Pediatr Blood Cancer 2008;50:826–830

Prevention and Management of Central Venous Catheter Occlusionand Thrombosis in Children With Cancer

Roderick Skinner, PhD, FRCPCH,1* Karin Koller, BSc, PhD,2 Nan McIntosh, RSCN,3

Anthony McCarthy, MB, FRCPCH,4 and Barry Pizer, PhD, FRCPCH5

INTRODUCTION

Central venous catheters (CVCs) provide reliable intravenous

access for blood sampling and administration of drugs, blood

products and parenteral nutrition in children undergoing treatment

for malignancy [1,2]. However, occlusion (CVC-occlusion) may

limits a CVC’s usefulness [3], whilst CVC-associated thrombosis

(CVC-thrombosis) may have serious consequences, including post-

thrombotic syndrome and potentially fatal thromboembolic events

[4–6]. The optimum strategies to diagnose, prevent and treat CVC-

occlusion and CVC-thrombosis/thromboembolism are not known

[4,6], so this survey was performed to document the views and

clinical practice of United Kingdom Children’s Cancer Study Group

(UKCCSG) centres. The intention was to determine the extent of

variation in practice and to stimulate both further research into the

reasons for this, as well as to promote the future development of

clinical practice guidelines.

METHODS

A questionnaire was sent to all 22 UKCCSG centres in 2001

concerning the centres’ opinions about the importance of CVC-

occlusion and CVC-thrombosis/thromboembolism, and their clin-

ical practices regarding prophylaxis, diagnosis and treatment.

The following definitions were used:

. CVC—any tunnelled cuffed catheter or implantable subcuta-

neous vascular port.

. CVC-occlusion (partial)—inability to sample from a CVC

lumen that nevertheless flushes satisfactorily.

. CVC-occlusion (total)—inability to sample blood from and

flush CVC lumen.

. CVC-thrombosis—clinical or imaging evidence of CVC-related

venous thrombosis.

. CVC-thromboembolism—pulmonary embolism, intracardiac

thrombosis, superior vena cava thrombosis, any other venous

thromboembolic event.

. ‘‘Positional’’ difficulty (blood can be sampled, or the lumen

flushed, only in certain positions) was not defined as CVC-

occlusion.

. Persistent ‘‘stiffness’’ in sampling/flushing was defined as partial

CVC-occlusion.

Relevant clinical features of CVC-thrombosis/thromboembo-

lism were suggested, detailed lists of possible investigations and

treatments provided and categorised responses requested. Centres

were asked whether they always, usually (�50% of episodes),

sometimes (<50% episodes) or never employed particular inves-

tigations or treatments. A Chi-squared test was used to compare the

numbers of centres inserting �101 or �100 CVCs per year that

always/usually investigated with the number that sometimes/never

investigated partial CVC-occlusion. Too few centres sometimes/

Background. The views and clinical practice of children’s cancerunits were surveyed regarding management of central venouscatheter (CVC) occlusion (CVC-occlusion), CVC-related thrombosis(CVC-thrombosis) and thromboembolism (CVC-thromboembolism).Procedure. A questionnaire was sent to all 22 United KingdomChildren’s Cancer Study Group centres, requesting informationabout their views of the importance of, and their practices regarding,prophylaxis, diagnosis and treatment of CVC-occlusion/thrombosis.Results. Twenty (91%) centres responded. Eighty percent, 80% and70%, respectively, stated that CVC-occlusion, CVC-thrombosis andCVC-thromboembolism were clinically important concerns. Allcentres used heparinised saline flushes as prophylaxis against CVC-occlusion, with little variation (�30% centres) in frequency, volumeand heparin concentration. Symptoms or signs suggesting partialCVC-occlusion, total CVC-occlusion, or CVC-thrombosis/throm-boembolism were always investigated in 20%, 55% and 85% ofcentres, respectively, but with considerable variability in the nature

and sequence of investigations performed, which included (depend-ing on the clinical scenario) chest X-ray, contrast linography orvenography, ultrasonography, echocardiography and magneticresonance venography. A fibrinolytic lock was administered beforeinvestigation of CVC-occlusion in 75% of centres. Although 45%,60% and 80%, respectively, always treated partial CVC-occlusion,total CVC-occlusion or CVC-thrombosis/thromboembolism, the typeand order of treatments differed greatly between centres, especiallyfor CVC-thrombosis/thromboembolism, in which CVC removal,systemic anticoagulation (heparin or warfarin), local or systemicfibrinolysis, or thrombectomy were performed in at least somecentres. Conclusions. The clinical practice of UKCCSG centresregarding prevention, investigation and treatment of CVC-occlusion/thrombosis varies greatly. Additional trials should facilitate develop-ment of evidence-based guidelines. Pediatr Blood Cancer 2008;50:826–830. � 2007 Wiley-Liss, Inc.

Key words: cancer; central venous catheter; children; occlusion; thromboembolism; thrombosis

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21332

——————This article contains Supplementary Material available at http://www.

interscience.wiley.com/jpages/1545-5009/suppmat.

1Royal Victoria Infirmary, Newcastle upon Tyne, UK; 2UKCCSG Data

Centre, Leicester, UK; 3Royal Hospital for Sick Children, Glasgow,

UK; 4Royal Hospital for Sick Children, Belfast, UK; 5Royal Liverpool

Children’s Hospital, Liverpool, UK

On behalf of the United Kingdom Children’s Cancer Study Group

(UKCCSG)/Paediatric Oncology Nursing Forum (PONF) Supportive

Care Group.

*Correspondence to: Roderick Skinner, Department of Paediatric and

Adolescent Oncology, Paediatric Oncology Day Unit, Royal Victoria

Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust,

Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

E-mail: Roderick.Skinner@ncl.ac.uk

Received 31 January 2007; Accepted 6 July 2007

never investigated or treated the other clinical scenarios to permit

statistical analysis.

RESULTS

Twenty centres (91%) responded. Results are expressed as

percentages (of responding centres), unless stated otherwise. The

questionnaire was completed by at least one consultant (paediatric

oncologist, haematologist, surgeon) in 75% centres, in collaboration

with a senior nurse (ward sister, clinical nurse specialist) in 20%,

and by at least one senior nurse in 25%. Medical and nursing staff

both contributed in 35% centres. Ten percent of centres inserted

>200 CVCs per year, 20% inserted 101–200, 55% inserted 51–100,

10% inserted 26–50 and only 5% placed �25.

Importance of CVC-Occlusion, CVC-Thrombosisor CVC-Thromboembolism

Most centres considered these complications to be clinically

important or major concerns (Table I). However, only two centres

(10%) had experienced any deaths (one each from cerebral sagittal

venous thrombosis and pulmonary embolism) due to CVC-

thrombosis/thromboembolism during the previous 5 years.

Written Protocols for Prevention,Investigation and Treatment

Although 80% of centres had a written protocol for prevention of

CVC-occlusion, only 40% had one for investigation and 55% for

treatment. 45%, 20% and 25% of centres had protocols for

prevention, investigation and treatment of CVC-thrombosis, whilst

20%, 15% and 10% had protocols for prevention, investigation and

treatment of CVC-thromboembolism.

Prophylaxis

Tunnelled external CVCs. Eighty-five percent of centres

flushed tunnelled external CVCs weekly, and 15% twice weekly.

All centres used heparinised saline flushes, most commonly 5 ml

(70% centres) of 10 U/ml solution (90%). A minority used different

volumes (range 2–15 ml) or heparin concentrations (1–100 U/ml).

Some centres varied flush frequency, volume or type according to

CVC type (25%), size (20%) or number of lumens (30%).

Subcutaneous vascular ports. Seventeen centres used sub-

cutaneous vascular ports, with the flush interval ranging from

fortnightly (6%) to monthly (82%), using 2–6 (71%) to 10–15 ml

(24%) of heparinised saline (100 U/ml in 88%, 10 U/ml in 12%).

Few centres varied the flush frequency, volume or type according to

the port type (6%) or size (18%).

Other methods of prophylaxis. Twenty-five percent of centres

used systemic low molecular weight (LMW) heparin and 15% low

dose warfarin in selected high-risk patients.

Diagnosis

Twenty percent centres always, 25% usually and 50% sometimes

investigated partial CVC-occlusion. The corresponding figures

were 55%, 35% and 10% for total CVC-occlusion. Eighty-five

percent centres always and 10% usually investigated patients with

clinical features of CVC-thrombosis or CVC-thromboembolism

(Table II). One centre never investigated partial CVC-occlusion, but

no centre stated that it never investigated the other three clinical

scenarios. The responses do not add up to 100% for CVC-

thrombosis or CVC-thromboembolism since one centre reported

no experience of these complications. Whether a centre always/

usually or sometimes/never investigated partial CVC-occlusion was

not related to the number of CVCs the centre inserted per year

(P¼ 0.1).

Only 15% of centres had a protocol that defined a specific

sequence of tests. Seventy-five percent of centres instilled a

fibrinolytic agent into the CVC (fibrinolytic lock) as treatment

before investigating CVC-occlusion, employing urokinase (65%),

streptokinase (5%) or recombinant tissue plasminogen activator

(rtPA; 5%).

Table II also shows the nature of the investigations used by

centres providing detailed information, including both first line

investigation and those employed at any stage. The results are

expressed as percentages of centres providing information about

each specific clinical scenario. A wide range of investigations was

performed, with marked variability between centres. Chest X-rays

were the most commonly performed investigation in all four clinical

scenarios, being the first-line investigation in 60–100% of centres

and performed at any stage in 73–100% (varying with each

scenario). Depending on the specific scenario, other investigations

performed included linograms (radiological imaging as radio-

opaque contrast material is flushed into CVC, used in CVC-

occlusion/thrombosis by 50–60% of centres), Doppler ultrasound

and echocardiography (used in CVC-thrombosis/thromboembolism

by 53–60% of centres), and radioisotope ventilation perfusion (V/

Q) scans (in CVC-thromboembolism in 53% of centres). Less

commonly performed investigations included magnetic resonance

venograms (MRVs) and investigation of coagulation pathways or of

pro-thrombotic factors (in CVC-thrombosis/thromboembolism in

13–20% of centres). There was no consistent pattern in the order in

which these investigations were performed.

TreatmentForty-five percent of centres always and 50% usually treated

partial, and 60% and 35%, total CVC-occlusion. Likewise 70–80%

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. Importance of CVC-Occlusion, CVC-Related Thrombosis and Thromboembolism

CVC-occlusion CVC-thrombosis CVC-thromboembolism

(1) It is not a significant problem 0 1 (5%) 6 (30%)

(2) It is a nuisance for patients and/or staff but not usually clinically important 4 (20%) 3 (15%) 0

(3) It is a clinically important concern 7 (35%) 9 (45%) 8 (40%)

(4) It is a major clinical concern and is important enough to merit efforts to

improve current practice

9 (45%) 7 (35%) 6 (30%)

Results expressed as number (percentages) of responding centres.

CVC Occlusion and Thrombosis 827

always and 5–20% usually treated patients with clinical features of

CVC-thrombosis/thromboembolism. There was no relationship

between centre experience and the centre’s likelihood of starting

treatment. Three centres stated that they had not recognised any

clinical problems due to CVC-thrombosis/thromboembolism (Sup-

plemental Table I). None of these three centres had a written

treatment protocol, although they inserted 26–50, 51–100 and

101–200 CVCs respectively per year. The form was completed by a

consultant in two of these centres and senior nurse in the other. Two

of these centres and one other centre graded the relative importance

of CVC-occlusion and CVC-thrombosis/thromboembolism as

neither significant nor clinically important, but there was no

apparent difference between these 3 and the other 17 centres in the

frequency or manner of treatment (except for those complications

that were not reported by 2 centres, when no further details were

provided). Only two centres (10%) had a protocol with a specific

sequence of treatment.

Supplemental Table I shows the nature of the treatments used by

those centres providing detailed information, including both first

line treatment, and that used at any stage of management. Several

different treatments were used, with wide variability between

centres in the nature of treatments and the order in which they were

employed. First line treatment of CVC-occlusion comprised a

fibrinolytic lock in 44–57% of centres, whilst the remainder used a

fibrinolytic infusion (6–29% of centres) or flushed the CVC with

crystalloid or heparin solution (14–50%).

CVC removal was performed more frequently as first line

treatment in the presence of signs (e.g. facial or limb oedema) of

CVC-thrombosis (35% of centres), symptoms (e.g. chest pain) or

signs of CVC-thromboembolism (44%), and where investigation

had revealed either CVC-thrombosis or CVC-thromboembolism

(17–19%), most commonly as a closed procedure (i.e. ‘‘pulling the

line’’ without direct visualisation of the venous incision). Systemic

anticoagulation (with either standard or LMW heparin) was also

used commonly in these scenarios (34–50% of centres), whilst

fibrinolytic locks and infusion were used less frequently (0–11%

and 0–33%, respectively).

Other treatments employed less frequently included warfarin

anticoagulation (for CVC-thrombosis, or symptoms or signs of

CVC-thromboembolism, in 35–50% of centres), systemic fibrinol-

ysis (rtPA infusion) (for CVC-thromboembolism in 31–38% of

centres, and confirmed CVC-thrombosis in 17%), and thrombec-

tomy (for CVC-thrombosis in 6–11% of centres, and CVC-

thromboembolism in 13–19%). Open CVC removal at thoracotomy

(with direct visualisation of the venous incision) was performed for

confirmed CVC-thromboembolism in 6% of centres.

When flushing, infusing or locking an occluded CVC, most centres

(85%) treated only the affected lumen, whereas 15% treated all lumens.

DISCUSSION

Occlusion and thrombosis/thromboembolism remain frequent

and potentially serious complications of CVCs in patients with

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE II. Investigation of CVC-Occlusion, CVC-Related Thrombosis and Thromboembolism

Clinical scenario

Number ofcentres providing

information First line investigation Investigation at any stage

(1) Partial CVC-occlusion 14 Chest X-ray 79% Chest X-ray 79%Linogram 7% Linogram 50%Not specified 14% Contrast venogram 14%

MRV 7%Doppler ultrasound 7%Echocardiogram 7%

(2) Total CVC-occlusion 15 Chest X-ray 100% Chest X-ray 100%Linogram 60%Echocardiogram 33%Contrast venogram 7%Doppler ultrasound 7%MRV 7%

(3) Signs of CVC-thrombosis 15 Chest X-ray 73% Chest X-ray 87%Doppler ultrasound 13% Linogram 60%Investigation of coagulation pathways 13% Doppler ultrasound 60%

Echocardiogram 53%Contrast venogram 40%MRV 20%Investigation of coagulation pathways 13%Investigation of pro-thrombotic factors 13%

(4) Symptoms or signs of 15 Chest X-ray 60% Chest X-ray 73%CVC-thromboembolism Doppler ultrasound 20% Doppler ultrasound 60%

Full blood count 7% Echocardiogram 53%V/Q scan 7% V/Q scan 53%Investigation of coagulation pathways 7% Linogram 33%

Contrast venogram 33%MRV 20%Investigation of coagulation pathways 20%Investigation of pro-thrombotic factors 20%Pulmonary angiogram 13%

See Methods Section for definitions; Linogram¼ radiological study where radio-opaque contrast material is flushed into CVC; MRV¼magnetic

resonance venogram; V/Q¼ radioisotope ventilation perfusion scan.

828 Skinner et al.

malignancy [2–4,6–12]. An early report of 1,019 children with

malignancy described 1141 CVCs of which 284 were removed non-

electively (39% of all removals), including 27 (10%) due to CVC-

occlusion [2]. More recently, a prospective study of 418 CVCs in

368 children with malignancy or undergoing haemopoietic stem cell

transplantation, observed for a mean of 256 days each, reported 84

episodes of CVC-occlusion (0.20 per CVC) and 9 of CVC-

thrombosis (0.02 per CVC) [11]. CVC removal was required in 44%

of CVC-thrombosis episodes [11]. These data may underestimate

the frequency of CVC-thrombosis since many episodes are

clinically silent. A recent review suggested that CVC-thrombosis

may occur in about 40% of patients, with only about 12% being

symptomatic [12]. A study of 24 children with malignancy under-

going removal of subcutaneous vascular ports (at completion of

therapy in 15 patients) demonstrated that 12 had venographic evidence

of CVC-thrombosis. Nine of these patients had no clinical features of

CVC-thrombosis [10]. Studies in adults have revealed venographic

evidence of CVC-thrombosis in up to 60% of patients [13,14]. The

long-term outcome of CVC-thrombosis is unknown [6], but CT

angiography demonstrated residual deep venous abnormalities 10–

30 months after CVC removal in 3 (12%) of 25 children previously

treated for malignancy [15]. Moreover, CVC-thrombosis/throm-

boembolism may have fatal consequences. The Canadian Childhood

Thrombophilia Program reported that 9 (3.7%) of 244 consecutive

children with CVC-thrombosis died as a result of pulmonary

embolism (7 children) or obstructive intracardiac thrombosis (2) [4].

The relatively small proportion of UKCCSG centres with

specific protocols for the management of CVC-occlusion and

especially CVC-thrombosis/thromboembolism, and the consider-

able variability in the clinical practice of centres, reflects the lack of

high quality evidence to guide practice. Furthermore, although most

centres believed CVC-occlusion/thrombosis to be an important

issue, a minority did not. Although the absence of experience with

CVC-thrombosis/thromboembolism reported by three centres was

not related to centre size, participation in a comprehensive

surveillance programme (analogous to the Canadian Childhood

Thrombophilia Program [4]) might generate greater awareness of

the potential importance of this complication.

It is possible that the results of this survey do not reflect current

practice in UK centres since it was performed in 2001/2002, but it

seems unlikely that practice has become more uniform subsequently

since no national guidelines have been developed during this time.

Moreover, marked inter-centre variability in practice was still

apparent when the Supportive Care Group reviewed CVC care

protocols used in UKCCSG centres in 2004/2005 in order to

evaluate the feasibility of developing consensus guidelines (A.

McCarthy, unpublished work). Another potential limitation of the

survey is that the questionnaire was completed by one respondent

only in 65% of centres. However, all replies were completed by at

least one experienced staff member (consultant or senior nurse)

involved in the use and care of CVCs. Medical and nursing staff

work together closely in paediatric oncology multidisciplinary

teams in the UK, suggesting that the survey should be representative

of UK practice.

Despite the frequency of CVC-occlusion and the potential severity

of CVC-thrombosis/thromboembolism, there is little agreement

about how to diagnose, prevent and treat them [6]. Considerable

uncertainty persists about the optimum choice of ‘‘flushing’’ protocol.

No large controlled study has been performed in children [16], leading

tovariability in practice [17]. Several prophylactic strategies to reduce

the frequency of CVC-occlusion/thrombosis have been studied [17],

including low dose warfarin [18–20], infused conventional [21] or

subcutaneous LMW heparin [13], but the overall risk-benefit balance

of these treatments remains unclear [12,22]. Relatively few studies

have included children [19,20].

Less invasive imaging modalities (e.g. MRV) [23] have been

used to detect CVC-thrombosis, but have not been shown to be

superior to contrast venography and ultrasonography [6,24]. One

study suggested that MRV several months after CVC removal

overemphasised venous stenoses in children [23].

CVC-occlusion is usually treated by infusing or ‘‘locking’’ a

fibrinolytic drug (urokinase [25,26], streptokinase or rtPA [27–31])

into the affected lumen. One study in adults found that rtPA was

more effective than urokinase in restoring function and clearing

thrombotic CVC-occlusion [32], but paediatric data are lacking. It is

agreed that the optimum treatment for CVC-thrombosis is CVC

removal, this is often impractical. Full dose anticoagulation with

warfarin or LMW heparin is usually employed [33], but the best

approach in children is not clear. An alternative strategy to use the

CVC itself to direct fibrinolytic treatment [34] may reduce the risk of

systemic toxicity, but this has not been studied in children. Finally,

uncertainty persists about how asymptomatic CVC-thrombosis

should be managed [6].

Although it is unclear how frequently CVC-occlusion heralds

the onset of CVC-thrombosis [6], it is possible that prevention of

CVC-occlusion may retard the subsequent development of CVC-

thrombosis [35].

The results of this survey demonstrate the need for further

research into several aspects of the management of CVC-occlusion

and CVC-thrombosis. For example, does the use of systemic LMW

heparin in addition to a conventional heparin CVC flush reduce the

frequency of CVC-thrombosis, especially in high-risk scenarios?

Although the 7th AACP Conference on Antithrombotic and

Thrombolytic Therapy did not recommend this strategy, this was

due to insufficient evidence [22]. Likewise, there is a need for a well-

designed comparative trial of urokinase and rtPA in the treatment of

CVC-occlusion in children.

Nevertheless, several professional groups have produced guide-

lines for the use of CVCs in children in an attempt to reduce the risk

of thromboembolic complications (including occlusion), especially

in children dependent on long-term CVCs for continued treatment.

Some of these documents have been published [36,37], but most are

based largely on a combination of low quality published evidence

(e.g. case series, descriptive studies), ‘‘expert opinion’’ and

institutional practice and/or experience. Unfortunately, it has not

been possible to develop guidelines based on rigorous systematic

review since there is a paucity of high quality clinical trials [6].

However, a formal critical appraisal of published paediatric

literature would identify knowledge gaps with the ultimate aim of

stimulating future research that would then facilitate the develop-

ment of evidence-based guidelines.

In conclusion, this survey of UKCCSG centres has demonstrated

considerable variability in clinical practice in the prevention,

diagnosis and therapy of CVC-occlusion and CVC-thrombosis/

thromboembolism in children with malignancy, and highlighted the

lack of consistency in those written protocols that are available. The

lack of high quality evidence makes it imperative to address

variability in care by designing studies and controlled trials of these

elements of CVC care, thereby enabling the development of

rigorous evidence-based guidelines.

Pediatr Blood Cancer DOI 10.1002/pbc

CVC Occlusion and Thrombosis 829

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