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Abstract

Catheter-related thrombosis is a relatively common complication of central venous catheter insertion. Central venous catheter use is ubiquitous in the critical care setting and often in patients with multiple risk factors for venous thromboembolism. With a trend towards increased use of peripherally inserted central catheters, the incidence of catheter-related thrombosis is likely to increase further. Despite the scale of the problem, there is a paucity of evidence-based guidelines concerning the management of patients with catheter-related thrombosis, particularly in critically unwell patients. This has led to heterogeneity in clinical practice. In this review, we describe the risk factors for developing catheter-related thrombosis and provide practical advice for clinicians on how to recognise, diagnose and treat this common problem.

Keywords

Introduction

Indwelling central venous catheters (CVCs) are ubiquitous in the critical care setting. Thrombotic complications can occur with CVC use with reported rates varying from around 5% for symptomatic events¹ to an overall rate of 14–18%.² Despite being relatively common, there is heterogeneity in clinic practice when it comes to the management of catheter related thrombosis (CRT). There are limited evidence-based guidelines for the best diagnostic approach and preventive measures for CRT, particularly in critically unwell patients. This review aims to provide clinicians with a pragmatic approach to dealing with CRT.

Risk factors

There are several risk factors for the development of CRT. They can, broadly speaking, be categorised as risks relating to the line itself, the insertion process and patient factors (see Table 1). It is useful to remember, in this context, how these factors relate to Virchow’s triad of endothelial damage, stasis and hypercoagulability, described as the components involved in thrombus formation (Figure 1).

Table 1.

Risk factors for the development of CRTs.

Factor	Variable	Effect on risk of CRT
Patient factors	Hypercoagulable states including malignancy, sepsis, critical illness, renal failure, previous VTE, use of certain drugs (e.g. thalidomide), possibly inherited thrombophillias	Increased
Catheter type	PICC	Increased (additional risk with increased diameter/number of ports)
	Closed-ended or open ended catheter	No difference
	Increased lumen diameter	Increased
Insertion	Tip located above the junction between the SVC and atrium	Increased
	Left sided	Increased
	Femoral	Increased
	Use of US guidance	No difference
	Multiple insertion attempts	Increased

CRT: catheter-related thrombosis; VTE: venous thromboembolism; PICC: peripherally inserted central catheter; SVC: superior vena cava syndrome.

Figure 1.

Postulated mechanisms by which the presence of a CVC may contribute to the development of thrombosis.

Prevention is better than treatment when it comes to CRT. Some of the risk factors for CRT such as (a) location of insertion and (b) the type of CVC are modifiable and careful consideration of these can minimise the risk for thrombosis. The International Society of Thrombosis and Haemostasis guidelines recommend that where possible, CVCs should be inserted on the right side, in the jugular vein with the tip located at the junction of the superior vena cava and the right atrium to minimise the risk of thrombosis.^3,4

Table 2 summarises the types of CVCs most frequently encountered in clinical practice. Tunnelled lines are infrequently inserted during acute admissions; however, they are encountered routinely in patients admitted from other departments such as haematology, oncology and renal departments. Within the critical care setting, temporary, non-tunnelled lines are most frequently inserted due to their ease of insertion, multiple lumens, and ability to monitor central-venous pressure. More recently, there has been a trend towards the use of PICC lines in patients with changing access needs following the acute phase of their illness or as an alternative to CVCs. Recent studies in critical care have suggested that they are associated with lower complication rates than previously thought, particularly relating to catheter-related blood stream infections (CRBSI).^5,6 A small retrospective report on the use of power injectable PICCs (ultra-resistant polyurethane devices allowing high-pressure infusions) in the critical care setting, reported excellent CRBSI rates and lower than expected symptomatic CRT rates. Of 89 power-PICC insertions, there were no CRBSIs and two cases of symptomatic CRT (routine screening did not occur). The authors claim that low complication rates were due to robust insertion protocols, including ultrasound guidance to ensure appropriate vein diameter and the use of intra-cavitatory ECG monitoring to ensure correct position.⁶ However, PICCs are generally considered to be associated with higher rates of CRT than other devices and it is not unreasonable to suspect that patients admitted to critical care may be particularly at risk.^7,8 One non-randomised, prospective trial found higher rates of thrombosis in patients discharged from critical care with PICC lines than CVCs, with rates of CRT of 7.7/1000 vs. 4.4/1000 catheter days respectively.⁸ With increased interest in the idea of PICC lines being a potential alternative to CVC insertion, one study aimed to prospectively evaluate outcomes in patients receiving triple-lumen PICCs. At interim analysis, this study was terminated due to unacceptably high CRT rates; 20% of the study group developed symptomatic CRTs, rising to 58% including asymptomatic cases.⁹ This would further suggest that increasing lumen diameter increases the risk of CRT in PICCs and perhaps supports the use of CVCs if more than two lumens are required. It is clear that high-quality RCTs are required to definitively establish the relative risks of PICC and CVC insertion with modern devices and care bundles.¹⁰ If in the interim clinicians do opt for PICC use, it is necessary to consider modifiable risks including the catheter-to-vein ratio, pragmatically aiming to use the smallest diameter catheter lumen in the largest diameter vein feasible and be mindful of potential thrombosis.^6,7,9,11,12

Table 2.

Summary of commonly encountered CVCs.

Venous catheter	Common brands	Lumens	Duration	General indications
Non-tunnelled	NA	2–4	Temporary: 1–3 weeks	Critical care
Tunnelled	Hickman® Broviac® Groshong®	1–3	Semi-permanent >30 days	Long-term uses: chemotherapy, parenteral nutrition, etc.
Implanted port	Port-a-cath®	1	Semi-permanent >30 days	Infrequent but long-term requirements Paediatrics
Peripherally inserted central catheter (PICC)	NA	1–3	Intermediate >7 days	Outpatient chemotherapy, intermediate-term access for sampling, antibiotics, etc.

Sepsis is of course commonly encountered in critical care patients and is widely recognised as a risk factor for venous thromboembolism (VTE). In relation to CRT there is evidence to suggest this relationship endures. The presence of a CVC-related infection increases the risk of symptomatic CRT, with the highest rates seen systemic rather than localised infection.¹³ It may be argued that the presence of catheter-related infection should prompt screening for CRT with ultrasound, even in the absence of other clinical features.¹³

Clinical symptoms

The majority of CRTs (two-thirds) are asymptomatic which can make identification difficult; a high index of suspicion is therefore required. The clinical features may be fairly self-evident such as arm or neck swelling and discomfort or venous distension. In some cases, patients may experience atypical symptoms such as jaw or shoulder pain (see Table 3).^14,15 CRT may also be suspected following difficulty with infusion or aspiration. It can be difficult to ascertain whether this is due to mechanical obstruction including malposition, fibrin sheath formation, an intraluminal clot, mural thrombosis, the rare ‘pinch off’ syndrome (compression between the first rib and lateral clavicle), or indeed a venous thrombus. Figure 2 provides a schematic image of possible thrombotic complications associated with CVCs.

Table 3.

Possible presentations of CRT.

Asymptomatic (majority)

Swelling of head/neck/limb

Localised pain/numbness

Jaw or shoulder pain

Headaches/sensation of head fullness

Superficial venous distension

Inflammation/phlebitis

Erythema of limb

Difficulty with infusion or aspiration

Incidental finding on CT

CT: computed tomography; CRT: catheter-related thrombosis.

Figure 2.

Schematic image of thrombotic events that may be associated with central venous catheters.

Is CRT the cause of symptoms?

Whilst it may be common practice in many centres to simply remove CVCs that are malfunctioning, difficulty with line aspiration or infusion may be secondary to CRT and a high index of clinical suspicion is required. It is also useful to consider other causes of line occlusion as some are amenable to simple measures. This is particularly relevant to patients with ‘precious lines’ such as those with difficult access

Check the tubing for mechanical obstruction such as a kinked line, an overtight suture or tip abuttal to vessel wall and inspect for a malpositioned port.¹⁴ Repositioning manoeuvres include raising the ipsilateral arm, having the patient sit or stand, or rolling the patient onto one side may be helpful in these cases.

It is worth reviewing preparations administered through the line. Lipid emulsions, such as parenteral nutrition, may leave a residue causing obstruction. These blockages may be amenable to instilling the line with a 70% ethanol solution, although no large studies have been conducted into this practice.¹⁶ A medicines review can also yield clues as to the cause of obstruction as incompatible medications may precipitate within the lumen.¹⁷

Occlusion by catheter thrombosis is the next consideration if no other cause is identified. In the case of an intraluminal clot or fibrin sheath formation (see Figure 2), lumen patency may be restored by instilling the line with a thrombolytic agent such urokinase which is commonly used in the UK and Europe. Urokinase 10,000 units/ml is reconstituted with 3 ml of 0.9% normal saline or water for injection. Each lumen of the occluded catheter is instilled with 5000 units of urokinase and left for 2 h.¹⁸ An alternative thrombolytic agent to urokinase is alteplase, which has been shown in the cardiovascular thrombolytic to open occluded lines trial (COOL) to have a good efficacy and safety profile. Following the administration of 2 mg alteplase with a dwell time of 120 min, 78% patency was achieved with one dose, rising to 87% after a second.¹⁹ Whilst the trial data on local thrombolytic therapy are not extracted from critically unwell patients, the doses of thrombolytic agents are small and for the majority of patients are unlikely to cause harm. It would however be prudent to review potential risks on an individual basis.

Complications

The consequences of CRT are not insubstantial; complications can include pulmonary embolism (PE) in 10–15%, loss of venous access in 10%, infection, post thrombotic syndrome (PTS) and delays in treatment.²

PE: whilst thankfully rarely fatal, PEs are the most serious complication.²

PTS: a chronic complication of VTE that manifests as oedema, chronic pain, a sensation of limb heaviness, and in the worse cases ulceration. It is thought that patients with large, proximal VTEs which fail to completely resolve are at the highest risk of developing PTS.

Future lines: there is consensus on the criteria for line removal when CRT develops; however, there is no evidence to guide when it is considered reasonable to insert a new CVC. Clinicians must therefore assess the risks of further thrombosis against the urgency for central access.

Diagnostic approach

A ‘linogram’ (contrast study) may theoretically be used to confirm internal line kinking or the presence of an intraluminal occlusion, but it is not commonly performed. In practice, trial of a thrombolytic agent empirically may be used which is particularly useful in ‘precious’ lines that cannot be easily replaced.¹⁴

Duplex ultrasound is the initial imaging modality of choice if a CRT is suspected clinically or if lumen patency is not restored with simple measures.²⁰ It is non-invasive and particularly reliable for assessing thrombi in anatomically accessible veins including the jugular, axillary, distal subclavian and arm veins. In the more proximal veins, sited inside the thorax, clearly duplex ultrasound is less sensitive.

If clinical suspicion of CRT is high despite a negative Duplex scan, then contrast venography may be considered as it is the ‘gold standard’ investigation but does confer risks associated with contrast and radiation exposure.^14,21

It is worth noting that the use of the D-dimer assay has not been validated for use in patients with suspected CRT and is therefore not recommended for use in this context.^18,22

Treatment

Factors to consider when treating CRT include

assessment of ongoing need for central access,

the functional status of the line,

the presence of an underlying prothrombotic state and

review of any contraindications to anticoagulation.

Systemic anticoagulation

There is limited good quality data available for the systemic anticoagulation in CRT, particularly relating to critical care patients. Recommendations are therefore largely extrapolated from data for lower limb DVTs and small, non-randomised studies on CRT (of which a significant number are conducted on patients with malignancies).³ Figure 3 provides a proposed treatment algorithm for the treatment of CRT.

Figure 3.

Proposed treatment algorithm for patients with confirmed CRT.

Consensus opinion for the treatment of CRT is for systemic anticoagulation for a minimum of three months.^3,13,23 In patients with malignancy, treatment dose low-molecular weight heparin (LMWH) is recommended due to its superiority over vitamin K antagonists (VKAs) in preventing recurrent thrombosis.^23–25 In critical care patients who frequently have unpredictable pharmacodynamics and are on multiple medications, this also confers the advantage of having fewer potential drug interactions which can be a problem with VKAs like warfarin. In patients with a rapidly changing clinical picture, such as developing acute kidney injury, LMWH may require monitoring with anti-Xa levels. In patients with extensive CRT and particularly high bleeding risk, the use of unfractionated heparin may also be considered due to its short half-life and ease of reversal.

If the catheter remains in situ beyond completion of three months anticoagulation, prophylaxis is recommended until line removal.²³ In patients without malignancy, VKAs may be commenced following an initial period of LMWH.

The duration of anticoagulation following line removal in patients without other ongoing thrombotic risk factors is again controversial due to a lack of good quality data. Some physicians continue to anticoagulate for three months whilst others shorten the duration. The decision making process should include thorough consideration of other potential risks for thrombosis, the size of the clot and the extent to which it occludes the vessel. Duration of six weeks’ anticoagulation may be appropriate if there are no risk factors and the clot is small and non-occlusive.^14,23

There are no trials yet published using non-vitamin K antagonist oral anticoagulants (NOACs), although in the absence of malignancy, there is probably no reason to exclude their use for CRT. Trials are underway with the use NOACs in cancer patients with VTE.

Line removal

The current recommendations^3,23 state that if the CVC is still required and functioning well, it does not have to be removed provided it

is well positioned

is non-infected

demonstrates good resolution of symptoms on surveillance.

The line should be removed if not all the criteria are met, if anticoagulation is contraindicated, if the thrombosis is life or limb threatening or if symptoms are not resolving.

The thrombocytopaenic patient

When CRTs develop in the context of thrombocytopaenia, there is often concern regarding the best management in view of increased bleeding risk. A risk–benefit analysis needs to be carried out on an individual basis and requires regular review. The first three months following thrombosis infer the greatest risk of recurrent thrombosis; therefore, every attempt should be made to provide safe anticoagulation during this period. Current practice is to modify treatment based on the severity of thrombocytopaenia which must be monitored closely. Table 4 provides an overview based on current UK guidelines.^26,27 Owing to its short half-life, intravenous unfractionated heparin can also be considered in patients with PE or extensive thrombosis in the presence of significant bleeding risk.¹⁸ The use of supportive platelet transfusion is addressed infrequently in the literature; however, recent BSCH guidelines for the management of cancer-related venous thrombosis suggest that platelet support may be used to allow full dose anticoagulation if at high risk of recurrence.²⁷ Temporary IVC filter insertion may also be considered if anticoagulation is contraindicated.²⁷

Table 4.

Treatment options in patients with CRT based on degree of thrombocytopaenia.

Platelet count	Treatment options
>50 × 10⁹	Full dose therapeutic anticoagulation taking into account additional bleeding risk factors e.g. renal failure	Bishop et al.²⁸, Baglin et al.²⁶
25–50 × 10⁹	50% dose LMWH Regular monitoring	Murray et al.¹⁸
<25 × 10⁹	No anticoagulation	Watson et al.²⁷

LMWH: low-molecular weight heparin.

Patients who develop thrombocytopaenia following anticoagulation with heparin should be reviewed to exclude heparin induced thrombocytopaenia (HIT).

Prophylaxis

Current guidelines, based on the evidence available, do not recommend anticoagulation for the routine prevention of CRTs,^7,25,28,29 although it is expected that the vast majority of critical care patients will receive LMWH prophylaxis as standard care.

Previously, low-dose warfarin (1 mg/day) had been used for patients with indwelling catheters and malignancy³⁰ but subsequent trials disproved its benefit.³¹ The largest contemporary trial, WARP (Warfarin thromboprophylaxis in cancer patients with CVCs) compared the use of adjusted dose warfarin (INR 1.5–2.0), low-dose warfarin (1 mg/day) and no anticoagulation in the prevention of CRT in cancer patients.³² The data from this trial did find a benefit in CRT reduction in the dose adjusted arm but this was offset by increased bleeding risk. There was no significant benefit in taking low-dose warfarin.

In 2011, a Cochrane review analysed the available data on prophylaxis with UFH and LMWH in the prevention of CRT. It concluded that despite no increase in bleeding risk, there was also no benefit in the reduction of symptomatic thrombosis.³³

There is ongoing debate in respect to maintaining line patency with local measures. Following The National Patient Safety Agency (NPSA) report in 2008, which highlighted potential dangers associated with heparin flushes, the use of saline-only flush solutions was recommended.³⁴ This led to a dramatic fall in the use of heparin flushes in critical care, with some centres questioning if this has resulted in increased thrombotic complications and reduced catheter lifespan. Tully et al. performed an observational study of 445 arterial lines flushed with either saline or heparin solutions and found significantly decreased rates of line occlusion with increased catheter lifespan in the heparin group.³⁵ Whilst there is insufficient evidence to recommend the practice of flushing lines with heparin to maintain line patency at this time,^28,36,37 it is an area that requires further evaluation with adequately powered, blinded randomised controlled trial.

Problem areas in relation to CRT

The increasing use of CVCs, and particularly increasing PICCs usage, will likely increase the incidence of CRT. Although most cases are easily treated, there are still some dilemmas when it comes to CRT. These include

Patients with thrombocytopenia – is not anticoagulating safe?

Choice of catheters – there is ongoing debate on the relative risks of PICC and CVCs in regards to thrombosis and infection

More data on sepsis/thrombosis relationship

Absence of epidemiological data for complications

Probably the biggest issue in relation to CRT management is lack of best evidence.

Conclusions

CRTs are a relatively common occurrence with the potential for significant morbidity. Given that the majority of cases occur asymptomatically, a high index of suspicion is required for diagnosis. The non-invasive nature and sensitivity of venous duplex scanning lends this imaging technique to be the imaging modality of choice in the majority of patients. To date, there is insufficient evidence to support prophylactic anticoagulation in the prevention of CRT; however, careful consideration of modifiable risk factors prior to line insertion can reduce risk. Where feasible, CVCs should be inserted in the right jugular vein with the tip at the cavoatrial junction and despite the increasing usage of PICCs, acknowledgment of their propensity to increase CRT risk needs to be addressed. Providing that a line is still required, functioning, in the correct position and there is no evidence of infection, current recommendations advise against removal. Except in the lowest risk groups, three months systemic anticoagulation is generally recommended. In patients with malignancy, LMWH is the preferred anticoagulant, with warfarin being an alternative in patients without malignancy once their critical illness has resolved. The most pertinent issue to be derived from this report is the lack of good quality evidence on CRT in the critical care population. We are currently extrapolating data from the management of DVTs and small studies of CRT in patients with co-existing malignancy. Adequately powered RCTs are required to definitively establish how best to managed CRT in the critical care arena.

Footnotes

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.

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Catheter-related thrombosis: A practical approach