research elective ‘the role of urokinase in central venous catheter...
TRANSCRIPT
Research elective
‘The role of urokinase in central venous catheter
dysfunction during hemodialysis’
Student: R.W. Schouten, student number 1642057, Rijksuniversiteit Groningen
Clinical tutor AMC: Dr. N.C. van der Weerd, Nephrologist AMC Amsterdam
Faculty tutor UMCG: Prof. Dr. W.J. van Son, Nephrologist UMCG Groningen
August 2014, Dianet & department of Nephrology AMC Amsterdam
Faculty of Medicine, University Medical Centre Groningen, University of Groningen
Research elective RW Schouten page 2 | 26
Contents
Summary .................................................................................................................................... 3
Introduction ................................................................................................................................ 4
Methods...................................................................................................................................... 9
Results ...................................................................................................................................... 12
Discussion ................................................................................................................................ 18
Conclusion ............................................................................................................................... 22
Ongoing (prospective) research ............................................................................................... 23
Acknowledgements .................................................................................................................. 24
Literature .................................................................................................................................. 25
Appendices ............................................................................................................................... 26
Research elective RW Schouten page 3 | 26
Summary
Written as an Abstract
Background and Objectives: Use of a central venous catheter (CVC) for hemodialysis (HD)
is associated with thrombotic complications and dysfunction resulting in a lower adequacy of
dialysis. Use of a CVC has higher morbidity and mortality compared to other vascular access
options. The primary aim of this study is 1) to evaluate the effectiveness of urokinase when
treating dysfunctional CVCs. Secondary aims are 2) to describe patient and dialysis
characteristics of patients using a CVC, 3) to identify indications resulting in the use of a
semi-permanent CVC and 4) to describe the incidence of dysfunction, CVC-removal and to
describe CVC-survival.
Methods: This is a retrospective cohort study were data was obtained from the digital patient
file. Analysis was performed with data from all patients with a semi-permanent CVC in 2012
and 2013 in Dianet (AMC). Data from 102 patients were used after exclusion. Dysfunction is
defined as a blood flow <200 ml/min measured on the dialysis machine. For the statistical
analysis of the primary aim, multivariate linear regression models were used.
Results: The mean age was 55 years, 49.5% is male and 60% is Caucasian. The total number
of dialysis sessions included is 12,906.
1) No significant effect from urokinase on catheter function has been found. In 63.5% of the
dysfunctional sessions urokinase was given as a bedside intervention. After urokinase 66.4%
of the CVCs were functional during the same dialysis session or at the start of the subsequent
dialysis session. However 60.3% of the dysfunctional CVCs became functional without the
use of urokinase.
2) In the multivariable analysis associations with the incidence of dysfunction were found for
number of CVCs removed during the study period and the incidence of lumen reversal. No
other associations between the incidence of dysfunction and patient characteristics were
found to be significant.
3) 46% of the patients with a semi-permanent CVC are waiting for fistula or graft placement
or maturation. In 19% no other vascular access option is available.
4) The incidence of dysfunctional sessions is 2.16% of the total sessions. Tunneled single
lumen CVCs show a slightly better CVC survival compared to tunneled double lumen CVCs.
Femoral CVCs show a higher incidence of dysfunction and lower CVC survival compared to
internal jugular CVCs.
Conclusion: When using urokinase to improve blood flow in dysfunctional central venous
catheters the outcomes are uncertain. No significant effect on blood flow improvement of
urokinase has been found. No relevant patient characteristics were found to predict the
incidence of dysfunction. New prospective research evaluating different interventions could
give more definitive results.
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Introduction
Aims
A central venous catheter (CVC) is a commonly used vascular access method for
hemodialysis (HD) patients. Dysfunction of CVCs is a frequent problem and a reason for
under-dialysis. 2 The primary aim of this study is 1) to evaluate the effectiveness of urokinase
when treating dysfunctional CVCs. Secondary aims are 2) to describe patient and dialysis
characteristics of patients using a CVC, 3) to identify indications resulting in the use of a
semi-permanent CVC and 4) to describe the incidence of dysfunction, CVC-removal and to
describe CVC-survival.
Goals and hypothesis
This study will investigate the effect of bedside interventions in case of dysfunctional CVCs.
The hypothesis is that urokinase locking solution will improve blood flow in dysfunctional
CVCs. This is a retrospective cohort study using the existing patient files in 2012 and 2013.
The goal of this study is to help nephrologists determine what bed-side intervention to use
and what the expected results are of these interventions. The secondary aims can contribute to
a better understanding of the patient and dialysis characteristics of patients using a semi-
permanent CVC for hemodialysis.
Vascular access
Effectiveness of the hemodialysis relies on a vascular access with steady blood flow. The
ideal vascular access delivers a stable dialysis blood flow, is long lasting and has little or no
complications.3 The preferred vascular access for HD is the surgically created arterio-venous
(AV)-fistula followed by the AV-graft. The AV-fistula has the lowest complication rates and
best 5-year survival. 3-5 A central venous catheter (CVC) can be used in the acute setting, as a
bridge therapy towards other vascular access options or when a graft or fistula is not possible.
Despite national and international guidelines CVCs are frequently used as a semi-permanent
vascular access and this portion has increased in recent years.6-8 The main disadvantages of a
CVC are the risk of infection, the frequent dysfunctional sessions and flow problems due to
thrombotic complications. 9-11 There is also a risk of central venous stenosis, especially when
using the subclavian veins. 10 This study will focus primarily on the noninfectious catheter-
related dysfunction.
Central venous catheter
The use of a CVC is associated with higher morbidity, mortality, more invasive interventions
and more hospital admissions compared to the AV-fistula. 11 The current guidelines in
Europe and the United States discourage the use of a CVC. Despite these guidelines and
recommendations over 17% of the semi-permanent vascular access for hemodialysis is a
CVC in the United States. 8 In Europe the numbers are diverse, ranging from 3% in Germany
to 23% in the United Kingdom.8
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Most CVCs are used in the acute setting for a limited time. Prolonged use of a CVC is
associated with relatively higher risks of thrombotic and infectious complications. This study
will focus on the semi-permanent use of a CVC. Indications for a CVC are shown in figure 1.
Especially for older patients the use of a CVC has shown higher mortality rates due to CVC
complications compared to younger patients.12
The preferred location of a CVC for the semi-permanent use is the right internal jugular vein
because of the anatomy that allows easy access to the right atrium. The right jugular vein is
associated with lower risk of dysfunction and more stable blood flows compared to the
femoral and subclavian veins. 13 The left internal jugular vein is a good alternative with
similar morbidity and mortality. Other options like the femoral or subclavian veins show
more complications like central venous stenosis and dysfunctional dialysis sessions. 14
Several kinds of CVCs are used for hemodialysis. A CVC can have a single or double lumen
and they can be tunneled, untunneled or straight untunneled. In the Netherlands the most
common used for semi-permanent access is the tunneled double lumen catheter. 15 The
evidence for the choice between single and double lumen or tunneled and untunneled CVCs
is limited and does not show consistent outcomes.14-17 Temporary untunneled CVCs are
associated with more complications compared to tunneled CVCs.18
Newer design of the tunneled double lumen catheters include an identical peripheral tip for
both lumens, which may reduce the amount of recirculation when dealing with dysfunction.
Literature shows little or no difference in performance comparing the different designs and
brands.14,19
Why using a CVC?
Acute setting
'Bridge' therapy
Renal Tx
Peritoneal dialysis
Shunt surgery or maturation
permanent
Shunt failure or not possible
Patient refusal or no show
Limited life expectancy
Fig 1. Indications for the use of a CVC for HD. This study has excluded the ‘acute setting’
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CVC dysfunction and complications
The most dangerous complication of a CVC is bacteremia and sepsis. With a semi-permanent
CVC in situ the chance of bacteremia is 27.5% in 1 year. Sepsis occurs with an incidence of
1.3/1000 catheter days. 20 Secondly there are dysfunctional CVCs leading to low blood flows
and inability to supply adequate HD. Dysfunctional CVCs are a frequent issue with chronic
hemodialysis patients. 17 Between 20-30% of CVCs have dysfunctions after 120 days.21 The
overall survival rate and incidence of dysfunction differs between multiple studies. 22,23 A
large study with the tunneled single lumen Tesio ® CVC shows a 1-year survival rate of 74%
and a 2-year survival rate of 44%.24 Thrombotic and infectious complications occur with an
incidence ranging between 0,254 – 5.5/1000 catheter days.9,21,25,26 Dysfunctional dialysis
sessions occur in a similar study around 6-7/1000 HD sessions. 27 Most studies show no
associations between patient or dialysis characteristics and the risk of dysfunction.14,16 Only
one small study shows patient factors like diabetes and the number of previous CVCs
increase the risk of dysfunction. 17
The effects of dysfunction and other complications are based the increased morbidity and
mortality, increased health care costs and a lower quality of life perceived by the
hemodialysis patients. Over 60% of the patients with a CVC suffers from anxiety concerning
the vascular access for hemodialysis. 28
Dysfunction is defined in Europe as a blood flow <200 ml/min or a pre-pump arterial
pressure <-250 mmHg. The definition of dysfunction in the United States differs because of
the different dialysis methods with higher flows and pressures compared to common practice
in Europe.3
Literature describes early and late dysfunction. 14 Early dysfunction occurs shortly after the
CVC placement, mostly due to mechanical problems like incorrect tip placement, damage to
the lumen, kinking of the CVC after placement or flow obstruction when the CVC tip lies
against the vessel wall. Late dysfunction
occurs mostly due to progressive occlusion
by fibrin sheaths or the forming of a
thrombus.
Types of thrombotic occlusions are shown
in figure 2. The thrombus may be located
inside the lumen or at the tip of the CVC or
it may be located outside the lumen causing
compression and thus dysfunction. Lastly a
fibrin sheath may form with connective
tissue causing a web of fibrin. Dysfunction is mostly due to thrombotic complications,
however research on this subject is limited. 14 The forming of a fibrin sheath was first
described in an in-vivo study where a silicon catheter was placed in rats. 29
The Virchow triad can be used to describe the pathophysiology of this thrombus forming.
First there is endothelial injury due to the insertion of the CVC. Second there are
hemodynamic changes like stasis during the interdialytic period and turbulence due to the
Fig 2. Types of thrombotic occlusions. Source: 1
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CVC tip disrupting normal blood flow. Third literature describes a hypercoagulability state
due to CVC insertion. 30
Signs of CVC dysfunction include not being able to aspirate blood freely, low blood flow,
increased arterial pressure and frequent pressure alarms not responsive to patient
repositioning or catheter flushing.4 The dialysis nurse plays a central role in the detection and
early treatment of CVC dysfunction. 31
Recirculation and reversal of lumens
A common problem with catheter dysfunction is the recirculation. Recirculation occurs when
dialyzed blood mixes with undialyzed blood thus lowering the adequacy and efficiency of the
dialysis session. Especially when reversing the lumens the recirculation can become as high
as >20%. Reversal of lumens of a CVC means connecting the arterial connection of the
dialysis machine to the venous connection of the CVC and the other way around. This results
in an Art-Ven, Ven-Art connection and thus reversing the normal blood flow inside the
lumen(s) of the catheter compared to the normal connection Art-Art, Ven-Ven. When dealing
with thrombotic complications this reversal can help to improve blood flow for a limited
amount of dialysis sessions.14 Literature shows high rates of recirculation occur mostly in
femoral catheters with an additional increased effect when reversing the lumens compared to
jugular CVCs, probably due to the longer lumens of femoral CVCs. 32 Reversal of jugular
CVCs show an increase of recirculation from 2 to 10%. 2 The consequences of higher
recirculation and possible lower adequacy have not been clearly stated in the literature. When
dealing with dysfunctional CVCs, reversal of lumens might improve adequacy of HD despite
the higher recirculation rates. Studies have shown increased urea clearance in reversed
dysfunctional CVCs compared to unreversed dysfunctional CVCs. 33
Prevention and interventions
Recent reviews in 2012 and 2013 make recommendations for the prevention and management
of CVC dysfunction and thrombotic complications.14 These interventions can be divided in
bed-side interventions and invasive interventions. The invasive interventions consist of
replacing the current CVC using the in situ guide wire or placing a new CVC. Replacement
of the CVC is relatively expensive, invasive, time-consuming and has an increased risk of
complications.14 Therefore it is seen as a last resort in catheter dysfunction. This study will
focus on the bed-site interventions, which are listed below.
1. Changing the position of the patient during dialysis
2. Flushing of both lumen during dialysis with NaCl
3. Reversal of lumens (arterial-venous and venous-arterial)
4. Locking solutions with urokinase, discussed below
Other, more invasive, interventions like stripping the lumen or intra-luminal brushing seem to
have a possible effect on improving blood flow in case of CVC dysfunction. However there
are concerns about showering micro-organisms in the circulation and possible arrhythmias.
Moreover the stripping has a high technical success rate but this is short lived when looking
at CVC survival. 14,34 Systemic therapy with Aspirin®, Warfarin® or Acenocoumarol® show
no positive effect on the incidence of dysfunctions. 4
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Interdialytic locking solutions
Locking solutions are solutions of anti-microbial and thrombolytic agents that can help to
prevent infectious and prevent or treat thrombotic complications like dysfunctional CVCs.35
The lumen is filled with 1.5 – 2.2 ml of locking solution for 30-60 minutes or left in place in
between dialysis sessions (interdialytic period). Commonly used locking solutions are citrate,
heparin and plasminogen activators like urokinase. 36. The pathophysiology is that ‘locking’
the CVC with an anticoagulant will prevent and possibly treat catheter related thrombosis and
extend CVC survival. Heparin has shown systemic anticoagulation complications, like
heparin-induced thrombocytopenia, especially when using higher doses >1000 units/ml.37,38
Because of these possible inadvertent and the anti-microbial effect, Citrate is favored above
Heparin, showing similar thrombosis and dysfunction rates and possible higher cost-
effectiveness. 21,39
Most relevant studies have been investigating the prophylactic effect of Citrate versus
Heparin locks. The few studies investigating plasminogen activators (PA) show an advance
of PA compared to heparin with better flows and fewer complications. 26,40 However these
were all small uncontrolled studies. 41,42 These studies use blood flow as the main parameter
of CVC dysfunction.
Research investigating the effect of these thrombolytics, like urokinase, when trying to
improve blood flow in dysfunctional CVCs is limited and don’t have consistent outcomes.
50-90% of the CVCs have better flows after the use of a thrombolytic locking solutions.42-45
Recent studies suggest thrombolytics can be used to prevent CVC dysfunction in vulnerable
patient groups. However the mean gain of CVC survival is 14 days or 5-7 dialysis sessions. 43,46 In a recent study investigating Tenecteplase, 34% of the dysfunctional CVCs were
functional after a 1 hour dwell in Tenecteplase. In the extended dwell group 49% was
successful. 47
One possible problem with interdialytic locking solutions might be the leakage of
anticoagulant into the systemic circulation because of the parabolic flow in the CVC. 48
Blood will replace the leaked anticoagulant and thrombosis might be accelerated, especially
in between dialysis sessions.
Dianet AMC
The dialysis department of Dianet (AMC) has 130 chronic HD patients. A relatively large
portion of the dialysis population uses a CVC as a semi-permanent vascular access for HD.
By investigating patient characteristics of this patient group and the interventions when
dealing with dysfunctional CVCs, protocolling might improve and more evidence based
interventions may be used.
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Methods
Study design and patients
This is a retrospective cohort study using the digital patient files. This study included all
patients on hemodialysis with a semi-permanent central venous catheter in Dianet (AMC)
who received hemodialysis in 2012 and/or 2013. A list of patients was acquired via the
financial database and treatment codes. Only chronic hemodialysis patients were included.
Patients who received hemodialysis via a CVC in the acute setting were excluded. The
definition of acute dialysis is intermittent hemodialysis <1 month. Only patients older than 18
years were eligible for enrollment.
Because of the retrospective design no ethics review board approval was acquired.
Data collection
Demographic data: Clinical and demographic data were collected through review of the
digital patient dialysis database Diamant®. Age was calculated using the 1st of January 2012.
Ethnicity was subtracted from the medical file in Diamant® or by using the patient’s picture
of the AMC patient file. When no picture or place of birth were found they were defined as
‘other/unknown’. The number of dialysis sessions was calculated between the start-and end-
date together with the prescripted number of dialysis per week.
Primary outcome (1): The primary outcome of this study is the effect of the urokinase
locking solution when dealing with catheter dysfunction. Dysfunction is defined as a inability
to maintain a blood flow <200 ml/min, despite flushing and positional changes of the patient.
This blood flow was extracted from the nurse report. The blood flow is not an actual
measurement but it is adjusted by the dialysis nurse. The dialysis nurse will adjust the blood
flow when either 1) No blood flow is possible 2) Arterial pressure is becoming <-250mmHg
or 3) frequent alarms not responsive to patient repositioning or catheter flushing.
Urokinase is administered as a 30-90 minute dwell when the patient is inside the dialysis
center or as an interdialytic locking solution. The indication for administering urokinase is
made by the dialysis nurse or the nephrologist.
A positive effect from the urokinase is defined as an increase of blood flow ≥ 200 ml/min. No
effect was defined as a blood flow remaining <200 ml/min, thus the CVC remains
dysfunctional. The effect could be in the same dialysis session, defined as an ‘early effect’ or
at the start of the next dialysis session, defined as a ‘late effect’.
As intervention urokinase locking solution with a concentration of 5000-25000 U/lumen was
used filling the lumen with 1.5-2.2 mL, depending on the brand of CVC and manufacturers
prescription.
This locking solution can be used either as a 30 or 60 minute dwell during the dialysis session
or for a number of days in the interdialytic period.
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Secondary outcomes (2-4):
Duration of the indication for a CVC was calculated between the start date of hemodialysis
via a CVC and the end date when the indication was no longer applicable. The following
grouping method was used for indications.
1. Short life expectancy
2. Waiting for AV-fistula/graft surgery or maturation
3. Waiting for a renal transplant
4. Waiting for peritoneal dialysis catheter placement
5. Shunt surgery is not possible or previous shunts have failed
6. Patient refusal
The nurse report of every dialysis sessions was analyzed for the words related to re-pooling.
The duration of a matured shunt and a CVC in situ at the same time was calculated using the
first date a matured shunt has been used and the removal date of the CVC.
The indication for the different kind of CVCs like tunneled or untunneled is made by the
nephrologist. CVC survival is calculated for CVCs removed because of infection,
dysfunction or dislocation. CVCs are placed by either the nephrologist or the vascular
surgeon in this center.
Literature research
For the literature research PubMed was searched for articles in English. The following search
items were used, "central venous catheters"[MeSH] OR "catheters" AND
("haemodialysis"[MesH] OR "renal dialysis"[MeSH] AND "complications" OR
"dysfunction". Secondly the following terms were used searching for the effect of urokinase
or other locking solutions: "locking solution" OR "urokinase" OR "heparin" OR "citrate"
AND "haemodialysis"[MESH]. Lastly the reference section of relevant studies was searched
for additional studies.
Data analysis
To evaluate the effect of urokinase on
the dysfunction a linear regression
model was used. Because multiple
dysfunctions can occur within one
CVC, and multiple CVCs can be
included from one patient, the results
were corrected for the multiple levels.
These levels are shown in figure 4. A
multi-level regression model was used
to correct for the effect of the multi-
level design of the data. In SPSS the
Generalized Linear Mixed Model
(GLMM) was performed.
Patient 1
CVC 1
Dysfunction 1
Dysfunction 2
Dysfunction 3
Dysfunction 4
CVC 2 Dysfunction 1
Patient 2 CVC 1 -
Patient 3
CVC 1
Dysfunction 1
Dysfunction 2
CVC 2 -
CVC 3
Dysfunction 1
Dysfunction 2
Level 1: Level 2: Cases:
Fig 3. Visualization of different levels when analyzing dysfunctions.
Research elective RW Schouten page 11 | 26
Statistical analysis
The data are presented as means with standard deviation (SD) or medians with interquartile
ranges (IQR). Results were considered statistically significant when a two-sided p-value of
≤0.05 was achieved.
The average percentage of missing values per variable was 2%. Most data were not normally
distributed. To identify possible confounding factors to the incidence of dysfunction the
Mann Whitney tests and Chi-Square tests in SPSS were used. A Mann Whitney test was used
to compare CVC survival between the different locations of the CVC and between the type of
CVC. A linear regression analysis was used to study the relation between each variable on
dysfunction and CVC-survival. Because of the multi-level design of this study a Generalized
Linear Mixed Model has been used to adjust for the effect of the patient-and CVC-level on
the individual cases.
All calculations were made by use of the 64-bit statistical package (SPSS for Windows
Version 20; SPSS Inc. Headquarters, Chicago, Illinois, US).
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Results
Baseline: Patients
A total of 102 patients were included for analysis. The baseline characteristics of the total
cohort is listed in table 1. The mean age was 55 years (±17). Of the 102 patients 50% were
male. 59% of the patients were Caucasian, 30% Negroid and 6% Asian. Primary renal disease
27% were vascular origin, 22% diabetic and 17% systemic. Medical history shows 77% of
the patients have confirmed hypertension and 37% have diabetes. 53% of the patients use
systemic anticoagulant therapy, like vitamin K antagonists and thrombocytes aggregation
inhibitors like Aspirin®. Dialysis history shows patients have a history of median 390 days
(IQR 0-3202) of renal replacement therapy before the start of this study. 50% of the patients
had an average of 2 CVC before this study.
Table 1. Baseline characteristics of the patient group receiving HD via a semi-permanent CVC.
Characteristic n or median % or SD/IQR
Number of dialysis sessions in 2012 and/or 2013 included 12.709 sessions
Number of patients included 102 patients
Demographic and social
Age group, mean (yrs.) 55 years ±17.3 yrs
.1-30, n (%) n13 12.6%
.31-45, n (%) n20 19.4%
.46-65, n (%) n34 33.0%
.>65, n (%) n34 33.0%
Gender male % 50 49.5%
Race
.Caucasian, n (%) n60 59.4%
.Negroid, n (%) n32 31.7%
.Asian, n (%) n6 5.9%
.Other / unknown, n (%) n3 3.0%
Primary renal disease
Vascular, n (%) n27 26.7%
Diabetic nephropathy, n (%) n22 21.8%
Systemic disease / nephritis, n (%) n17 16.8%
Cystic disease, n (%) n6 5.9%
Other, n (%) n29 28.7%
Medical history
Diabetes, n (%) n37 36.6%
Hypertension, n (%) n78 77.2%
Myocardial infarction, n (%) n22 21.8%
Vascular disease, n (%) n24 23.8%
Cerebral vascular incident, n (%) n17 16.8%
Systemic use of anti-coagulants
.No anti-coagulants n48 47.5%
.Thrombocytes aggregation inhibitors n28 27.7%
.Vitamin K antagonists n25 24.8%
Dialysis history
Total duration of renal replacement therapy 390 days IQR 0-3202
Total duration of (semi-)permanent CVC 27 days IQR 0-1061
CVC in history, n (%) n50 50%
.Average number of CVC in history 2 CVCs IQR 0-4
Average number of fistula’s/grafts in history 1 shunt IQR 0-1
Research elective RW Schouten page 13 | 26
Aim 1: Effect of urokinase
Figure 1 shows the number of dysfunctions, interventions and effects of these interventions.
A total of 274 dysfunctional dialysis sessions occurred during the study period. In 64% of
these dysfunctional sessions urokinase is given (A), in 7% a new CVC is placed (B) and in
29% no urokinase has been given (C).
A. When urokinase is given, in 64% the catheter function is restored, 45% in the same
dialysis session and 55% in the subsequent dialysis session. In 36% of the cases the catheter
remains dysfunctional with a flow <200 ml/min.
B. In 7% a new CVC is placed without urokinase. All replaced CVCs were functional
directly after (re)placement.
C. When no urokinase is given, in 60 % the catheter function is restored in the next dialysis
session. In 40% the catheter remains dysfunctional.
Effect urokinase on dysfunction: regression analysis and GLMM
A total of 274 dysfunctions in 119 different CVCs in 51 different patients are included. In the
multi-level linear regression model no significant effect from the urokinase has been found.
Dysfunctions
n274 sessions
= 2.16% of total sessions
Intervention with urokinase
n174 = 63.5%
Effect: Dysfunction
Flow <200ml/min
n62 = 35.6%
Effect: No dysfunction
Flow >200 ml/min
n112 = 64.4%
'Early' effect
(same dialysis session)
n50 = 44.6%
'Late' effect
(following dialysis session)
n62 = 55.4%
CVC replacement
n19 = 6.9%
No urokinase is given
n78 = 28.5%
Effect: No dysfunction
Flow >200 ml/min
n47 = 60.3%
d
Effect: Dysfunction
Flow <200 ml/min
n31 = 39.7%
A B C
Fig 4. Urokinase and its effect on catheter dysfunction
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Aim 2: Patient and dialysis characteristics
Results of patient and dialysis history are shown in the baseline table 1. When looking for
confounding factors to the incidence of dysfunction, two groups were formed by using the
relative portion of dysfunctional dialysis sessions. Group 1 (n70) has patients with 0-5% of
dysfunctional dialysis sessions. Group 2 (n31) has >5% dysfunctional dialysis sessions. Table
2 shows the associations between the two groups. The total number of CVCs and the total
number of CVCs removed within the study period is significantly higher in group 2 (P
<0.01). Furthermore the incidence of reversal of lumens is significantly higher in group 2
(P<0.01).
Other variables such as the number of previous CVCs and patient history like Diabetes were
not associated with the risk of dysfunction (P>0.05). No other significant factors were
associated with the incidence of dysfunction have been identified.
Table 2. Mann Whitney and Chi-Square test to compare means group 1: less 5% dysfunction and group 2: >5% dysfunction
Variable Group 1: low incidence n71
Group 2: high incidence n31 Sig. between groups
Seks 51% male 45% male 0,133
Age 54 yrs (±18) 54 yrs (±16) 0,590
Systemic anti-coagulant therapy 49% no therapy 45% no therapy 0,175
Diabetes Mellitus 36% 39% 0,751
Primary diagnosis
23% vascular 16 interstitial 30% other
29% vascular 19% interstitial 26% other 0,641
Number of CVCs in history 2 (IQR 0-4) 2 (IQR 0-3) 0,691
Total length of renal replacement therapy in history 471 (IQR 0-2775)
379 (IQR 0-3534) 0,753
% reversal of lumens 6% (IQR 0-10) 16% (IQR 6-22) 0,001*
No CVCs included in this study 1 (IQR 1-2) 2 (IQR 1-4) <0,001*
No CVCs removed in this study 1,27 (±1,03) 2,61 (±2,28) <0,001*
Aim 3: Indications for a CVC
In figure 5 indications for the CVC are listed. Patients who are waiting for shunt placement
have a CVC for a median length of 159 days (IQR 88-248). The minimum waiting time for a
shunt is 20 days, the maximum 1491 days. Patients waiting for renal transplantation use a
CVC for a median of 189 days (IQR 131-726). Patients were no shunt is possible have a CVC
for a median of 1506 days (IQR 508-2274).
Research elective RW Schouten page 15 | 26
Mature shunt
When a fistula or graft is matured the CVC is left in place for a median of 40 days (IQR 12-
68). This means in the group ‘Waiting for shunt placement’ that patients who have a matured
shunt and it has been proven to be functional, the existing CVC is left in place for a number
of weeks.
Aim 4: CVC dysfunction and survival
56 patients had one or more dysfunctional dialysis sessions. The total number of
dysfunctional dialysis sessions is 274, leading to an incidence of dysfunction of 2.16%.
CVC characteristics
Types, brands and locations of CVCs used are listed in table 3. 12 Different brands of CVC
were used in this center in 2012 and 2013. The most frequently used brands are the
Palindrome (28%), Kimal (13%) and Tesio (10%). 29% of the CVCs is a double lumen
tunneled catheter, 24% an untunneled double lumen and 10% a tunneled single lumen
catheter. The majority of CVC are placed in the right and left internal jugular vein (39% and
14% respectively), 14% was placed in the right or left femoral vein.
45,5
12,9
5,9
19,8
11,9
4
0 5 10 15 20 25 30 35 40 45 50
Waiting for shunt placement
Waiting for renal transplantation
Waiting for peritoneal dialysis
Shunt or PD not possible
Patient factors
Limited life expectation
% of total number of patients
CVC indication
Fig 5. Indications for semi-permanent CVC for HD
Research elective RW Schouten page 16 | 26
Table 3. Central venous catheter (CVC) characteristics
Characteristic n %
Type CVC
Tunneled double lumen 93 42,7
Untunneled double lumen 76 34,9
Tunneled single lumen 32 14,7
Other 16 7,3
Brand CVC
Palindrome 88 40,4
Kimal 41 18,8
Tesio 32 32,0
Joline 8 3,7
Gamcath 14 6,4
Jet 1 0,5
Ash split 5 2,3
Medcomp 12 5,5
Other / unknown 16 7,3
Location of CVC
Right internal jugular vein 122 56,0
Left internal jugular vein 45 20,6
Left or right femoral vein 43 19,7
Left or right subclavian vein 5 2,3
Other / unknown 3 1,4
CVC survival
Results for CVC survival are listed in table 5. The survival of a CVC varies between 3 till
3234 days. Median survival is 117 days (IQR 36-253). Median survival in the tunneled
double lumen group was 168 days (IQR 69-282) and thereby significantly shorter (P<0,001)
compared to the median survival in the tunneled single lumen group of 256 days (IQR 68-
933). Median survival in the right jugular vein is 152 (IQR 47-263), while median survival in
the femoral veins is 32 (IQR 10-72), significantly different with P<0,001. Kaplan-Meier
curves show the difference in CVC survival in figure 6 and 7.
Research elective RW Schouten page 17 | 26
Table 4. CVC survival
Characteristic median survival IQR
CVC survival
Minimum - maximum 3-3234 days
Mean ±SD 260 ± 446
Type CVC
Tunneled double lumen 168 69-282
Untunneled double lumen 45 17-118
Tunneled single lumen 256 68-933
Other 31 11-188
Location of CVC
Right internal jugular vein 152 47-263
Left internal jugular vein 176 54-562
Left or right femoral vein 32 10-72
Left or right subclavian vein 228 151-358
Other / unknown 36 36-133
CVC removal
184 of the total of 218 CVCs were removed
during the time period of this study. Reasons
for CVC removal are listed in figure 8. The
main reason for CVC removal is catheter
dysfunction (21%), followed by a matured
shunt (17%), protocol (12%) or infection
(8%). 6% of tunneled, cuffed catheters were
removed because of dislocation (6%), for
example when the tunneled CVC stitching
failed or when patients accidently pulled the
CVC out.
20,6
8,3
17,0
1,8
5,5
8,7
12,4
6,4
4,1
0,0 5,0 10,0 15,0 20,0 25,0
Disfunction
Infection
Shunt in use
Peritoneal dialysis in use
Transplantation
Death
Protocol
Dislocation
Other / unknown
% of total n
Reasons CVC removal n=184
Fig 8. Reasons for CVC removal during study period in percentages of total removal
Fig 6. Kaplan-Meier survival plot of different CVC types in days
Fig 7. Kaplan-Meier survival plot of different CVC locations in days
Research elective RW Schouten page 18 | 26
Discussion
Summary results (aims)
1. This retrospective study suggests that urokinase gives no statistically significant
improvement of the blood flow when dealing with catheter dysfunction.
2. Patient and dialysis characteristics show no relevant associations to the incidence of
dysfunction.
3. The most common indication for semi-permanent use of a CVC is waiting for fistula or
graft surgery or maturation followed by the impossibility for creation of a graft of fistula.
When a fistula or graft is matured the CVC is left in place for a median of 40 days.
4. The incidence of CVC dysfunction is 22/1000 dialysis sessions. Furthermore the results
show a slight advance of tunneled single lumen catheters in CVC survival compared to
the tunneled double lumen CVCs.
Aim 1: Effect of urokinase
Current literature shows thrombolytics are commonly used to help dissolve thrombotic
occlusions causing catheter dysfunction. However studies investigating the effectiveness of
urokinase don’t have consistent outcomes. Our results show that 60% of the dysfunctional
CVCs have better flows when urokinase is given, compared to other studies ranging between
50-90%. However the regression analysis shows no significant effect from urokinase.
Despite the use of new designs of CVCs, urokinase and other locking solutions most CVCs
still become dysfunctional. Much of the etiology of dysfunctional CVCs is still not clearly
understood. One possible explanation for the failing of urokinase to treat dysfunctional CVCs
is that there might be no thrombotic etiology in a portion of the dysfunctional CVCs. For
example a malposition of the CVC-tip against the vessel wall might play a role when dealing
with dysfunctional CVCs.
Implications for daily practice
When dealing with CVC dysfunction the bed-side interventions are the main treatment for
prolonging CVC survival. After these interventions only a CVC replacement is the last resort
for improving the blood flow and therefore the dialysis adequacy. This study shows no
significant effect from urokinase, however this study has several limitations that will be
discussed later. For the clinician this study might help to judge the effect of urokinase when
considering it as a treatment. However since it is one of the last interventions before CVC
removal, urokinase will probably still be given despite its moderate effect. The possible
positive effect on the blood flow and avoiding high complication rates due to CVC
replacement make it a preferably intervention.
Research elective RW Schouten page 19 | 26
Aim 2: Patient and dialysis characteristics
Compared to other studies similar primary renal disease and medical history are found in this
study. 15 However to adequately compare the group using a semi-permanent CVC with the
fistula, graft or PD group, these groups should be investigated in the same manner in the
same center.
When looking for confounding factors to the incidence of dysfunction, no relevant factors
were found. This is in line with most of the available literature. This study has a relatively
large study population and number of CVCs compared to existing literature. However the
study population of this and other studies remains low, making it difficult to draw
conclusions and compare means between samples within the population.
Implications for daily practice
For clinicians it might be helpful to predict higher incidence of dysfunction in certain patient
groups. This study shows no patient of dialysis characteristics that can help clinicians. Only
the number of CVCs removed during a study period is a significant confounder. Therefore
this study shows dysfunction is not easily predictable when looking at patient and dialysis
characteristics.
Aim 3: Indications for a CVC
Only 20% of the patients have a semi-permanent CVC because another vascular access
method is not possible. Most patients with a semi-permanent CVC are waiting for fistula or
graft placement or maturation (45.5%). There are several possible reasons for this relatively
large group. First there is a waiting list for fistula or graft surgery, second the operation can
be cancelled due to patient specific reasons like a bad overall condition of the patient. Third
when a patient has a functioning and matured fistula or graft the CVC is left in place for a
mean of 55 days. A possible explanation is that the clinician prefers to have an escape option
when the shunt cannot be used. However to have a good view on the reason for this relatively
large group the reasons should be investigated separately.
12% of the patients have a semi-permanent CVC because they refuse a fistula, graft or PD. A
possible explanation might be that patient with a good functioning CVC don’t want to go
through the process of surgery, shunt maturation and punctures.
Implications for daily practice
Important implications for the clinicians are to reduce waiting lists for fistula or graft surgery
to minimize morbidity and mortality due to CVC complications. Clinicians should remove a
CVC when a fistula or graft is functional and matured. Unnecessary prolongation of the CVC
in situ leads to possible complications of the CVC like infection or thrombosis. Furthermore
patient education might help to reduce the number of patient refusals to switch to other, more
safer, vascular access options.
Research elective RW Schouten page 20 | 26
Aim 4: CVC dysfunction and survival
The incidence of CVC dysfunction is 2.16% of all dialysis sessions included, which is
comparable with existing literature. When comparing the group with high number of
dysfunction, >5% of dialysis sessions, and the group with low number of dysfunction, 0-5%
dysfunctional dialysis sessions no significant difference in patient characteristics and patient
history has been found. Thus no patient factors can help to predict possible CVC dysfunction.
When looking at CVC survival the mean survival is 260 days. This is comparable with
existing literature, however literature shows a great variation in CVC survival. The single
lumen tunneled catheter has a longer survival compared to the double lumen tunneled
catheter. A possible explanation might be the single lumen catheter has less thrombus
forming due to the different flow directions. Similar studies focused on comparing single
versus double lumen CVCs show no clear advantage. The setup of this study with no
randomization, no clear indication to which CVC type a patient will receive and a limited
amount of follow-up make these results difficult to interpret for daily practice. Lastly one
major disadvantage of a single lumen CVC is that it can only handle relatively low blood
flows compared to the double lumen CVCs, leading to possible under dialysis or prolonged
dialysis time.
The location of a CVC is preferably the right or left jugular vein. Together with existing
evidence this study shows a higher number of dysfunctional sessions when using a femoral
vein access.
The main indications for removing a CVC are as expected, dysfunction, infection or another
available vascular access. 6% is removed due dislocation of the CVC. This might be
avoidable when a CVC is properly glued or stitched and monitored during each dialysis
session.
Implications for daily practice
CVC survival shows a great variance. For the clinician it is difficult to predict survival for an
individual patient. However the femoral access has shown disadvantages in incidence of
dysfunction and lower survival rates. When it is possible the femoral vascular access should
be avoided. The decision for a single versus double lumen or tunneled versus untunneled
CVC should be based on existing literature, doctor- and center-experience.
Dislocation of a CVC might be avoided by adequately monitoring signs of dislocation and
proper stitching or gluing.
Overall strengths and limitations
This study had several limitations.
This is a single center study with a population that differs from the general Dutch
population. The AMC hospital has more Afro-American patients compared to similar
dialysis centers in the Netherlands.
Furthermore the retrospective cohort design and the time period of 2 years resulted in the
use of different protocols, doctors and nurses leading to a non-uniform reporting in the
patient files. This non-uniform reporting might have resulted in a possible under-reporting
of catheter dysfunction and missing data, especially missing blood flow measurements.
Research elective RW Schouten page 21 | 26
Besides this the variation between doctors whether to use urokinase or not has not been
uniformly protocolled in this center during the study period. This might have resulted in
different decisions and a doctor-bias whether to use urokinase or not.
The lack of a uniform protocol resulted in a variety of uses of the urokinase locking
solution. Some locking solutions were left in place for 20 minutes, while others were left
in the catheter for 120 minutes or for several days during the interdialytic period.
Decisions and indications for deciding which type of CVC to use, for example a tunneled
versus an untunneled CVC are not clearly protocolled.
The effect of other minor-invasive bed-side interventions like reversal of lumens and
CVC flushing cannot be investigated in this study. Because of the lack of uniform
reporting and the frequent reversal and flushing the effect of these minor interventions
cannot be determined. Therefore the measured effect of urokinase might be affected by
these other interventions.
The use of blood flow as the main dysfunction and effect parameter has disadvantages.
The blood flow is regulated by the nurses input in the dialysis machine based on the
number of alarms and desired filtration rate. The use of the blood flow as an effect
therefore depends on the dialysis nurses input in the machine. Besides this, no other
parameters of dialysis effectiveness were obtained in this study. However the blood flow
is the most frequent used parameter in existing literature for catheter function and
therefore dysfunction. Furthermore the definition of a blood flow lower than 200 ml/min
is commonly used an indicator for a non-effective dialysis session or dysfunction in
national and international guidelines.
In July 2013 the dialysis center switched from Citralock® locking solution to Taurolock®
locking solution, however no significant difference in incidence of dysfunction has been
found between 2012 and 2013.
Prospective
The perfect locking solution to prevent or dissolve thrombotic complications in CVCs has yet
to be found. This study, together with other literature, show varying results on catheter
function when using urokinase. However this and other studies have many limitations. The
retrospective design of this study and low number of patients make it difficult to interpret the
results.
New studies should be prospective in nature and use a clear study treatment protocol to
address the limitations resulting from this study. A multi-center study should be undertaken
to limit bias per center or doctor. Ultimately a randomized controlled trial comparing the
different locking solutions can help the practitioner making an evidence based decision. This
and future research can help to make uniform and clear treatment protocols for preventing
and treating thrombotic complications in CVCs. Together with the signal function from the
dialysis nurse these future protocolling can help to maintain a reliable vascular access for
hemodialysis patients.
Research elective RW Schouten page 22 | 26
Conclusion
Aim 1) No significant improvement on blood flow has been found using urokinase.
However the retrospective cohort design of this study and lack of uniform protocolling during
the study period make it difficult to interpret the results.
Aim 2) No patient or dialysis characteristics have been found to significantly associated to
the incidence of CVC dysfunction. This makes assessing the risk of dysfunction difficult to
assess.
Aim 3) Most patients with a semi-permanent CVC are waiting for fistula or graft surgery or
maturation, with a median waiting time of 152 days. It is important waiting lists and delays in
fistula or graft placement must be kept to a minimum to reduce serious morbidity and
mortality due to CVC complications. Furthermore patient education from the nephrologist
and dialysis nurse is important in reducing the number of patient refusing a fistula, graft or
PD. Lastly it is important clinicians remove the existing CVC after the fistula or graft has
been matured. By not removing the CVC prolongation of the infectious and thrombotic risks
increase patient morbidity and mortality.
Aim 4) The total incidence of CVC dysfunction is 22/1000 dialysis sessions. Single lumen
tunneled CVCs show a slight advance in CVC survival compared to double lumen tunneled
CVCs. Femoral CVCs show a clear disadvantage in CVC survival and incidence of
dysfunction and thus should be avoided when possible.
New research should be prospective in nature with clear protocolling. Ultimately randomized
controlled trials to compare different bed-side interventions and the different locking
solutions should give more definitive answers. This and future research can lead to clear,
evidence-based protocols for preventing and treating dysfunctional CVCs and thereby
ensuring a reliable, sustainable vascular access for hemodialysis patients.
Research elective RW Schouten page 23 | 26
Ongoing (prospective) research
Together with my local clinical tutor, Dr. N.C. van der Weerd, I will continue on this subject
and we are planning to work on publications resulting from this study. Baseline data from
groups of patients using a fistula or a graft during the same study period will be added to the
database.
Besides this retrospective study we are working on a prospective study that is already taking
place in Dianet Utrecht and Dianet Amsterdam. With this prospective study some of the
limitations of this study are addressed. In this new study we are investigating the effect of
multiple (minor) interventions when dealing with dysfunctional CVCs, like reversal of
lumens, flushing with NaCl and urokinase locking solution. A clear study protocol for the
dialysis nurse and a clear treatment protocol for the nurses and nephrologist has been issued
and explained. From June 2014 data has been collected for this prospective study. Results are
expected to be available by the end of 2014.
Research elective RW Schouten page 24 | 26
Acknowledgements
The following people helped to contribute to this study and research elective:
N.C. van der Weerd (Neelke), nephrologist at the AMC hospital
R. Visser (Ronald), nurse researcher at Dianet (AMC)
J. Bijlsma (Joost), nephrologist at Dianet (AMC)
W.J. van Son (Willem), nephrologist at the UMCG hospital from the faculty of the
Rijksuniversiteit Groningen
M. Noordzij (Marlies), epidemiologist at the AMC hospital
H. Peters Sengers (Hessel), PHD Candidate AMC hospital
Research elective RW Schouten page 25 | 26
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