic therapy was effective, this does not mean that MD will not be successful upon recurrence, one-fifth of such cases were successful in our study.
Discussion
The generally accepted notion is that the presence of a FS on the catheter is aetiologically responsible for PWO. The high success rate of MD (53.5%) is consistent with the previously accepted hypothesis that a FS represents a mechanical barrier that should be mechanically dislodged. A number of interventional radiology techniques for cleaning the catheter have been developed, e.g. percutaneous FS stripping from a femoral vein approach or the balloon dilation method.19,20 However, the success rate in the studies did not reach the level achieved in our cohort, with frequent recurrences, not to mention the invasiveness of the method and its costs. Many studies included patients with dialysis catheters, and some have not shown benefits of stripping over the use of urokinase, 21 while others recommend catheter exchange using a guidewire. 22 A significantly shorter time (3 weeks) to referral was demonstrated with successful MD. If the patient is referred for desobliteration sooner, there is a higher chance of restoring the port function by MD only, using lower pressure. One-third of patients were referred after more than one month after PWO was detected. There is a very real possibility that anti-cancer therapy was administered to a port in which blood return was not detected. Such practice is risky due to the possibility of inappropriate drug administration and led to practice changing educational activities.
The overall success rate of achieving desobliteration by MD alone or in combination with a thrombolytic (urokinase or alteplase) administration was 97.4%. We are increasingly inclined to support the hypothesis that the presence of tissue build-up on the catheter can be addressed by MD, but in some cases, this procedure fails, and we have experience with the beneficial effect of thrombolytic agents. This can be somewhat confusing. However, if we imagine the turbulent flow which occurs when blood circulates around a catheter, the surface of which is not smooth but deformed by the presence of irregular edges, the hypothesis of possible formation of small clots on the irregular surface of the catheter, including the distal portion of the catheter, presents itself. This hypothesis could be an explanation for the effectiveness of thrombolytic administration, which should otherwise have no effect in the case of ‘pure’ FS. However, clinical practice proves the opposite. Some smaller studies demonstrated the effect of thrombolytics.23–25 The histologic specimens showed thrombi as a part of FS in one study. 26 We also obtained FS specimen after the catheter had been pulled out at the friendly workplace of the Ostrava University Hospital (Figure 3) and we examined it histomorphologically. Next to fibroblasts and smooth muscle cells, an older organizing thrombus was detected in the special CARST staining (Figure 4), supporting our hypothesis.
Fibroblastic sleeve on the catheter, with permission of Iveta Constantine and Zuzana Figurová, PICC team Faculty Hospital Ostrava.
Histopathological image of fibroblastic sleeve with the presence of thrombus (Carstairs staining, 100x magnification), with permission of prof. Jozef Škarda, FH Ostrava.
Misplacement of the catheter outside the cavoatrial junction area is known to lead to a higher incidence of complications in general. However, in our patient group, there were only six cases with a primary suboptimal placement of the catheter tip, in most cases it was a secondary malposition, arising later during the use of the port. It was caused due to the changes in the patient's habitus probably, most often due to weight loss or regression of mediastinal lymphadenopathy. In the analysis of catheters that were inserted suboptimally in relation to CAJ, there was a tendency for the development of more recurrences in short catheters and a lower risk in long catheters, but the results were not statistically significant. Therefore, placing the distal tip of the catheter probably does not affect the formation of a FS.
The potential limitations of our study include the focus on one patient group only, with one type of venous access. We did not include any cancer-free patients; we do not have any precise comparison with the PWO incidence in other types of catheters (e.g. PICC). It would also be advisable to monitor the comedication the patient has been taking, including any antiplatelet or prophylactic anticoagulant therapy. Limitation of this project is the absence of sample size analysis.
At present we have no explanation as to why females should have a higher incidence of PWO, similar results brought one smaller study concerning the management of PWO in cancer patients. 8 Age over 50 years was found in 72 females (76.6%), so it can be concluded that these patients were mostly postmenopausal, but it cannot be clearly concluded that menopausal status influences the risk of PWO. We have also no evident explanation for higher recurrences in the age group over 50 years. We cannot rule out the possibility that some of the healthcare professionals repeatedly flushed the port before referring the patient to our centre, which could have then influenced the findings of the contrast fluoroscopy. The use of fluoroscopy itself is a limitation, as the modern trend is not to use sources of ionizing radiation. FS was detected only in 70% of patients using fluoroscopy, thus the cause of the malfunction may not be revealed if the pathological findings are subtle. Subjective evaluation of the findings during diagnostic fluoroscopy may influence the assessment of the cause of PWO. Nonetheless, in view of the results of the project, we adjusted the procedure for PWO management and began to perform the flush with/without the administration of thrombolytics without the need for diagnostic fluoroscopy. EDTA testing in prevention of PWO is also new.
Conclusion
Detecting the cause of PWO in venous ports is crucial for subsequent possibilities of adjustment. The presence of FS is the most common cause of PWO. Based on the results of our project, we recommend attempting MD by the flush method, which is the more effective the earlier it is performed. If the flush fails, a thrombolytic can be administered. This method for resolving PWO using MD +/- application of thrombolytics had 97.4% success rate. Current evidence showed that FS is not likely to be affected by thrombolytic drugs; however, we have ascertained an effect of these drugs, proposing a hypothesis of microthrombotic events at the tip of the catheter if fibroblastic expansion is present. Further studies on this topic are needed.
Footnotes
Acknowledgements
The authors thank all patients and members of Vascular Access Center of Agel Nový Jičín Hospital.
Author contributions
VM, LO, IK, KD and IF managed the patients, collected data, wrote the manuscript and reviewed the literature; VM and LO where responsible for procedures; JZ performed the statistical; JŠ provided histological images; VCH and DV reviewed the literature. All authors reviewed the final manuscript version and gave approval for submission.
Data availability
The data analysed during the study are available from the corresponding author.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Author biographies
V Maňásek graduated the Faculty of medicine, Palacky University Olomouc, Czech republic in 2004. He is a medical oncologist. Specialization in the field of clinical nutrition and intensive metabolic care, the chairman of the Working Group of nutritional care in the Czech oncology society, the scientific secretary of the Society for ports and catheters, Vascular access team leader, interested in urooncology. He is currently finishing PhD program on the topic of venous access occlusions in oncology.
J Zapletalová received her master's degree in Mathematical informatics, theoretical cybernetics and systems theory (1987) from Palacky University Olomouc. She obtained her PhD degree in Generally questions in mathematics and informatics (1993) from Masaryk University Brno. She is currently working at Palacky University Olomouc and Faculty hospital Olomouc as an assistant professor and statistician-analyst.
L Olosová graduated the Faculty of medicine, Palacky University Olomouc, Czech republic in 2005. She is a medical oncologist. Her areas of interest include vascular access, breast cancer, nutritional care in oncology. 15 years of port implantations and PICC insertions experience.
I Filáková graduated from the Secondary Medical School in 1986. 1986-present employed at AGEL Nový Jičín hospital, since 2004 at the oncology department. Assistance in the introduction of venous access devices since 2014.
I Kociánová graduated from the Secondary Medical School in 1986. The head nurse of oncology department AGEL Nový Jičín hospital from 2014, completed university studies the first degree BSc Nursing field - University of Health and Social Work St. Elizabeth in 2015. Vascular access team leader, PICC and midline insertions certificate holder.
K Drdová graduated from the Secondary Medical School in 2003. Since 2021 the memeber of Vascular Access team in AGEL Nový Jičín hospital, PICC and midline insertions certificate holder from 2022.
J Škarda graduated on medical school in 2002 (Fauclty of medicine, Palacky University Olomouc) and gained the PhD degree in Multidrug resistence in lung cancer. His further research focused mainly on the molecular characterisation of small and large cell carcinoma of lung.
V Chovanec is a vascular interventional radiologist. The topic of his PhD degree was transjugular intrahepatic portosystemic shunt. His areas of interest include vascular access, lymphatic interventions, mechanical trombectomy in stroke and embolotherapy. He currently works at the University Hospital in Hradec Kralove, Czech Republic.
D Vrána graduated on medical school in 2006 (First Faculty of Medicine Charles University Prague) and gained the PhD degree in 2011 in molecular biology studying the genetic polymorphisms of pancreatic cancer. He further focused mainly on new radiotherapy techniques, breast cancer and lung cancer treatment. He received Asooc. Prof. Degree in 2017 and starting 2019 is the head of the Comprehensive cancer center in Novy Jicin.