Download Preventing Infections Related to Central Venous and Arterial Catheters Fredrik Hammarskjöld

LINKÖPING UNIVERSITY MEDICAL DISSERTATIONS NO: 1360
Preventing Infections Related to
Central Venous and Arterial Catheters
Fredrik Hammarskjöld
Department of Anaesthesia and Intensive Care, Ryhov County Hospital, Jönköping
Division of Infectious Diseases and Clinical Immunology,
Department of Clinical and Experimental Medicine,
Faculty of Health Sciences,
Linköping University, Sweden
Linköping 2013
© Fredrik Hammarskjöld, 2013.
Published articles and figures have been reprinted with the permission of the copyright holder.
Printed in Sweden by LiU-tryck, 2013.
ISBN 978-91-7519-661-9
ISSN 0345-0082
Wij hålla vth!
Peder Michilsson Hammarskiöld (around 1560-1646)
The Ancestor of the Noble Hammarskjöld Family.
CONTENTS
SAMMANFATTNING PÅ SVENSKA .................................................................................... 6
ABSTRACT ............................................................................................................................... 8
LIST OF PAPERS ...................................................................................................................... 9
LIST OF ABBREVIATIONS .................................................................................................. 11
INTRODUCTION .................................................................................................................... 12
HISTORY............................................................................................................................. 12
NOSOCOMIAL INFECTIONS ........................................................................................... 13
CENTRAL VENOUS CATHETERS .................................................................................. 14
Background ...................................................................................................................... 14
Indications ........................................................................................................................ 14
Choice of catheter............................................................................................................. 14
Insertion ............................................................................................................................ 16
Catheter care and removal ................................................................................................ 17
Local guidelines for central venous catheter insertion and care. ..................................... 18
ARTERIAL CATHETERS .................................................................................................. 20
Background and indications ............................................................................................. 20
Choice of catheter............................................................................................................. 20
Insertion ............................................................................................................................ 20
Catheter care ..................................................................................................................... 20
INFECTIOUS COMPLICATIONS RELATED TO THE USE OF CENTRAL VENOUS
CATHETERS AND ARTERIAL CATHETERS. ............................................................... 21
Mechanisms ...................................................................................................................... 21
Definitions ........................................................................................................................ 22
Culture methods ............................................................................................................... 26
Microbiology .................................................................................................................... 27
Diagnosis and treatment ................................................................................................... 27
Epidemiology, mortality and healthcare costs ................................................................. 32
Hygiene strategies, CVC teams and evaluation ............................................................... 33
CANDIDA TRANSMISSION ............................................................................................. 33
Background ...................................................................................................................... 33
Transmission .................................................................................................................... 33
PREVENTING NOSOSCOMIAL INFECTIONS ON THE INTENSIVE CARE UNIT IN
JÖNKÖPING ....................................................................................................................... 34
Central venous catheter insertion and care in Jönköping ................................................. 36
THE AIMS OF THE STUDIES IN THIS THESIS ................................................................. 37
MATERIAL AND METHODS ............................................................................................... 38
SETTING ............................................................................................................................. 38
STUDY DESIGN ................................................................................................................. 38
CATHETER INSERTION AND CARE.............................................................................. 39
DEFINITIONS ..................................................................................................................... 39
MICROBIOLOGY ............................................................................................................... 40
STATISTICS ........................................................................................................................ 41
ETHICS ................................................................................................................................ 41
RESULTS................................................................................................................................. 42
CENTRAL VENOUS CATHETERS .................................................................................. 42
ARTERIAL CATHETERS .................................................................................................. 49
CANDIDA TRANSMISSION ............................................................................................. 50
DISCUSSION .......................................................................................................................... 54
CONCLUSIONS ...................................................................................................................... 60
REFERENCES ......................................................................................................................... 61
ACKNOWLEDGEMENTS ..................................................................................................... 70
SAMMANFATTNING PÅ SVENSKA
Centrala venkatetrar är oumbärliga inom modern sjukvård. De används framför allt inom
narkos och intensivvård för att ge intravenösa läkemedel och vätskor samt för att övervaka
blodcirkulationen. De har även kommit att användas inom andra verksamheter, såsom
cellgiftsbehandling, långvarig antibiotikabehandling, bloddialys och näringstillförsel via
blodbanan. Fördelarna är många, men tyvärr kan katetrarna ge upphov till infektioner som kan
orsaka blodförgiftning och dödsfall. De ökade vårdkostnaderna för varje enskild sådan
infektion är avsevärda. Studier, som framför allt gemomförts på intensivvårdsavdelningar, har
visat att man med god följsamhet till enkla och fasta rutiner kan minska denna
infektionsproblematik och följaktligen minska lidande och dödlighet. Långtidseffekterna av
att införa dessa rutiner på ett helt sjukhus har aldrig tidigare studerats.
Artärkatetrar används för blodprovstagning och övervakning av blodcirkulationen inom
narkos och intensivvård. Dessa har länge ansetts ge upphov till färre infektioner jämfört med
centrala venkatetrar. Studier på senare år har dock visat att så inte är fallet.
Infektionsproblematiken för artärkatetrar är endast undersökt i ett fåtal studier och aldrig
tidigare i Skandinavien.
Svampinfektioner med Candida-arter har på senare år ökat inom intensivvården och har
bidragit till förlängd vårdtid och ökad dödlighet. Den gängse uppfattningen har varit att dessa
infektioner orsakas av stammar som finns i patientens normalflora. Några studier har dock
visat att vissa Candida-stammar skulle kunna överföras mellan patienter inom en
vårdavdelning. Svamp är en av de tre vanligaste mikroorganismerna som orsakar infektioner
relaterade till centrala venkatetrar.
Innan detta avhandlingsprojekt påbörjades, infördes strikta rutiner för inläggning och skötsel
av centrala venkatetrar och artärkatetrar på vårt sjukhus. Patienterna får dessa katetrar inlagda
på intensivvårds- eller på operationsavdelningen. Under vårdförloppet kan patienter med
centrala venkatetrar vårdas på alla sjukhusets avdelningar, på vårdhem eller i hemmet.
Rutinerna har under åren ändrats mycket lite och ett ständigt pågående utbildningsprogram
och lättillgänglig rådgivning har inneburit att rutinerna har hållits aktuella. Nyanställd
personal får adekvat utbildning för att rätt kunna vårda patienter med centrala venkatetrar och
artärkatetar.
De huvudsakliga syftena med avhandlingen har varit att, efter införande av strukturerade
hygienrutiner, studera förekomsten av infektioner relaterade till centrala venkatetrar och
artärkatetrar. Vi har också varit intresserade av att kartlägga vilka mikroorganismer och
riskfaktorer som bidrog till uppkomsten av dessa infektioner. För centrala venkatetrar har vi
även önskat kontrollera långtidseffekterna av de strukturerade hygienrutinerna. Slutligen har
vi även studerat om det förekom överföring av Candida-stammar mellan patienter som
vårdades på vår intensivvårdsavdelning, på samma sätt som är väl visat för ett flertal
bakterier.
Resultaten av detta arbete visade att förekomsten (incidensen) av så kallad blodburen
infektion associerad med centrala venkatetrar var låg i jämförelse med internationella studier.
Den första studien mätte infektioner över 16 månader och omfattade 495 katetrar. Den
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uppföljande studien omfattade 2045 katetrar under sex år. I denna fann vi en kontinuerligt låg
årlig förekomst av infektioner relaterade till centaral venkatetrar. Vi tror att de positiva
resultaten beror på god följsamhet till rutinerna för inläggning och skötsel av centrala
venkatetrar. I sexårsstudien följdes förekomsten av infektioner under varje kvartal. Vid endast
ett tillfälle noterades fler infektioner än förväntat, baserat på vår analys med så kallad
statistisk processkontroll. De mikroorganismer som identifierades var desamma som setts i
internationella studier, men vi fann en högre andel Candida-stammar. Vi fann att
användningstid och bloddialys var riskfaktorer för infektioner associerade med centrala
venkatetrar. Det visade sig också att en central venkateter som var inlagd i den inre halsvenen
hade större risk för att vara associerad med infektion när detta jämfördes med inläggning i
nyckelbensvenen.
I artärkateterstudien, som omfattade 600 kateterar, fann vi inga fall där mikroorganismer från
artärkatetern återfanns i blodet. Vi fann dock ett fåtal fall där patienten fått allmänna
sjukdomssymptom av mikroorganismer på katetern och dessa fall orsakades samtliga av vita
stafylokocker. En riskfaktor för att patienten skulle få artärkateterinfektion var försvagat
immunförsvar. Många patienter i studien hade både en artärkateter och central venkateter
samtidigt. Det visade sig då att om det växte mikroorganismer på den centrala venkatetern,
eller om patienten hade en infektion av denna kateteter, så ökade risken för att patienten även
skulle få en artärkateterinfektion. Artärkaterinfektioner var nästan lika vanliga som
infektioner relaterade till centrala venkatetrar. Sambandet mellan infektioner på dessa båda
katetrar måste vägas in i bedömningen av en patient med infektionssymptom. Vi
rekommenderar att man överväger att avlägsna patientens samtidiga centrala venkatetrar och
artärkatetrar om en av dessa orsakar en infektion med allmänna symptom. För patienter med
långtidssystem, exempelvis venportar och tunnelerade centrala venkatetrar kan andra
överväganden behöva göras.
DNA-analys av de 180 funna Candida-stammarna på intensivvårdsavdelningen visade 27
genetiska varianter av arten Candida albicans och tio av arten Candida glabrata. Vissa av de
genetiska varianterna återfanns oftare på intensivvårdsavdelningen än i en kontrollgrupp.
Detta fynd tillsammans med så kallad klusteranalys talade för att det sker en överföring av
vissa stammar mellan patienter på intensivvårsavdelningen.
7
ABSTRACT
Central venous catheters (CVCs) are indispensable in modern medical practice. Serious
complications associated with CVC use include catheter-related infection (CRI) and catheter
related-bloodstream infection (CRBSI) both of which contribute to morbidity, mortality and
healthcare costs. Several studies have shown that implementation of basic hygiene routines,
for CVC insertion and care, can significantly reduce the number of CRBSIs. However, there
are limited data on the long-term effects after such an intervention. CVC infections, in terms
of incidences and microorganisms, vary between different units and countries. Studies from
Scandinavian hospitals are rare and not published recently. It has been stated that arterial
catheters (ACs) are less prone to be responsible for CRI and CRBSI when compared with
CVCs. However, recent studies outside Scandinavia have shown that they cause infections in
significant numbers. The general view has been that nosocomial Candida infections in ICU
patients evolve from the patient’s endogenous flora. However, a few studies have indicated
that transmission of Candida spp. can occur between patients on an ICU as is well-described
for certain bacteria. Candida spp. are among the most common microorganisms responsible
for CRI/CRBSI.
The aim of this thesis was to study the incidences of, and microorganisms related to CVC
(Study 1) and AC (Study 2) infections after implementation of evidence-based routines for
insertion and care. The populations studied were patients with CVCs treated throughout the
entire hospital (Studies 1 and 4) and patients with ACs treated on the ICU (Study 2). The aim
was further to analyse risk factors contributing to these infections (Studies 1, 2 and 4). We
also evaluated the long-term effects and endurance, of evidence-based routines, assessed as
temporal variations in CVC colonisation and infections over a six-year period (Study 4). As
we found that Candida spp. were common causes of CRI/CRBSI in Study 1, we decided to
see if transmission of Candida spp. possibly occurred between patients on our ICU (Study 3).
We found low incidence rates, compared to international studies, for CRI and CRBSI related
to the 495 CVCs studied over a short period (16 months, Study 1) and the 2045 CVCs studied
over long-term follow-up (six years, Study 4). We found no cases of AC-CRBSI but a low
number of AC-CRI in the 600 ACs studied. The type of microorganisms responsible for
infections related to CVCs and ACs were similar to those found in international studies.
However, the proportion of Candida spp. was high in Studies 1 and 4 evaluating CVC
infections. There was no difference in the CVC-catheterisation time for CRI/CRBSI caused
by Candida spp. as compared to CRI/CRBSI caused by bacteria. Risk factors for CRI
associated with CVCs were chronic haemodialysis (Study 1), all haemodialysis in general
(Study 4) and CVCs inserted via the internal jugular vein as compared to the subclavian vein
(Study 4). Risk factors for CRI related to ACs were colonisation or infection of a
simultaneous CVC and immunosuppression. Genotypes of Candida albicans and Candida
glabrata had a heterogeneous distribution between ICU patients over time. Comparison with
a reference group and cluster analysis indicated that transmission of Candida spp. between
ICU patients is possible.
In, conclusion, we have found, after implementation of evidence-based routines for CVC and
AC insertion and care, low incidences of CRI and CRBSI associated with these catheters.
Furthermore, we found that transmission of Candida spp. between patients on the ICU is
possible.
8
LIST OF PAPERS
1. Central venous catheter infections at a county hospital in Sweden: a prospective
analysis of colonisation, incidence of infection and risk factors. Hammarskjöld F,
Wallén G, Malmvall BE. Acta Anaesthesiol Scand. 2006; 50(4):451-60.
2. Low incidence of arterial catheter infections in a Swedish intensive care unit: risk
factors for colonisation and infection. Hammarskjöld F, Berg S, Hanberger H,
Malmvall BE. J Hosp Infect. 2010; 76(2):130-4.
3. Possible transmission of Candida albicans on an intensive care unit: genotype and
temporal cluster analyses. Hammarskjöld F, Mernelius S, Andersson R, Berg S,
Hanberger H, Löfgren S, Malmvall BE, Petzold M, Matussek A. Submitted to J Hosp
Infect.
4. Sustained low incidence of central venous catheter-related infections in a Swedish
county hospital following implementation of a hygiene program: a six year follow-up
study. Hammarskjöld F, Berg S, Hanberger H, Taxbro K, Malmvall BE. Manuscript.
9
10
LIST OF ABBREVIATIONS
AC
AC-CRI
AC-CRBSI
Apache
C.
CDC
CFU
CI
CoNS
CRBSI
CRI
CVC
ECDC
G-charts
I-charts
ICU
IDSA
n
NI
NIM
PRCT
S.
SCHA
SFAI
SIRS
Spp.
T-CVC
Arterial catheter
Arterial catheter-related infection
Arterial catheter-related bloodstream infection
Acute Physiology and Chronic Health Evaluation
Candida
Centers for Disease Control and Prevention
Colony-forming unit
Confidence interval
Coagulase-negative Staphylococci
Catheter-related bloodstream infection
Catheter-related infection
Central venous catheter
European Centre for Disease Prevention and Control
Geometrical charts
Individual charts
Intensive care unit
Infectious Diseases Society of America
Numbers
Nosocomial infection
Needles injection membrane
Prospective randomised controlled trial
Staphylococcus
0.5% chlorhexidine (w/v) in 70 % alcohol
Swedish Association for Anaesthesia and Intensive Care
Systemic Inflammatory Response Syndrome
Species
Tunnelled-central venous catheter
11
INTRODUCTION
HISTORY
The first described infusion in man took place in 1667 when a silver cannula was inserted in
the antecubal veins, for saline infusion. A pig’s bladder was used as a syringe. During the
same year the first successful blood transfusion from lamb to man was performed. However,
due to fatal complications, this therapy was banned by the English church and Parliament
until 1818. An English obstetrician had then saved several women with severe haemorrhage
by injecting human blood, using a syringe1.
The first successful attempt to monitor blood pressure was performed in horses in 1773, when
glass tubes were inserted into veins and arteries1.
It is not fully clear when the first central venous catheterisation was performed. The first
paper on central venous catheterisation, performed via the antecubital vein, was supposedly in
1929 by Forssmann, but there are reports as early as 1905 by Bleichroeder. Forssmann
proposed, in 1931, that CVCs could be used in emergency situations for rapid delivery of
drugs1.
Several flexible polyethylene catheters were introduced in the 1940’s which started the
general use of intravascular catheters. However several complications such as thrombosis and
infections were seen which lead to a continuing search for better catheter materials. This
resulted in modern catheter materials such as polyurethane, silicone and Teflon1.
The Swedish radiologist, Sven-Ivar Seldinger, published in 1953 his work on a new technique
for inserting intravascular catheters. This “catheter over guide-wire” technique was
revolutionary and has since become the main technique for CVC insertion throughout the
world2.
CVCs were predominately inserted via a vein in the upper extremity or the femoral vein, often
using a cut-down technique. That is until 1952 when percutaneous infra-clavicular insertion
via the subclavian vein was first described. The first descriptions of the supra clavicular
approach in the same vein and the internal jugular vein was published in 1965 and 1969,
respectively1.
The pulmonary artery catheter was first described by Swan and Ganz in 1970 3 4. This catheter
has since been the gold standard for advanced haemodynamic monitoring. The first Swedish
description, to our knowledge, of the pulmonary artery catheter in humans was from
Jönköping in 19805.
To overcome the problems of infections and mechanical problems associated with long-term
venous access for parenteral nutrition and chemotherapy, new silicone catheters (i.e. Broviac
and Hickman catheters) were introduced in the Seventies. These were flexible t-CVCs with a
subcutaneous cuff1. Surgically implanted subcutaneous ports were first described in 1982 and
are preferred for long-term chemotherapy and parenteral nutrition6.
12
To increase the safety of CVC insertion ultra-sound guidance was proposed in 1982 and has
now become an established technique for the insertion of CVCs1.
Since the beginning of the Seventies there has been increasing focus on preventing CVC
infections. Maki has been the leading light in this field and has contributed much to our
present knowledge concerning strategies for the prevention of infections. The most wellknown guidelines for prevention of CVC-infections were, to our knowledge, published in a
first edition by CDC in 19837.
There has been a considerable amount of research in this field throughout the world, and over
the two last decades there has been a revolution in the care of patients with intravascular
access. New catheters, ultrasound-guided insertion and improved hygiene routines have
increased the safety for patients with a CVC, and since 2010, a world congress on vascular
access has been organised every second year (www.wocova.com).
NOSOCOMIAL INFECTIONS
The evolution of modern medical care has increased our ability to treat severe and advanced
medical conditions. This progress has accelerated over recent decades and many patients, who
were previously beyond therapy, can now be treated and cured.
Simultaneously, there has been an awakening to the problem of hospital-acquired infections,
so-called nosocomial infections (NIs)8. NIs, to a large extent, affect vulnerable patients such
as those with advanced chemotherapy, after surgery, on intensive care, with implanted foreign
bodies (i.e. orthopaedic prostheses, and intravascular devices) and after transplantation,
immuno-compromised patients, and neonates. Misuse of antibiotics, crowded and
understaffed wards, insufficient adherence to hygienic-routines, and transportation of patients
between units are also realities that increase the risk for NIs.
The most common NIs are surgical wound infections, urinary tract infections, intravascular
device infections (i.e. catheters and pacemakers), pneumonia including ventilator-associated
pneumonia, antibiotic-associated diarrhoea, and prosthesis infections (i.e. orthopaedic and
vascular-). Unfortunately, NIs are closely related to the increasing problem of multi-resistant
microorganisms9.
The incidence of NIs and type of microorganisms involved vary greatly between similar units
depending on patient population, geographical location, adherence to hygiene routines, use of
antibiotics etc. Furthermore, the incidence and microorganisms involved can vary over time
within the same unit.
It is obvious that NIs contribute to morbidity, mortality and enormous healthcare costs8.
Several studies have shown that these complications can, to a large extent, be avoided using
various approaches that have been shown to reduce morbidity, mortality and healthcare costs8
10-13
.
The medical profession has to engage several strategies to prevent NIs and antibiotic
resistance. These include well-functioning basic hygiene routines in all aspects of medical
care, the rationale use of antibiotics, special medical techniques/routines in highly vulnerable
13
situations, thorough clinical evaluations of previously known factors and research. Most of
these strategies should be well-known in view of the efforts made to spread knowledge. In
spite of this, international studies have shown that there is surprisingly low knowledge and
adherence to the guidelines and education programmes that substantially reduce the
incidences of NIs12 14 15. Over recent decades many authorities in the West have focused
attention on this problem, examples of this including USA: save 5 million lives campaign
(www.ihi.org), Europe: the ECDC (www.ecdc.europa.eu) and Sweden: Swedish Strategic
Programme against Antibiotic Resistance (www.strama.se) and campaigns launched by The
Swedish Association of Local Authorities and Regions (www.skl.se).
CENTRAL VENOUS CATHETERS
Background
Modern medical care is highly dependent on vascular access for treatment and monitoring.
Peripheral venous catheters, predominately inserted in the veins of the upper extremity, are
the most commonly used catheter for intravascular injections and infusions. Peripheral venous
catheters are rarely responsible for serious NIs, the reasons for this could be the relatively
short catheterisation time.
In certain circumstances a peripheral venous catheters is insufficient and has to be replaced by
a CVC which is an intravenous catheter with the tip positioned in the central circulation. The
CVC is usually inserted via the internal jugular or subclavian vein but the femoral vein and
the veins of upper extremity are also used.
Indications
The indications for a CVC are numerous:
 Intravenous therapy with large amounts of fluids over a short-term, i.e. trauma,
surgery, ICU treatment.
 Intravenous administration of vascular irritant drugs and solutions with high
osmolarity.
 Intravenous treatment over a long-term period (> 4 weeks), i.e. parenteral nutrition,
antibiotics, chemotherapy, blood products.
 Repeated blood sampling over a long-time
 Haemodynamic monitoring during intensive care and anaesthesia.
 Haemodialysis
Choice of catheter
Modern CVCs are made of polyurethane or silicone. Neither of these is superior in preventing
CVC infections and the choice of material is predominantly based on mechanical
preferences16. Over the last ten years there has been an evolution of CVCs treated with
various antimicrobial substances (antibiotics, antiseptics) or other substances that inhibit
microorganisms adhering and growing on a CVC. There have also been trials using low
current and ultraviolet light, but these methods are not yet ready for clinical use. Only
14
catheters impregnated with chlorhexidine/silver-sulfadiazine or minocyckline/rifampin have,
until now, been shown to be effective in PRCT17. There are those who claim that these two
catheters carry the risk for increased microbial resistance. These fears, however, have not
been founded18. However, these catheters can never replace insufficient hygiene routines.
Depending on what the CVC is to be used for, there are several kinds of catheters. The
catheter can contain one to several lumina (=channels), depending on the number of infusions
that the patient requires simultaneously, or concomitant haemodynamic monitoring. The
calibre of the catheters varies widely depending of the amount of flow required. The length of
the catheter is often between 15 and 25 cm but can be up to 80 cm, as for example, the
pulmonary artery catheter. The catheters are inserted through the skin and the subcutaneous
tissue into the vessel. The subcutaneous part may be deliberately prolonged (> 5-10 cm) and
this is called a tunnelled-CVC (t-CVC). This technique has been shown to be effective in
reducing the number of CVC infections when the catheters are inserted via the internal jugular
or femoral vein19 20. A t-CVC can be attached to a surgically implanted subcutaneous infusion
chamber. This system is called a subcutaneous venous port. Infusions using this system are
achieved via a special needle that is forced through a silicone diaphragm that lies just below
the skin.
Figure 1: Examples of central venous catheters and an arterial catheter (from top:
pulmonary artery catheter, single lumen central venous catheter, four lumen central venous
catheter, subcutaneous venous port, arterial catheter and central dialysis catheter).
15
The CVC are often divided accordingly:
1. Single or multi-lumen catheters: narrow catheters for short-term use on the wards,
ICUs and during anaesthesia (Figure 1). Multi-lumen catheters may have an increased
risk for CVC infections and the number of lumina should be kept to a minimum21.
2. Tunnelled single or multi-lumen catheters: relatively small gauge catheters
predominately used for long-term infusion for parenteral nutrition or chemotherapy
outside the hospital.
3. Non-tunnelled (Figure 1) and tunnelled-CVCs for haemodialysis: relatively large
calibre catheters which are used for short and long-term haemodialysis.
4. Pulmonary artery catheters (Figure 1): long small gauge catheters used for advanced
haemodynamic monitoring.
5. Peripherally inserted CVCs, termed PICCs: long small gauge catheters inserted via a
vein in the upper extremity, predominately for chemotherapy but have also gained
popularity in the acute care setting and for parenteral nutrition.
6. Subcutaneous venous ports (Figure 1): aimed for long-term treatment outside the
hospital, and used for chemotherapy, blood products, and parenteral nutrition.
Insertion
Several studies have shown that the number of complications, including infections, secondary
to CVC insertion, are decreased if performed by a well-trained operator22. Hence, the operator
should be fully trained and beginners should insert catheters under supervision and preferably
perform their first insertions on dummies23-26. All CVC insertions should be performed
according to a checklist and be fully documented14.
In recent years substantial evidence has been gained that real-time ultrasound insertion
decreases the mechanical complications associated with CVC insertion. This is especially so
for the internal jugular vein, but also for the subclavian and femoral veins27-29. It has not been
shown, however, that ultrasound insertion affects the incidence of CVC infections.
Insertion of a CVC should preferably be performed in a location intended for surgery.
Unfortunately, due to clinical considerations, this is not always possible and therefore the
procedure is often performed in such places as the emergency department and ICU.
The person inserting the CVC should be dressed with maximal sterile precautions, which
includes sterile gloves, hat, mask and sterile gown. Furthermore the patients should be well
covered by large sterile drapes30-32.
The insertion site should be carefully treated with a disinfection solution prior to insertion.
Several different solutions have been used alone or in combination for this purpose. However
it has been shown that the most effective solution in preventing CVC infections is SCHA33-35.
The optimal concentration of chlorhexidine has to be evaluated in further studies, and
currently there are different solutions between 0.5 and 2%. The effect of a preoperative
chlorhexidine shower or bath, which is frequently a recommended procedure to prevent
surgical site infection, is scarcely studied36.
Prophylactic antibiotics should not be used as a routine, but may be considered under special
circumstances such as in patients with neutropenia and complicated insertion37.
16
CVC for short-term use should be secured with monofilament sutures38. New commercial
suture-less devices have not been evaluated in PRCTs. The insertion site should be covered
with sterile gauze or a semi-permeable polyurethane dressing39. Polyurethane dressings or
sponges containing chlorhexidine could, decrease the risk for CVC infections even further4042
.
Catheter care and removal
All handling of the catheter should be performed under sterile conditions. A checklist could
be a valuable tool for the procedure and its documentation14 32. The CVC and the insertion site
should be inspected every day for complications and the need for the catheter should be
questioned. The CVC should promptly be removed when it is no longer required14 32.
Several ICU studies have demonstrated a lower CRBSI incidence if a daily whole body wash
with chlorhexidine is performed43.
Most studies, but not all, have shown a reduction in CVC colonisation or infections when
using NIMs44-51. To gain the positive effect of using these devices it is mandatory that they be
used according to instructions. This includes using NIMs of split-septum type and scrubbing
the membrane (“scrub the hub!”) with SCHA before each use32 52.
Connectors, valves, lines and NIMs should be changed every third day for inpatients and, at
least every seventh day for outpatients. This time-interval for CVCs in patients getting blood
products or lipid solutions is controversial. Studies dealing with this problem are conflicting
and some recommendations, based on old studies, advocate a time interval of only one day if
these solutions are to be used32 53-61.
CVC dressings should be changed at least every fifth day and more often when necessary32 62.
Outpatients usually, for practical reasons, have their dressing changed every seventh day.
During the change should the insertion site be treated with SCHA33-35.
T-CVCs should have dressings, changed as above, until the subcutaneous cuff has firmly
healed and the sutures have been removed.
CVCs should be flushed with saline after each use and the catheter should be filled with this
solution, while not in use. Heparin has traditionally been used as a lock solution to prevent
occlusion, trombosis and possibly also infections. No well-designed studies support this63.
However, there are some new lock solutions that are promising either alone or in
combination. These are hydrochloric acid, ethanol, methylene blue, vancomycin and several
other antimicrobial drugs32.
The older routines of changing CVC once a week to prevent infections has not been shown to
be successful64 65.
CVC-exchange over a guide-wire can be performed in the case of CVC malfunction or switch
to another CVC-type. This implies a decreased risk for mechanical complications, even
though microorganisms can be transferred to the new catheter. Hence, change over guide-wire
is not suitable when there is a local infection or high suspicion of CRI/CRBSI. CVC-exchange
over a guide-wire should be performed under the same sterile precautions as insertion at a
new site32 65
17
Local guidelines for central venous catheter insertion and care.
In 1998 the Department of Anaesthesia and Intensive Care in Jönköping started a quality
improvement programme with the aim of optimising the insertion and care of CVCs and ACs
to achieve low infection rates related to these catheters. This resulted in a document which
described the problem, defined the infections, and established evidence-based routines for
catheter insertion and care. All staff participated in the education programmes and was
obliged to follow these recommendations that, with minor revisions, have been used ever
since.
Table 1 summarises the evidence-based recommendations used at the Jönköping Hospital for
CVC insertion and care. These recommendations are now also national guidelines, presented
by SFAI (www.sfai.se), the Swedish Association of Local Authorities and Regions
(www.skl.se), and the Handbook for Healthcare (www.vardhandboken.se).
18
Table 1: The evidence-based recommendations from Jönköping for central venous catheter insertion
and care.
General remarks
Implement full adherence to basic hygiene routines
Organise a CVC team on every unit that inserts and uses CVCs
Create evidence-based routines for insertion and care of CVCs
Perform regular education on CVC insertion and care
Document insertion and care of CVCs in standardised documents
Monitor adherence to basic hygiene routines
Monitor adherence to CVC routines
Monitor incidence of CVC infections over time
Routines for CVC insertion
Only use CVCs on correct indications
Use ultrasound guidance when possible
Use the most suitable vessel for each patient and take both mechanical and sterility considerations
Treat the insertion site with SCHA solution prior to insertion
Use maximal sterile precautions
Use CVCs with as few lumina as possible
Use sutures for fixation
Cover insertion site with sterile gauze or semi-permeable dressing
Insert tunnelled CVC or subcutaneous venous port for catheterisation time >3-4 weeks
Routines for CVC care
Evaluate the need for the CVC every day
Examine the CVC for complications at least once day.
Change dressings every 1-5 days (every 7th day in outpatients)
Change sterile dressings under sterile conditions
Clean the insertion site with SCHA solution when dressing is changed
Use NIMs for all injections
Clean and scrub the NIM with SCHA solution prior to each use (“scrub the hub”)
Flush the CVC with saline repeatedly after each use to prevent occlusion
NIMs, hubs and infusion lines should be changed every third day (every 7th day in outpatients)
Lipid solutions should be administered in a separate lumen if a multi-lumen CVC is used.
A CVC can be used for blood transfusion and blood sampling.
CVC exchange due to malfunction, or to another CVC-type should be performed over a guide-wire,
whenever possible
Remove the CVC when it is no longer needed
Additional options to decrease CVC infections in selected situations
Consider antimicrobial CVCs
Consider chlorhexidine sponges
Consider semi-permeable films containing chlorhexidine
Consider antimicrobial lock solutions
On the ICU: consider daily whole body wash with chlorhexidine
CVC: Central venous catheter
SCHA: 0.5% chlorhexidine (w/v) in 70 % alcohol
NIM: Needless injection membrane
ICU: Intensive care unit
19
ARTERIAL CATHETERS
Background and indications
ACs are mainly inserted for repeated blood sampling, including arterial blood gases, and
intravascular haemodynamic monitoring during advanced anaesthesia and ICU treatment.
Contrary to the number of studies on CVCs there are very limited data on ACs in terms of
catheter care, complications and their risk factors. Therefore, most routines are extrapolated
from studies on CVCs.
Choice of catheter
ACs are non-antimicrobial, single lumen catheters made of polyurethane or Teflon.
Insertion
ACs are mostly inserted in the radial or femoral artery, but other arteries such as the ulnar,
brachial and dorsalis pedis artery are also used. Contrary to CVCs, which are mainly inserted
using the Seldinger technique, ACs are inserted with a catheter over cannula (as peripheral
venous catheters), or Seldinger technique.
One study has evaluated the use of maximal sterile precautions during insertion of an AC.
This showed no advantage regarding infectious complications when compared with the use of
sterile gloves and ordinary hospital clothing only66. The insertion site should be treated with
SCHA prior to insertion and the operator should wear sterile gloves. Sterile drapes may be
considered, especially for insertion in the femoral artery.
Ultrasound guidance when inserting ACs is much less studied than with CVCs. However
some studies have shown that this technique enhances the success rate67. ACs are secured
with sterile stripes or monofilament sutures. The insertion site should be covered with sterile
gauze or a semi-permeable polyurethane dressing39.
A blood sampling pressure set containing saline is always connected to the AC. New closed
sampling pressure sets have been shown to reduce the need for blood transfusion in patients
staying on the ICU for a long time68 69. Microbial colonisation seems to be reduced with these
systems but no study has evaluated the effect on AC infections70. Furthermore, closed
sampling sets reduce the chance of staff coming into direct contact with the patient’s blood.
Catheter care
All handling of ACs should be performed under the same sterile conditions as with CVCs. A
checklist is a valuable tool for the procedure and its documentation. The AC and the insertion
site should be inspected every day for complications and the need for the catheter should be
questioned. The AC should promptly be removed when it is no longer required32.
It is recommended that the blood sampling pressure sets and dressings are changed every
second to fourth day32 71 and the insertion site should be treated with SCHA33-35.
20
INFECTIOUS COMPLICATIONS RELATED TO THE USE OF CENTRAL VENOUS
CATHETERS AND ARTERIAL CATHETERS.
Mechanisms
The mechanisms of infectious complications from intravascular catheters are often divided in
three categories (Figure 2)72:
1. Cutaneous spread of microorganisms from the skin on the outside of the catheter
during or after insertion.
2. Contaminated infusate, hubs and lines, commonly caused by inappropriate handling.
3. Haematogenous spread of microorganisms.
The two first mechanisms are probably the most common causes of catheter infections and
can to a large degree be prevented by high adherence to structured hygiene routines. The third
mechanism and can only be prevented by the use of anti-microbial catheters.
Figure 2: Causal factors of central venous catheter-related infections. Reprinted, with
permission, from the Centers for Disease Control and Prevention72.
21
Definitions
The difficulties in diagnosing CVC infections have over the years resulted in a variety of
definitions which has to be considered in the evaluation and comparison of scientific studies
on infectious complications. Traditionally these infections have been divided into local
infections around the insertion site or the subcutaneous tract and bloodstream infections. The
first two are diagnosed by inspection and local cultures and the third by tip and blood cultures
in patients with signs and symptoms of general infection. The problem with this
categorisation is that most CRI/CRBSI show no local changes73 and cultures can be falsely
negative or positive. To overcome this problem, a third definition has been proposed
including positive tip culture, signs and symptoms of general infection where there is no other
obvious source of infection. However this definition carries the risk of falsely categorising a
CVC colonisation as an infection when there is a non-CVC explanation for the patient’s
symptoms. Hence, we propose the following definitions for CVC colonisation and infection:
Colonisation
Microbial growth on the catheter tip.
Local infection
Inflammation or pus at the insertion site with a positive culture from the site or the
subcutaneous tract.
Catheter-related infection (CRI)
Positive CVC tip culture with symptoms of systemic inflammation and no other obvious
source of infection.
Catheter-related bloodstream infection (CRBSI)
Indistinguishable microorganisms are isolated from peripheral blood and the catheter tip or
blood taken via the CVC.
Systemic inflammation
The definition mostly used for general infection in the diagnosis of CVC-infections has
included fever, chills and hypotension74. However, most CVCs are used in ICU or immunecompromised patients and these symptoms can be present or absent depending on the illness
or its treatment (i.e leukopenia, steroid treatment, haemodialysis, inotropes, induced
hypothermia, sedation, and muscle relaxants). It is our opinion that the well-established
definition of systemic inflammation in the ICU setting, the so-called Systemic Inflammatory
Response Syndrome (SIRS) is a better alternative when evaluating patients with suspicion of
CVC infection75. SIRS caused by an infection is called sepsis, and with increasing severity it
is further divided into severe sepsis and septic shock (Table 2).
Unfortunately, there is no absolute consistency in the definition of CVC infections (Table 3).
Furthermore, it has also been shown that several studies have referred to the same original
definition but have used it in a modified way76. These factors have to be considered when
comparing different studies
22
Table 2: Criteria for the Systemic Inflammatory Response Syndrome (SIRS), sepsis, severe
sepsis and septic shock75:
SIRS
At least two of the following symptoms:
 Body temperature >38°C or <36 °C
 Heart rate >90 beats per minute
 Respiratory rate >20 per minute PaCO2 <4.3 kPa
 B-Leukocytes >12x109/l or <4x109/l, or >10% immature granulocytes
SEPSIS
SIRS caused by microorganisms
SEVERE SEPSIS
Sepsis associated with organ dysfunction.
SEPTIC CHOCK
Sepsis with refractory hypotension or hypoperfusion abnormalities despite adequate fluid
resuscitation
..
23
Table 3: Our simplified comparison of four definition systems regarding central venous
catheter infections.
74
77
*
**
CDC
IDSA
ECDC
SFAI
This thesis
Colonisation
>15 CFU on tip culture
≥1 CFU on tip
culture
Positive tip culture
(≥103 CFU/ml or ≥15
CFU)
≥1 CFU on tip
culture
Local infection
Exit site local infection:
Inflammation (without pus)
<2 cm at insertion sitea
Microbial exit site:
Exudate at exit
site and positive
local cultureb
Positive tip culture
(≥103 CFU/ml or ≥15
CFU) and
pus/inflammation
at insertion site
Positive tip
culture
without clinical
symptoms
Inflammation at
insertion site
without
bloodstream
infection
General CVC-related
infection:
Positive tip culture
(≥103 CFU/ml or ≥15
CFU) and clinical signs
improve within 48
hours after catheter
removal
Positive tip
culture and
symptoms of
systemic
inflammationd, e
without any
other obvious
reason
Positive tip culture
and
symptoms of
systemic
inflammatione
without any other
obvious reason
No positive blood
culture
d
Clinical exit site local
infection: Inflammation >2
cm and pus at insertion
sitea
a
in the absence of
concomitant BSI
Clinical exit site:
Inflammation <2
cm at insertion
siteb, c
Can be
associated with
BSI
c
Can be
associated with
purulent drainage
Positive peripheral blood culture in a patient with
a CVC and symptomsd of systemic inflammation
and no other obvious source of infection
One of the following should also be present:
Positive tip culture (semi-quantitative or
quantitative) with the same (antibiogram)
microorganism or positive paired blood culture
d
No positive blood
culture
b
CVC-related
infection
CVC-related
bloodstream
infection
Fever, chills and hypotension
Positive tip culture and
blood culture
performed 48 h prior
or after insertion with
same microorganisms
or positive paired
blood culture
Fever, chills
and
hypotension
e
Two out of
four SIRS
symptoms
Positive tip
culture and
blood culture
performed 48 h
prior or after
insertion with
same
microorganisms.
Symptomsd, e of
systemic
inflammation
and no other
obvious source
of infection or
positive paired
blood culture
d
Fever, chills
and
hypotension
e
Two out of
four SIRS
symptoms
*
Inflammation
and/or pus at
insertion site.
Positive local
culture
www.ecdc.europe.eu
www.sfai.se
**
24
e
Two out of four
SIRS symptoms
Positive tip culture
and blood culture
performed 48 h
prior or after
insertion with
indistinguishable
(antibiograms)
microorganisms or
positive paired
blood culture
CDC: Centers for Disease Control and Prevention
IDSA: Infectious Diseases Society of America
ECDC: European Centre for Disease Prevention and Control
SFAI: Swedish Association of Anaesthesia and Intensive Care
CFU: Colony-forming units
BSI: Bloodstream infection
CVC: Central venous catheter
SIRS: Systemic Inflammatory Response Syndrome
25
Culture methods
Tip culture
The dominating method for culture of intravascular catheter tips has, since 1978, been the
roll-plate method described by Maki78. This method is considered positive when ≥15 CFU are
isolated. The problem with this method is that it predominately cultures microorganisms from
the external surface on the catheter and not the internal lumen. To overcome this problem an
alternative method has been developed which also cultures microorganisms from the interior
lumen of the catheter and is considered positive when >102 or 103 CFU per ml79. However,
there are no data that clearly show one culture method to be is superior to the other80-82.
The tip culture method has several limitations.
 The catheter has to be removed for culture.
 The distinction between catheter colonisation and infection can be difficult.
 The culture results can be influenced by antimicrobial treatment culture technique,
transportation and time77 80 83.
 There has been little evaluation of tip culture techniques for antimicrobial CVCs.
 There are limited data on culture cut-off values for different microorganisms.
Blood culture
Since CRBSI has been the standard for diagnosing intravascular catheter infections, a blood
culture is mandatory. A blood culture drawn from a catheter can reflect colonisation and
therefore a simultaneous sample from another vessel has to be performed to verify that the
microorganism has spread to the blood. However, haematogenic spread of microorganisms
will, of course, regardless of focus give positive blood cultures from a vessel or a catheter.
Therefore, blood cultures taken for the diagnosis of CRBSI should be performed as follows:


Perform paired blood culture i.e. simultaneous blood cultures from the CVC and
another vessel84 85
The paired blood culture is considered positive for the CRBSI diagnosis if blood
culture from the CVC is positive >120 minutes before the peripheral blood culture86 or
the ratio between CVC and peripheral blood is 3-5:1 CFU/ml87.
The blood culture method has several limitations.
 Blood samples must be taken through all the lumina in a multi-lumen CVC88.
 The culture results can be influenced by antimicrobial treatment, culture technique,
and transportation time80 89.
 Microorganism can be intermittently released to the bloodstream
 There are limited data on culture cut-off values for different microorganisms
concerning analyses of time to positivity or CFU per ml.
 Microorganisms found on tip and blood cultures are regarded as indistinguishable if
phenotype and antibiograms are equal. This may not be correct since different
genotypes of the same phenotype could have the same antibiogram.
Culture in daily practice
Since tip- and blood cultures have limitations both methods must be available for clinical
assessment of a patient with CVC infection symptoms. Unfortunately, cultures can be falsely
positive or negative. The patient’s symptoms may be depressed by illness or treatment and
therefore a unique clinical judgement has to be performed in every situation, evaluating both
26
culture results and clinical signs. Both CRI and CRBI are valuable entities in patient care and
for monitoring infectious complications related to CVCs77.
Microbiology
There is a myriad of microorganisms reported to cause CRI/CRBSI. However the most
common agent is CoNS followed by S. aureus and Candida spp. Other microorganisms that
should be considered are gram negative rods and Enterococcus spp.77.
Diagnosis and treatment
The questions that have to be answered in a patient with a CVC and infection symptoms are:
1. Is the CVC responsible for the patient’s infection symptoms?
2. Should the CVC be removed?
The ability to answer the question of the catheter’s role in the patient’s symptomatology is
influenced by several different factors and it is not always possible to arrive at a correct
answer. In severely ill patients on several antibiotics and where there is no possibility to wait
for cultures, the only alternative is to remove the catheter and treat the patient. In ICU patients
with short-term catheters this is not a problem since it is usually easy to remove the catheter
and insert a new. However, in patients with long-term access this may not be so easy.
There are limited data, from PRCTs, on treatment strategies for infectious complications
related to CVCs and most data are based on “expert opinion”77. However a useful approach to
management is to ask the following questions:
1. Has the patient severe sepsis or septic shock?
2. Does the patient need the CVC?
3. Is the CVC a short- or long-term catheter?
Thereafter, following treatment strategies are applicable in patients with a CVC and
symptoms of infection77:
Short-term catheters, both CVCs and ACs:
Local infection without other clinical symptoms
 Remove the catheter and perform culture from blood, insertion site and catheter tip.
Consider administrating systemic antibiotics. Positive tip culture strengthens the
indication for antibiotics.
Non-infected insertion site
 Severe sepsis or septic shock: remove the catheter and take culture samples from
blood, insertion site and catheter tip. Administer systemic antibiotics.
 Sepsis (but not severe sepsis or septic shock) and suspicion of CRBSI: remove the
catheter and take culture samples from blood and catheter tip or change the catheter
over a guide-wire and take culture samples from blood and catheter tip. Consider
systemic antibiotics. Alternatively, perform paired blood cultures with the catheter in
situ. Consider systemic antibiotics.
27
If cultures confirm the CRI/CRBSI diagnosis the CVC has to be removed and a new
catheter should be inserted at a new insertion site. There are no data evaluating the
routine to wait a day or longer before inserting a new CVC after that an infected catheter
has been removed.
Long-term catheters (tunnelled CVCs and subcutaneous venous ports):
 Severe sepsis or septic shock, with or without local infection: perform paired blood
culture and take culture samples from insertion site and subcutaneous tract. Remove
the catheter and perform tip culture. Give systemic antibiotics
 Sepsis (but not severe sepsis or septic shock), with or without local infection: perform
paired blood cultures and take culture samples from insertion site or subcutaneous
tract. Administer antibiotics and wait for culture results. If cultures reveal S. aureus or
Candida spp., then remove the catheter. Continue with suitable antibiotics. For other
microorganisms watchful treatment, with a catheter in situ, is allowed. In case of
unsuccessful treatment or relapse of infection the catheter should be removed.
Antimicrobial lock treatment could be considered as an adjuvant treatment for
catheters in situ.
PRCTs have not addressed the length of antibiotic treatment for CRI/CRBSI. However, the
general agreement is as follows:
 S. aureus: systemic antibiotics for at least 14 days. Consider periods of 4-6 weeks for
long-term systems.
 Candida species: systemic antifungals for 14 days after first negative blood culture.
 Other species: systemic antibiotics for 7-14 days.
If the CRBSI is complicated by endocarditis, osteomyelitis, infected thrombosis etc. the
treatment period has to be prolonged.
SFAI (www.sfai.se) has developed treatments algorithms, adopted from IDSA77, for
suspected CVC infection in short and long-term catheters. These are presented in Figures 3
and 4.
28
29
Figure 3: Suggested management of infections associated with short-term CVCs. Solid arrows
indicate positive and dashed arrows negative answers (www.sfai.se).
Is CVC needed?
Suspected/verified
short-term CVC
related infection

Draw coupled blood
cultures
Remove CVC
Catheter tip culture


Draw coupled blood cultures
Exit-site infection?




Remove CVC
Catheter tip culture
Insert new CVC in
new vessel
Give
appropriate
antibiotics
Severe sepsis or septic shock?



Look for alternative
source of infection
Consider antibiotics


Exchange CVC over
the wire or wait for
blood culture results if
low clinical suspicion
Consider antibiotics
Positive tip culture
CVC-infection/colonisation
unlikely
Positive tip
culture?
CVC-infection/colonisation
possible
Positive blood
culture?




CVC-related blood
stream infection



Remove CVC
Insert new CVC in different
vessel
Look for alternative source of
infection
Consider antibiotics
30
Remove CVC
Insert CVC in another vessel
Adjust antibiotics according to
culture
Figure 4: Suggested management of infections associated with long-term CVCs. Solid arrows
indicate positive and dashed arrows negative answers (www.sfai.se).
Suspected/verified
long-term CVC
related infection






Is CVC needed?
Severe sepsis, septic
shock or infectious
complication
(endocarditis,
osteomyelitis,
epidural abcess,
septic
thromboembolism)?
Coupled blood cultures
Remove CVC
Catheter tip culture
Swab culture tunnel/pocket
Give appropriate antibiotics
Adjust antibiotics according
to cultures




Adjust antibiotics if necessary
Insufficient or recurrent signs of
infection during/after antibiotic
treatment
Coupled blood cultures
Swab culture from tunnel/pocket
Give appropriate antibiotics
Consider lock therapy
Growth of Staphylococcus
aureus or Candida albicans?




31
Remove CVC
Catheter tip culture
Swab culture from
tunnel/pocket
Adjust antibiotics
according to cultures
Epidemiology, mortality and healthcare costs
The number of CVCs used in Sweden every year is estimated by SFAI to be around 50.000
(www.sfai.se). There are no data on the nationwide number of infectious complications
related to these catheters. In the United States there is an estimation of around 80.000 CRBSIs
every year77.
The CRBSI rate varies significantly in different studies, depending on several factors such as
patient groups, type of unit, catheter type, adherence to hygiene strategies, and definitions
used. The regular view has been that ACs are seldom responsible for catheter-related
infections90 91. However, a few recent studies have suggested that they do occur in significant
numbers, comparable with CVCs92-94. Pooled incidence figures for CRBSI with different
intravascular devices are showed in Table 495.
Table 4: Pooled incidence figures for catheter-related bloodstream infections with different
intravascular devices according to a meta-analysis by Maki 200695.
Type of
catheter
Number of
studies
Incidence (mean)
per 1000 catheter-days
95%
CI
110
14
13
15
79
18
3
29
16
16
14
0.5
1.7
3.7
1.1
2.7
1.6
1.2
1.6
4.8
1.6
0.1
0.2-0.7
1.2-2.3
2.4-5.0
0.9-1.3
2.6-2.9
1.3-2.0
0.3-2.1
1.5-1.7
4.2-5.3
1.5-1.7
0.0-0.1
Peripheral venous catheter
Arterial catheter
Pulmonary artery catheter
PICC
Non-tunnelled CVC (not antimicrobial)
Non-tunnelled CVC (Ch/s)
Non-tunnelled CVC (M/r)
Cuffed and tunnelled-CVC
Non-tunnelled dialysis catheter
Cuffed and tunnelled dialysis catheter
Subcutaneous venous port (central)
CI: Confidence interval
PICC: Peripherally inserted central venous catheter
CVC: Central venous catheter
Ch/s: Chlorhexidine/Silver-sulfadiazine
M/r: Minocycline/rifampin
True analysis of the healthcare cost of CRBSI is difficult96. Increased costs are due to
prolonged hospitalisation, drugs, supplies, lab tests and specialist visits. Estimations from the
United States have shown an increased cost of 10.000-45.000$ per CRBSI10 96-98. Studies from
Europe have demonstrated costs of approximately 10.000 €99. Unpublished data from the ICU
at the Sahlgrenska University Hospital in Gothenburg have shown a 200.000 SEK increase in
ICU cost for each CRI (personal communication, Sophie Lindgren, PhD, Senior Consultant).
The direct mortality caused by CVC infections has been difficult to define and mortality rates
in international studies vary between zero and 25%16 100-102.
32
Hygiene strategies, CVC teams and evaluation
Several studies have shown that implementing simple basic hygiene routines can significantly
reduce the number of CRBSI10 98 103-105. Most of these studies have focused on ICUs and other
patient groups of with special risk for CRBSI. A few studies have also been able to show that
these efforts will reduce the CRBI incidence over sustained periods of time103 105 106. One
study has also indicated that the concept decreases overall mortality107. It is therefore
fundamental that all units were CVCs are inserted or used have a CVC team22 32 108. These
teams should implement evidence-based strategies and run continuous education if one is to
decrease the number of infectious complications secondary to CVCs. This includes basic
strategies for insertion, care and handling of complications. Furthermore, there must be a
continuous evaluation programme on adherence to routines and follow-up of complications32.
CANDIDA TRANSMISSION
Background
Candida colonisation and invasive fungal infections, especially with Candida spp., have
increased in the ICU setting throughout the world over the recent decades109. Furthermore,
there has been an increased focus on Candida spp., causing infections and not only
colonisation. The reasons for this increasing problem are probably the advances in medical
technology, i.e. transplantation, chemotherapy, advances in surgery and intensive care,
invasive catheters, use of broad-spectrum antibiotics, and haemodialysis. Most of these
infections are caused by C. albicans. Unfortunately, there has been an increase in the
frequency of fluconazole-resistant species, especially C. glabrata109.
There are several risk factors for Candida infections on the ICU, i.e. surgery, total parenteral
nutrition, fungal colonisation, renal replacement therapy, infection and/or sepsis, mechanical
ventilation and high Apache II/III110. Furthermore, blood stream infections with Candida spp.
increase length of stay, mortality, and healthcare costs109.
Transmission
The transmission of pathogenic bacteria between patients on an ICU is well documented8, but
the role of this mechanism in the case of Candida spp. has not fully been explored and
previous studies have shown conflicting results111-118. Traditionally it has been stated that
fungal infections evolve from the patient’s endogenous flora, especially from the
gastrointestinal tract119. However, a few studies have indicated transmission between patients
within the ICU and the neonatal ward111-114 116 117 120. It has also been shown that healthcare
workers carry fungal species on their hands111 112 121 and nosocomial outbreaks have been
reported113 122.
The study of transmission is complex and depends on several factors:
1. Candida colonisation varies significantly in different reports, depending on several
factors such as diagnosis, type of surgery, length of ICU stay as well as selection of
culture sites and sampling techniques118.
33
2. Analysis of relation between isolates demands DNA-analysis which is complex, time
consuming and expensive, especially for multi-locus sequence typing, which is the
standard method. This method can now in the clinical setting be replaced with
simplified techniques such as the rep-PCR method, which is commercially available,
DiversiLab (bioMérieux, Marcy l'Etoile, France)123 124.
3. Since variations of Candida spp. genotypes in different populations, at specific times,
not are known, statistical support of transmission is complex. A higher incidence of a
specific genotype in simultaneous patients at a specific time could be explained by
natural variations within the population, and is not necessarily caused by transmission.
Statistical analysis of transmission within a unit demands cluster analysis, and
temporal cluster analysis has never been attempted on Candida transmission125 126.
4. A reference group is difficult to define since it will demand a similar case mix of
patients regarding age, medical treatments, immune status, surgery, antibiotics and
geographical location127. Two identical ICUs in different geographical locations will
not necessarily have the same genotypes or variations in genotypes over a specified
time period. The same problem exists when using healthy people outside the ICU or
patients within the same hospital but outside the ICU. A suitable reference group
could be patients with blood cultures positive for Candida species outside the ICU.
This patient group represent a cohort of severely ill patients from the same
geographical area as the ICU patients.
PREVENTING NOSOSCOMIAL INFECTIONS ON THE INTENSIVE CARE UNIT
IN JÖNKÖPING
In1998 the ICU in Jönköping started several healthcare quality improvement programmes
with the aim of improving all aspects of critical care and reducing complications, including
NIs. This resulted in documents describing the problems, defining various infections, and
introduction of several evidence-based routines for patient care which could influence the
incidence of NIs.
There was also the implementation of systems evaluating the incidence of complications
including NIs, microbiological epidemiology, and antibiotic use and resistance. The cornerstones of this concept are summarised in Table 5.
Continuous assessment of different outcome data has indicated that the overall programme on
the ICU has been successful in terms of low incidence of NIs. Registered nosocomial
infections in the ICU between years 2000 and 2012 are presented in Table 6.
34
Table 5: The Jönköping intensive care unit concept for preventing nosocomial infections
Staffing
High continuity of well-educated ICU-physicians.
Adequate nurse: patient ratio.
All nurses have critical care education.
Preventive strategies
Thorough routines for patient care and hygiene precautions.
Isolation of patients with suspected or verified multi-resistant bacteria.
Daily visiting infection specialist.
Continuous collaboration with the Department of Microbiology.
Education
Educational programmes to increase the awareness of nosocomial infections.
Educational programmes on the prevention of nosocomial infections, including insertion and
care of central venous catheters.
Evaluation
Weekly surveillance cultures from all patients with an ICU stay >72 hours.
Evaluation of routines by the hospital’s Department of Hygiene.
Continuous evaluation of patient outcome and overall complications.
Continuous evaluation of nosocomial infections, antibiotic prescription and microbial
resistance patterns.
Participating in the Swedish Intensive Care Register.
Participating in the Swedish Strategic Programme against Antibiotic Resistance.
Research
Research in the field of nosocomial infections.
ICU: Intensive care unit
Table 6: Annual nosocomial infection rates on the Jönköping intensive care unit
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
ICU patients (n)
542
535
459
500
506
489
510
496
530
517
571
554
VAP (n)
3
5
5
4
5
6
4
2
5
2
3
2
CRI/CRBSI (n)
7
6
3
1
5
3
4
3
5
3
0
2
2
5
6
2
8
5
4
3
3
Cl. difficile (n)
ICU: Intensive care unit
n: numbers
VAP: Ventilator-associated pneumonia
CRI: Catheter-related infection
CRBSI: Catheter-related bloodstream infection
Cl: Clostridium
35
Central venous catheter insertion and care in Jönköping
A CVC team, including two anaesthesiologists and one ICU nurse, are responsible for all
written documents concerning CVC and AC insertion, care and removal at the hospital. These
instructions are distributed to all units using these catheters and are also available on the
hospitals intranet. All anaesthesiologists are trained under supervision to perform CVC and
AC insertion according to the written documents. All ICU nurses are trained at the start of
their employment and thereafter every second year to assure a high adherence to these
routines. The CVC team also has a network for education and the team or a trained
anaesthesiologist is available around the clock for problem solution on all hospital wards and
outpatient departments. Since 2006 there have been monthly measurements of adherence to
basic hygiene routines throughout the hospital.
The quality control of CVC infections throughout the hospital includes continuous tip culture
analysis of all CVCs removed.
This quality improvement programme developed into a scientific project resulting in this
thesis.
36
THE AIMS OF THE STUDIES IN THIS THESIS

To study the incidence of colonisation and infections related to central venous
catheters, after implementation of evidence-based routines throughout our hospital
(Study 1).

To study the incidence of colonisation and infections related to arterial catheters, after
implementation of evidence-based routines on our intensive care unit (Study 2).

To study the long-term effects and endurance, after implementation of evidence-based
routines throughout our hospital of evidence-based CVC routines, assessed as
temporal variations in central venous catheters colonisation and infections. (Study 4).

To study microorganisms responsible for colonisation and infections related to central
venous catheters and arterial catheters. (Studies 1, 2 and 4)

To identify possible risk factors for central venous catheter and arterial catheter
microbial colonisation and infections (Studies 1, 2 and 4)

To study possible transmission of Candida spp. between patients on an intensive care
unit (Study 3).
37
MATERIAL AND METHODS
SETTING
Jönköping hospital is a 500-bed public hospital supporting most medical and surgical
specialities, except thoracic and neuro surgery. The number of operations performed per year
is approximately 12.000. The ICU has resources for seven patients (two single rooms, one
double room and one four-bedded room) and admits around 500 patients a year. The nurse:
patient ratio is 1.3:1 and the median Apache II score is 18.
STUDY DESIGN
All studies were prospective observational cohort studies.
Inclusion criteria:
Study 1. All patients ≥18 years with a CVC inserted at our hospital between September 2001
and December 2002.
Study 2. All patients ≥18 years with an AC inserted on our ICU between March 2006 and
April 2008.
Study 3. All patients on our ICU with a positive Candida culture, between January 2007 and
July 2008, were included. Patients who had a blood culture isolate of C. albicans or C.
glabrata isolated between 2006 and 2008 in our county but not treated on our ICU were
chosen as reference group.
Study 4. All patients, excluding neonates, with a CVC removed at our hospital, regardless of
insertion hospital, between 2004 and 2009 were included.
Patients with subcutaneous venous ports, PICCs and CVCs inserted using cut-down technique
were not included in Studies 1, 2 and 4.
All clinical and microbiological data were collected manually from patient records by the
author, according to predefined study protocols.
The numbers of patients and catheters included in each study are presented in Table 7.
Table 7: Numbers of patients and catheters examined in each study.
Study 1
Study 2
Study 3
Study 4
Number of patients Number of catheters
354
495
482
600
77
1674
2045
38
CATHETER INSERTION AND CARE
The CVCs were inserted by an anaesthesiologist using maximal sterile precautions (cap,
mask, gown, gloves and large drape) and the Seldinger technique was used. ACs were also
inserted by an anaesthesiologist, wearing ordinary hospital clothing and sterile gloves.
Ultrasound-guided insertion was introduced during Study 4. The short-term multi-lumen
CVCs inserted in Jönköping during Study 4 were all impregnated with chlorhexidine/silversulfadiazine. All other catheters were non-antimicrobial. The insertion site was treated with
SCHA and allowed to dry for one to two minutes prior to insertion. No prophylactic
antibiotics were given. All CVCs and the ACs inserted in the femoral vein were secured with
monofilament sutures and the other ACs were secured with sterile adhesive stripes. After the
procedure the insertion sites was covered with a semi-permeable dressing. The CVC and AC
insertion was documented in the patient records after completed procedure, and registered in a
database. In Studies 1 and 2, insertion documentation was also registered in study protocols.
T-CVC sutures were removed when the subcutaneous cuff had firmly healed and no semipermeable dressings were used thereafter. Every third day (every seventh day for outpatients),
dressing, stopcocks, pressure sets and injection membranes were changed, and the insertion
site was treated with SCHA. Heparin flushing and locks were not routinely used, except for
patients on haemodialysis outside the ICU. The CVCs were flushed four times after every
infusion with ten millilitres of saline to prevent occlusion. Closed sampling pressure sets were
not used for the ACs. Resting CVCs (> 24 hours) were not routinely flushed. Lipid solutions
were administrated via a separate lumen when using multi-lumen catheters. All CVCs and
ACs were supposed to be cultured on removal.
DEFINITIONS
CVC or AC colonisation74 128
Studies 1 and 2: positive tip culture with ≥1 CFU without clinical symptoms
Study 4: positive tip culture with ≥1 CFU regardless of clinical symptoms
Both definitions were compared with a commonly used definition ≥15 CFU78.
CRI (both CVC and AC)128
Positive tip culture from a patient having at least two SIRS75 symptoms at CVC or AC
removal, and no other obvious source of infection.
CRBSI (both CVC and AC)74
Isolation of indistinguishable microorganisms from the tip culture and a blood culture sample
drawn from another vessel (within 48 hours prior to or after CVC or AC removal). Isolates
were regarded as indistinguishable if they shared the same phenotype and antibiogram.
Duration of catheterisation
The number of days from insertion to removal of the CVC or AC.
ICU-CVCs
All CVCs that were used to some extent on the ICU were regarded as ICU catheters.
Candida infection (Study 3)
Candida growth with clinical symptoms related to Candida spp. as judged by the attending
ICU physician in consultation with the daily visiting infectious disease specialist.
39
MICROBIOLOGY
CVC and AC tip culture (Studies 1-4)78
The catheters were removed after site treatment with SCHA that was allowed to dry. The
distal 3-5 cm of the catheter tip was cut off with sterile scissors and deposited in a sterile
container and cultured using a semi-quantitative standardised roll plate method. The tip
culture result was considered positive if ≥1 CFU were found. The catheter tips were all
cultured within 18 hours after removal.
Blood cultures (Studies 1-4)
Blood cultures were performed when clinically indicated by aspirating blood from another
vessel. The bottles were incubated ≤6 days using an automated blood culture system
(BAc/ALERT, bioMériuex, Inc, Durham, NC). Isolates were identified using standard
methods at the local microbiology laboratory. Antibiotic susceptibility tests were performed
according to Swedish standards (www.srga.org).
Candida culture and analysis (Study 3)
Surveillance cultures (tracheal secretion, catheter urine, perineal swab, wounds and incision
sites) were collected every Monday from all patients with an ICU stay longer than 72 hours.
Directed cultures were collected at the request of the physician responsible or the daily
visiting infectious disease specialist.
Candida samples were cultured on BBL™ CHROMagar™ Candida medium (bioMérieux),
and incubated at 35 °C overnight. Species determination of Candida isolates was performed
on the VITEK2 compact, using the YST-card, according to the manufacturer’s
recommendation (bioMérieux). Extraction and purification of DNA was performed using the
Ultra Clean™ Microbial DNA Isolation Kit (MO BIO Laboratories, Inc. Carlsbad, CA) in
accordance with the manufacturer’s instructions for fungi, with the following modifications:
after addition of the MD1™-solution the samples were incubated at 80 °C for 30 minutes and
after 45 minutes of bead beating, the samples were centrifuged for two minutes. The isolates
from blood cultures were also incubated with 15 units of Zymolyase (Zymo Research, Irvine,
CA) at 37 °C for 30 minutes prior to the addition of the MD1™- solution. DNAsamples were
amplified using the Candida fingerprinting kit according to the manufacturer’s instructions
(bioMérieux).The fragments were separated using an Agilent 2100 Bioanalyzer (Agilent
Technologies, Santa Clara, CA). Finally, web-based software (DiversiLab v3.4) was used to
analyse the genotypic similarity of isolates, by the Kullback-Leibler method123. An internal
positive control was chosen based on the number and distribution of produced fragments.
Repeated analysis of the internal positive control gave an inter-run similarity of 97%. The
limit for indistinguishable isolates, and thus our definition of a genotype was therefore set at
97% similarity instead of the recommended 95% (bioMérieux).
40
STATISTICS
Associations and differences between groups were assessed using χ2-test, Fisher’s exact test,
Student´s t-test or Mann-Whitney test as appropriate. The correlations between different
incidences were evaluated with Spearman’s rank correlation test. Variations of variables over
time were analysed with linear regression analysis.
Univariate logistic regression analyses were performed to estimate the risk for colonisation,
CRI and CRBSI (Studies 1, 2 and 4). Multiple logistic regression models, controlling for
catheterisation time with following stepwise introduction of significant risk factors, were
performed (Studies 1, 2, and 4).
In Study 3, possible clustering of genotypes was evaluated by two analyses. Firstly; temporal
clustering of individuals carrying the same genotypes using a method analogous to the spatiotemporal cluster method described by Knox125. We analysed the interaction between presence
of specific genotypes and time instead of space and time, by cross classification of all the
possible pairs of patients according to whether they harboured the same genotype or not in
relation to time. A time window of 3, 7, 10, 14 and 21 days between the dates of the first
positive culture was used for defining closeness in time. The inference of the observed versus
the expected number of pairs was made assuming a Poisson-distribution. Secondly; which
only included the most frequent genotype, a goodness-of-fit comparison between Poisson
regression and negative binomial regression was intended to statistically test for temporal
clustering. The outcome measure was defined as the maximum number of days between ICU
stays (3, 7, 10 or 14 days)126.
The discriminatory power of Diversilab for C. albicans was assessed using Simpson’s index
of diversity (Study 3)129.
In Study 4 variations of incidences over time were analysed with statistical process control
methods130. Seldom occurring events (CRI and CRBSI) were analysed with G-charts,
evaluating the number of CVCs removed between each infection episode. Frequently
occurring events (colonisation) were analysed with I-charts, evaluating quarterly incidences of
colonisation. Special causes of variation were defined as a run of eight or more points on one
side on the central line, one point outside the upper or lower control limit, or a run of six or
more points all trending up or down.
ETHICS
All studies were approved by the Regional Ethics Review Board in Linköping.
41
RESULTS
CENTRAL VENOUS CATHETERS
Six hundred and five CVCs in 456 patients were included in Study 1. Complete data were
obtained on 495 (82%) CVCs in 354 patients (Table 8). The reasons for the drop-outs were:
missed culture 74, transfer to other hospital 16, accidental removal 14, still in use 3, and
incomplete patient-records 2.The median duration of catheterisation was 7.5 days (range 0.5407 days). The total number of patient days with a CVC in place was 9010 days.
Two thousand and fifty-three CVCs in 1682 patients were included in Study 4. This
represented 74% of all CVCs used in the hospital. Complete data were obtained on 2045
CVCs in 1674 patients, since insertion date was not found for eight CVCs (Table 8). The
median duration of catheterisation was 8 days (range 0-1617 days). The total number of
patient days with a CVC in place was 45.026 days.
Study 4 showed a continuous increase in the number of CVCs used each year from 269 to 424
(logistic regression; adjusted r2=0.95, b=33.6, p=0.001). There was also an increase in the use
of the internal jugular vein from 31% of all CVCs to 58% (logistic regression; adjusted
r2=0.90, b=6.0 p=0.003) and a decrease in the use of the subclavian vein, from 49% to 22%
(logistic regression; adjusted r2=0.91, b=-5.9, p=0.002) over the study period (Table 8). There
were no other trends detected over time concerning patient and CVC characteristics.
42
Table 8: Comparison between Study 1 and the annual numbers of central venous catheters,
incidences for colonisation and infections in Study 4.
Study 1
f
Study 4
16 months
2001-2002
2004
2005
2006
2007
2008
2009
Total
All
a
495
267
267
332
369
387
423
2045
ICU
350
203
200
233
270
268
279
1453
Non-ICU
145
64
67
99
99
119
144
592
34
14
13
21
10
26
23
107
314(63)
130(49)
114(43)
116(35)
93(25)
80(21)
94(22)
627(31)
161(33)
83(31)
103(39)
151(46)
200(54)
236(61)
244(58)
1017(50)
12(2.4)
39(15)
44(17)
56(17)
61(17)
61(16)
71(17)
332(16)
All
7.5
7.2
5.9
5.6
7.7
8.8
6.7
7.0
ICU
13.9
16.7
14.1
15.7
12.6
19.2
15.0
15.5
Non-ICU
4.4
3.5
1.8
2.6
4.7
4.4
4.2
3.6
7.4
2.3
3.0
2.4
10.4
5.0
1.6
3.0
All
a
1.6
1.8
0.9
1.2
1.1
1.3
0.8
1.2
ICU
3.8
4.7
2.8
4.7
1.7
3.2
1.7
3.0
Non-ICU
0.7
0.8
0
0
0.8
0.5
0.5
0.4
1.9
0.5
0
0
2.6
1.0
0
0.4
a
All
0.4
0.6
0.9
0.8
0.5
0.7
0.5
0.6
ICU
1.9
0.7
2.8
2.6
0.4
1.2
0.9
1.4
Non-ICU
0
0.5
0
0.2
0.5
1.2
0.4
0.3
0
0.5
0
0
2
0,5
0,3
0.4
CVCs
b
Haemodialysis
Vein
c
Subclavian vein, n (% )
c
Jugular vein, n (% )
c
Femoral vein, n (% )
Colonisation
d, e
a
b
Haemodialysis
e
CRI
b
Haemodialysis
CRBSI
e
b
Haemodialysis
a
All CVCs in the study
Haemodialysis outside the ICU
c
Percentage of all CVCs
d
Colonisation independent of systemic symptoms
e
Per 1000 CVC-days
f
Study period: September 2001-December 2002
b
CVC: Central venous catheter
ICU: Intensive care unit
CRI: Catheter-related infection
CRBSI: Catheter-related bloodstream infection
43
Colonisation
Sixty-nine (14%) of all CVCs showed microbial growth in Study 1. The corresponding
number in Study 4 was 314 (15%). This represented an incidence of 7.7 and 7.0 per 1000
CVC-days, respectively.
In Study 4 was there a significant correlation between the quarterly colonisation incidences
defined as ≥1 CFU as compared to ≥15 CFU (ρ=0.89, p<0.05) (Figure 5).
The predominant species responsible for colonisation in both studies was CoNS, followed by
Candida spp. and S. aureus (Table 9). We found no isolates with vancomycin-resistant
enterococci or methicillin-resistant S. aureus.
Table 9: Microorganisms found on central venous catheter tip cultures in Study 1 (80
isolates) and 4 (378 isolates).
Microorganism
Study 1 (%a)
Coagulase-negative staphylococci
60
Candida albicans
8.8
Staphylococcus aureus
6.3
Enterobacter spp.
5.0
Escherichia coli
2.5
Pseudomonas aeruginosa
2.5
Candida glabrata
2.5
Enterococcus faecalis
2.5
Enterococcus faecium
0
Klebsiella pneumoniae
2.5
Others
7.4
a
Study 4 (%a)
63.8
7.9
7.5
1.1
1.3
0.8
0.5
5.8
2.1
0.8
8.4
Percentage of all microorganisms found in Studies 1 and 4, respectively.
Spp: species
CRI and CRBSI
Fourteen (2.8%) and four (0.8%) patients were classified as having CRI and CRBSI
respectively, in Study 1. The incidence of CRI was 1.6 and of CRBSI 0.4 per 1000 CVC-days.
Fifty-two (2.5%) and 29 (1.5%) patients were classified as having a CRI and CRBSI,
respectively in Study 4. The incidence of CRI was and CRBSI was 1.2 and 0.6 per 1000
CVC-days, respectively. The incidences of CRI and CRBSI over time for all patients and
different subgroups are presented in Table 8.
There was a significant correlation between the quarterly incidences of CRI and CRBSI
(ρ=0.83, p<0.05) in Study 4. However, there were no significant correlations between the
quarterly incidences of colonisation, using either of the definitions, and CRI or CRBSI
(Figure 5).
44
Figure 5: Quarterly incidences of central venous catheter colonisation, catheter-related
infection and catheter-related bloodstream infection in Study 4.
CFU: Colony-forming units
CRI: Catheter-related infection
CRBSI: Catheter-related bloodstream infection
Blood cultures in relation to CRI are shown in Table 10. Antibiotics on CVC removal was
analysed in Study 4. Eight of the patients with CRI had a negative blood culture of whom
seven were on antibiotics. In three patients the microorganisms, found on tip culture, were
sensitive to the drug used. In 21 of the 29 cases of CRBSI, the patients were receiving
antimicrobial drugs at removal of the CVC and in twelve of these the microorganisms were
sensitive to the antimicrobial drug. Two cases of CRBSI were not classified as CRI in Study 4
since documentation of SIRS symptoms was missing.
All patients with a CRI or a CRBSI in Studies 1 and 4 were successfully treated with
antimicrobial drugs.
The microorganism isolated on tip culture from the catheters responsible for CRI or CRBSI
are presented in Table 11.
The median catheterisation time to CRI/CRBSI was 14.5 (range: 3-339) days in Study 1 and
14 days (range: 1-645) in Study 4. All cases of CRI/CRBSI with Candida spp. were
diagnosed before Day 16 in Study 1. There was no significant difference in catheterisation
time for CRI/CRBSI caused by bacteria or Candida in Study 4, with a median catheterisation
time of 14 days (range: 3-645) and 13 days (range 1-30), respectively.
45
Table 10: Blood cultures in relation to catheter-related infection.
CRI (n)
Study 1
14
Study 4
52
a
Positive
Negative
Blood culture
blood culture (n) blood culture (n) not performed (n)
4
8
2
8a
27
17
Seven patients were on antibiotics
CRI: Catheter-related infection
n: numbers
Table 11: Microorganisms isolated from tip cultures and blood culture on all cases of catheter-related
infection and catheter-related bloodstream infection in Study 1 (14 patients) and Study 4 (54
patients).
Study 1
Study 4
Number of isolates found
Number of isolates found
a
on tip culture(% )
Coagulase-negative Staphylococci
Candida albicans
Staphylococcus aureus
Enterococcus faecalis
Candida glabrata
Serratia marcescens
Pseudomonas aeruginosa
Escherichia coli
Enterobacter spp.
Klebsiella pneumoniae
Diphtheroid rods
Morganella morgagni
Stenothrophomonas maltophillia
Burkholderia spp.
Citrobacter freundii
Enterobacter cloacae
Achromobacter spp.
Total
in blood
3 (20)
4 (27)
3 (20)
1
1
2 (13)
1 (7)
1 (7)
1 (7)
2
a
on tip culture(% )
in blood
21 (31)
16 (24)
13 (19)
6 (9)
2 (3)
1 (1)
1 (1)
8
7
b
9
b
1
1
1
1
1
1
1
1
1
1
1
15
4
a
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
68
1
1
1
1
30
Percentage of all positive cultures responsible for catheter-related infection and catheter-related
bloodstream infection in Studies 1 and 4, respectively.
b
One patient had a positive blood culture with both Staphylococcus aureus and Enterococcus
faecalis. The same isolates were found on the simultaneously performed tip culture.
n: numbers
46
Statistical Process Control (Study 4)
There were no occasions were the variations in incidence for colonisation was higher or lower
than expected by natural (common cause) variation. However, analysis for CRI and CRBSI
revealed two occasions were the number of CVCs removed between each CRI and CRBSI
were higher than expected, which indicated a period with lower infection rates than expected.
Six measurements of CRBSI revealed a continuous downward run indicating a period of
poorer performance (Figure 6).
Figure 6: Statistical process control: Geometric charts representing the number of central venous
catheters removed between each episode of catheter-related infection and catheter-related
bloodstream infection in Study 4. Lined circles represents four periods of low infection rates not
explained by natural variation. Dotted ovals represents a period with increasing infection rate not
explained by natural variation.
CVC: Central venous catheter
CRI: Catheter-related infection
CRBSI: Catheter-related bloodstream infection
47
Risk factors
Univarate analysis revealed that catheterisation time was a significant risk factor for both
colonisation (odds ratio: 1.011 per day (95% CI: 1.004-1.017)) and CRI (odds ratio : 1.009
per day(95% CI: 1.003-1.015) in Study 1 but only for CRI (odds ratio: 1.002 per day (95%
CI: 1.000-1.004)) in Study 4. Multivariate analysis revealed that chronic haemodialysis was
the only risk factor for colonisation (OR: 4.4 (95% CI: 2.0-9.8) in Study 1 and no risk factors
were found for CRI or CRBSI. Risk factor analyses for Study 4 are shown in Table 12.
Table 12: Risk factor analyses in Study 4 controlling for catheterisation time using multiple
logistic regression for central venous catheter colonisation, catheter-related infection and
catheter-related bloodstream infection.
Colonisation
OR (95 % CI)
CRI
OR (95 % CI)
CRBSI
OR (95 % CI)
Age
ns
ns
ns
Gender
ns
ns
ns
Diagnosis
ns
ns
ns
Apache II score
ns
ns
ns
1.33 (1.03-1.74),
p=0.029a
ns
ns
Non-ICU use
Haemodialysis
ns
Multi lumen CVC
ns
ns
ns
Insertion Hospital
ns
ns
ns
Mortality
ns
ns
ns
IJV compared to SV
2.41 (1.75-3.33),
p<0.0001
2.61 (1.19-5.68),
p=0.016
ns
FV compared to IJV and
SV
1.39 (1.02-1.89),
p=0.035
ns
ns
No antibiotics on removal
1.65 (1.26-2.13),
p<0.0001
ns
ns
a
2.79 (1.01-7.69),
p=0.048
4.47 (1.34-4.89),
p=0.015
Not statistically significant when haemodialysis or antibiotics were controlled for.
OR: Odds ratio
CI: Confidence interval
IJV: Internal jugular vein
SV: Subclavian vein
FV: Femoral Vein
ns: not statistically significant
48
ARTERIAL CATHETERS
Six hundred and ninety-one ACs were inserted in 539 patients. Complete data were obtained
on 600 (87%) catheters in 482 patients. The median duration of catheterisation was 2 days
(range: 0.5- 38 days). The total number of patient days with an AC in place was 2567 days.
Twenty catheters exhibited microbial growth, of which four had two different isolates. The
incidence of colonisation was 7.8 per 1000 catheter-days. The microorganisms identified were
22 CoNS, 1 C. albicans and 1 Klebsiella pneumoniae. Eighteen of these were radial arteryand two were femoral artery catheters.
Five of the catheters were associated with AC-CRI. The incidence of AC-CRI was 2.0 per
1000 catheter-days. Tip culture revealed that three of these catheters had < 15 CFU. Two of
these three catheters were removed while the patient already had suitable antibiotic treatment.
None of the patients were treated with antibiotics when the two catheters with ≥15 CFU were
removed. The only microorganism responsible for AC-CRI was CoNS In all five cases the
AC was inserted in the radial artery.
Only one of the five patients with AC-CRI had a blood culture performed and this was
negative. The patient was given vancomycin prior to culture. We found no cases of ACCRBSI.
Three hundred and ninety-three patients (73%) had a simultaneous AC and CVC. Seventeen
of the 20 patients with AC colonisation had simultaneous CVC, and in six of the 17 patients
tip cultures revealed indistinguishable isolates on the AC and CVC. There was a total of ten
CVC-CRI and in four of these patients AC tip culture showed indistinguishable isolates.
According to definition they both had an AC-CRI and a CVC-CRI.
Significant risk factors for AC-colonisation and AC-CRI are shown in Table 13.
Table 13: Risk factors for arterial catheter-colonisation and arterial catheter-related infection.
Risk factor
AC-colonisation
(OR: 95% CI)
Colonisation of a simultaneous CVC 104.5 (18.7-584.7)a
CRI on a simultaneous CVC
20.6 (5.0-85.8)a
b
253.8 (22.1-2518.0)a
7.3 (1.0-52.9)b
Immunosuppression
a
AC-CRI
(OR: 95% CI)
384.0 (34.7-4244.0)a
p<0.0001
p=0.048
AC: Arterial catheter
OR: Odds ratio
CI: Confidence interval
CVC: Central venous catheter
CRI: Catheter-related infection
49
CANDIDA TRANSMISSION
During the study period 714 patients were treated on 792 occasions on our ICU. A
microbiological culture was performed in 679 (86%) of the ICU stays.
Candida spp. were isolated from 77 patients with 78 ICU stays. Hence, patients harboured
Candida spp. in twelve per cent of ICU stays in which a culture was performed. Seventy-five
per cent of the patients had a negative candida culture within a week prior to the first positive
culture. Clinical data and comparison between patients with negative and positive Candida
cultures are shown in Table 14.
Table 14: Baseline characteristics of four groups of intensive care unit patients according to Candida
ssp. findings.
Group 1
Group 2
Comparison
Group 3
Group 4
Comparison
Patients
with neg
Candida
culture
Patients
with pos
Candida
culture
Group 1 and
a
2
Patients
with
Candida
colonisation
Patients
with
Candida
infection
Group 3 and
b
4
Patients(n)
625
77
65
12
ICU stays (n)
679
78
66
12
61 (0-90)
69 (17-89)
p=0.0012
70 (17-89)
72 (54-79)
ns
58/42
50/50
ns
42/58
67/33
ns
Apache II score
Median (range)
18 (0-48)
24.5 (11-41)
p<0.0001
24 (11-41)
27 (21-30)
ns
ICU stay (days)
Median (range)
1 (0.1-56)
14 (1-56)
p<0.0001
12 (1-56)
18 (14-43)
p=0.036
ICU mortality (%)
9
10
ns
9
17
ns
Surgery (%)
22
41
p<0.0001
36
58
ns
Age (years)
Median (range)
Male/Female (%)
a
χ2 or Student's t-test
Fishers' test or Student's t-test
neg: negative
pos: positive
n: numbers
ICU= intensive care unit
ns= not statistically significant
b
50
Antibacterial drugs were prescribed within seven days prior to the first positive Candida
culture in 74 (95%) cases. The median number of different antibacterial drugs given to each
patient within this period was 3 (range: 0-5). Antifungal therapy was administered to 32
(41%) patients, 22 before and ten after the result of the fungal culture was known. Twelve
(15%) of the patients harbouring Candida spp. were judged to have one or more clinical
Candida infections. Clinical data and comparison between patients with Candida infection and
those with Candida colonisation are shown in Table 14. Candida spp. contributed to mortality
in two cases.
Cultures and genotypes
A total of 180 isolates were found on the ICU of which 81% and 19% were obtained from
surveillance and directed cultures, respectively. The Candida spp. found were: C. albicans
(129), C. glabrata (36), C. krusei (6), C. parapsilosis (4), C. dubliniensis (4) and C. sphaerica
(1).
DiversiLab analysis revealed 27 C. albicans genotypes (Ca1 to Ca27) in 55 patients and ten
C. glabrata genotypes (Cg1 to Cg10) in 16 patients. The other species were excluded from
molecular analysis due to the few isolates found. The diversity index for C. albicans by
Simpson index of DiversiLab was 0.94. The median number of patients for each C. albicans
genotype were 2 (range: 1-19) and the three most disseminated genotypes were Ca8 (19
patients), Ca11 (ten patients) and Ca12 (eight patients) (Figure 7). Five C. glabrata genotypes
were found in more than one patient and Cg3 was the most disseminated (five patients)
(Figure 7). There was no difference in the distribution of genotypes between patients
colonised and infected with C. albicans within the ICU.
Possible clustering, indicated by overlapping ICU stays of patients with indistinguishable
genotypes, was observed on seven occasions with C. albicans and on two occasions with C.
glabrata (Figure 7). Genotypes Ca8 and Ca11 represented six of these possible clusters
(Figure 8).
No overlapping was seen for the frequent genotypes Ca12 or Cg3. By using the modified
spatio-temporal cluster analysis, we found a non-significantly increased number of pairs at
intervals of 3, 7, 10 and 14 days. At a 21 day-interval clustering was observed
(Observed/Expected-ratio=1.42, p=0.016). The other cluster analysis could not be performed
due to limited sample size.
There were no differences between patients in the reference group and the ICU patients with
positive Candida culture as regards age, gender, surgery and antibiotic treatment. Analysis of
isolates from the reference group revealed 24 C. albicans genotypes in 21 patients, and eight
C. glabrata genotypes in ten patients. Three C. albicans genotypes were found in both the
ICU and reference groups. None of these genotypes had a temporal occurrence in the ICU
indicating transmission. The most frequently isolated C. albicans genotypes in the ICU group
(Ca8 in 19 patients and Ca11 in ten patients) were not found in the reference group (p=0.004
and p=0.03). Fourteen C. albicans genotypes were found in more than one patient in the ICU
group and three in the reference group (p=0.0013).
No identical C. glabrata genotypes were found in both the ICU and the reference group (not
significant).
51
52
1
Ca= Candida albicans
Cg= Candida glabrata
1
Ca1 Ca2
P13 P6
Number of overlapping
Intensive care unit stays
per genotype
Number of patients
per genotype
Genotype
Patients
2
3
1
5
1
1
4
P57
P59
P60
P69
19
P41
P44
P45
P50
Ca3 Ca4 Ca5 Ca6 Ca7 Ca8
P53 P53 P24 P49 P29 P3
P78 P63 P25
P6
P29
P7
P33
P10
P37
P14
P19
P20
P21
P22
P30
P34
4
1
2
10
Ca9 Ca10 Ca11
P24 P22 P3
P50
P4
P54
P7
P63
P8
P10
P13
P38
P40
P41
P69
8
2
1
2
1
3
1
2
1
3
2
1
3
1
1
1
Ca12 Ca13 Ca14 Ca15 Ca16 Ca17 Ca18 Ca19 Ca20 Ca21 Ca22 Ca23 Ca24 Ca25 Ca26 Ca27
P5 P28 P8 P73 P22 P15 P59 P17 P2 P2 P11 P11 P11 P11 P11 P3
P22 P36
P77
P35
P74
P23 P67
P43
P36
P62
P25
P58
P39
P42
P52
P66
P71
3
1
5
1
3
1
2
1
2
1
1
1
Cg1 Cg2 Cg3 Cg4 Cg5 Cg6 Cg7 Cg8 Cg9 Cg10
P13 P47 P12 P68 P3 P47 P61 P76 P18 P18
P26
P25
P9 P49 P72
P70
P55
P75
P56
P67
Figure 7: Patient distribution per genotype. Overlapping of intensive care unit stays for patient with the same genotype is shown by bold borders.
53
P9
P10
P13
P14
P16
P19
P50
P52
P53
P80
Patients
harbouring
genotype Ca11
20 08
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
20 07
Ca= Candida albicans
P= Patient
P9
P12
P13
P16
P20
P26
P28
P29
P30
P39
P43
P53
P56
P57
P62
P68
P70
P71
P80
Patients
harbouring
genotype Ca8
Figure 8: Intensive care unit stay for patients harbouring genotype Ca8 (dark boxes) and C11 (light boxes) over the study period
Year
Week number
DISCUSSION
CVCs are necessary in modern healthcare but infections related to these catheters contribute
to significant morbidity, mortality and healthcare costs. In this thesis, we report continuously
low annual incidences of CRI/CRBSI in both short- (16 months) and long-term (six years)
follow-up studies after implementation of evidence-based hygiene routines for CVC insertion
and care at our hospital. We did not observe any mortality caused by CVC infections. We
believe that our results are due to high awareness of CVC infections and high adherence to
evidence-based hygiene routines throughout our hospital.
Our routines for insertion and care are based on previous recommendations from the CDC.
These recommendations have been evaluated in previous studies by others10 14 92 105, but never
in Scandinavia. The hospital’s CVC team, available for education and support in the care of
patients with a CVC, is now well-established. The team or a trained anaesthesiologist is
available for support around the clock. The team arranges practical and theoretical education
sessions on a regular basis for the ICU staff and on demand for personnel on other units. The
team has a continuous surveillance system for the entire hospital, in that all CVCs removed
should have their tips cultured. All departments receive annual reports on colonisation rate
and microorganisms for their unit compared to the hospital as a whole.
We have used the incidence rates of three different indicators of infectious complications
related to the use of a CVCs and ACs; colonisation, CRI and CRBSI. Most studies have used
quantitative or semi-quantitative methods to demonstrate colonisation78 79. We used a more
sensitive definition (≥1 CFU) than the commonly used (≥15CFU) since several factors such as
antimicrobial CVCs, antimicrobial treatment, removal technique, and time from removal to
culture, may influence the culture results77 80 83. We compared our data using cut-off values ≥1
CFU with ≥15 CFU and found a significant correlation between these two measurements.
Furthermore, data on the cut-off values for different microorganisms in relation to the semiquantitative culture techniques are limited. In Study1 colonisation was defined as microbial
growth on tip culture in the absence of SIRS-symptoms and in Study 4 as microbial growth
regardless of SIRS-symptoms. The reason for this shift is that in Study 4 we looked to see if
tip culture alone could be used as a surrogate-marker for CRI or CRBSI131. Furthermore, this
definition is more in consistency with international recommendations74 77
(www.ecdc.europe.eu).
The reason for studying colonisation is that it provides a picture of possible microorganisms
involved, including their resistance patterns, thus providing guidance when treating CVC
infections. The culture procedure and presence of microorganisms on cultured catheter tips is
itself a reminder, serving to increase clinical awareness of the risk of a CVC infection106. A
positive tip culture is a prerequisite for a diagnosis of CRI. A large proportion of all patients,
especially on the ICU, have SIRS symptoms on CVC removal due to different causes132. The
catheter has to be evaluated as one origin of the SIRS symptoms. These three factors justify,
in our opinion, the routine of CVC tip culture for all CVCs removed. However, we could not
verify previous findings that colonisation may be used as a surrogate indicator of CRI or
CRBSI131.
Most studies have used CRBSI as an endpoint for severe infections where the entry of the
causative microorganism is the CVC10 14 98 103-105 132 133. CRBSI is well-defined and suitable
for research if a high degree of blood cultures is secured in patient with a CVC and SIRS
symptoms. However CRBSI, in our opinion, is too narrow a definition since it requires
54
positive blood cultures and thus has several limitations; cultures not always performed,
antimicrobial treatment preventing growth of microorganisms, intermittent release of
microorganism to the blood, inappropriate transportation or delay in coming to the
laboratory89. The paired blood culture test, which is mandatory for diagnosing CRBSI, with a
catheter in situ is also problematic in severely ill patients on the ICU. These patients tend to
have several different intravascular catheters at the same time (i.e. 4-lumen CVC,
haemodialysis-CVC, pulmonary artery catheter with an introducer-CVC, and arterial catheter.
Blood cultures must be taken from all lumen repeatedly, resulting in a considerable amount of
blood taken from a severely ill patient.
We consider CRI, to be the most valuable clinical measurement as it captures all patients with
SIRS symptoms who have microorganisms on their CVC, shown by positive tip culture.
Recent European studies have used a CRI definition similar to ours42 132. One difficulty with
the CRI definition is that the CVC must be removed for culture. Another difficulty is that
most patients having SIRS symptoms and a CVC in place have their symptoms from causes
other than a CRI. This means that several catheters will be removed for culture without being
the source of the patient’s symptoms. However, in clinical practice these patients must be
evaluated by the physician responsible who must decide which action shall be taken.
Depending on several factors such as underlying disease, immune status, clinical symptoms,
type of catheter, possible microorganisms, coagulation status, available veins and the need for
the catheter, the decision must include individualised considerations of whether the catheter
should be removed or not, correct cultures, and the implementation or not of antimicrobial
therapy77.
Many reports have used CRBSI incidences as an indicator of quality of care of patients with a
CVC10 14 103 104 132. CRBSI incidences reported by others, from both ICU and non-ICU settings
vary from zero to ten per 1000 CVC-days98. Rates below 2 per 1000 CVC-days are difficult to
achieve on an ICU under long periods103. Our CRBSI incidence was 0.4 and 0.6 per 1000
CVC-days in Study 1 and 4.The corresponding incidences on the ICU were 1.9 and 1.4 per
1000 CVC-days, respectively. However, the incidences of CRI for all CVCs were higher
(Study 1: 1.6, Study 2: 1.2 per 1000 CVC-days) compared to CRBSI. The discrepancy
between the incidences of CRI and CRBSI has also been reported by others42 132. Thus, in the
clinical setting, we prefer recording the incidence of CRI as an indicator of the quality of
CVC care since it reflects a larger proportion of the patents with CVC infection than does
CRBSI.
Several studies, mainly from ICUs, have shown that the implementation of simple CVC
routines is successful in decreasing the incidence of CRBSI to a very low level10 14 98 103-105.
We have found only three studies evaluating the long-term effect of an intervention. All these
studies indicate that the implementation of evidence-based routines is successful over a long
period of time103 105 106.There is no study, to our knowledge, running over such a long period
of time as our continuous six year follow-up investigation. Our results also indicate that it is
possible to achieve low rates of infection over a long period of time. Quarterly registration of
incidences of colonisation, CRI and CRBSI showed greater variations compared to annual
incidences. Hence, in our setting quarterly CRI/CRBSI rates are preferable as quality
indicators since these and statistical process control methods can identify periods of
insufficient CVC care.
Statistical process control, adopted from the technical industry, has been used in several
medical studies134. To our knowledge only one study has used SPC for analysing CRBSI105.
55
Our study design made it possible to analyse variations in the incidence rates of colonisation,
CRI and CRBSI by using statistical process control, over time. Although the incidences of
CVC colonisation and infection varied during the study period we could only identify one
period in which an increased rate of CRBSI could not be explained by natural (common
cause) variation. Natural variation, as shown by statistical process control, highlights the
importance of continuous measurements and efforts to reduce the incidence of CVC
infections. Hence, point prevalence and evaluations over short periods of time could provide
erroneous information on the incidences of CVC colonisation and CRI/CRBSI.
Risk factor analysis should be regarded with caution, since confounding factors are difficult to
fully control for. Several studies have shown that catheterisation time is an important risk
factor for CRI and CRBSI and the removal of a CVC that is no longer required is a
cornerstone in CRBSI prevention10 32(www.sfai.se, www.sbu.se). We found in Studies 1 and 4
that catheterisation time was a weak risk factor for CRI and not a risk for CRBSI. We believe
that the explanation for catheterisation time not being a significant risk factor for CRBSI is
the continuously high adherence to hygiene routines, including the removal of CVCs no
longer required.
We have also found that the jugular vein is associated with a higher CRI incidence as
compared to the subclavian vein. This is in accordance with other studies, none of which has
been PRCT135. The insertion of CVCs in the femoral vein is controversial as regards CVC
infections. We could only verify this vein as a risk factor for colonisation. This could reflect
the few femoral catheters used (16%). We have preferably used the femoral vein on the ICU
in situations where coagulopathy is a problem, thereby decreasing the risk for severe bleeding
complications. Other studies have found conflicting results, but the only PRCT comparing the
femoral and then internal jugular vein on an ICU found no difference in infectious
complications136. In Study 1 only patients on chronic haemodialysis showed increased risk for
CRI. The risk for CRI and CRBSI is increased for all patients on haemodialysis in Study 4,
which is in accordance with other studies. However, chronic haemodialysis was not a risk
factor for CVC infection in Study 4 and the incidence of CRBSI in this group was low (0.4/
1000 CVC-days). A meta-analysis revealed incidence rates of CRBSI with CVCs and tCVCs for haemodialysis to be 4.8 and 1.6 per 1000 CVC-days, respectively.
We have found a spectrum of microorganisms responsible for colonisation and CVCinfections similar to that found by others, but the proportion of Candida spp. was high
compared to others77 94 106 137. We found no vancomycin-resistant enterococci or methicillinresistant S. aureus, which probably reflects the situation in our hospital, where the frequency
of these bacteria is low. The high proportion of Candida spp. has also been found in another
study evaluating CRBSI on an ICU98. Possible explanations for this could be differences
between our hospital and hospitals abroad in patient case-mix, varied patient microbial flora,
and antimicrobial treatment. Different microorganisms have different abilities to cause
CRI/CRBSI. The species most often isolated from colonisation and CRI/CRBSI is CoNS.
However, only few of the CoNS isolated on tip culture were responsible for CRI/CRBSI. The
other more commonly found microorganisms such as Candida spp., S. aureus, gram negative
rods, and Enterococcus spp. are much more often associated with CRI/CRBSI when they are
found on tip culture. These observations must be considered when on evaluating the presence
of a pathogen on tip culture.
There are limited data on the type of microorganism responsible for CVC infections in
relation to catheterisation time. In our Study Candida infections were not diagnosed later than
56
bacterial infections, as proposed by others138. This implies that anti-fungal treatment must be
considered in the treatment of CVC infections, regardless of catheterisation time.
There are no published Scandinavian studies on AC-related infections. The general view has
been that ACs seldom cause CRI or CRBSI90 91, although recent international studies have
shown that they do so in a significant number of cases92-94 139 140. We found a total AC-CRI
rate of 2.0 per 1000 catheter-days. This is less than the CVC-CRI incidence of 3.8 and 3.0 per
1000 catheter-days that we found on our ICU in Studies 1 and 4, respectively. We found no
cases of AC-CRBSI, although the incidence may be underestimated because blood cultures
were not always performed and the majority of patients were on antibiotics. A meta-analysis
has shown a mean AC-CRBSI incidence of 1.7 per 1000 catheter-days95. The lower rate of
CRI/CRBSI with ACs compared to CVCs is in agreement with most other studies92 93 140. ACs
may be less prone to causing CRI/CRBSI than CVCs. Possible reasons for this could be the
differences in use of an AC and a CVC, oxygenation of the blood, blood flow etc. This must
be further studied. We believe that adherence to hygiene routines, including AC insertion and
care, is the reason for the low rate of AC infection found in this study. Most of our catheters
were inserted using catheter over cannula technique. This is contrary to most other studies and
may have influenced the colonisation and infection rates30 90. However, since AC infections
are a significant problem, blood-cultures exclusively drawn from the AC cannot be
recommended since a positive culture will not distinguish between AC-colonisation, AC-CRI
and bacteraemia from other sources. In the clinical situation where there is suspicion of
CRI/CRBSI caused by an AC or CVC, a peripheral blood culture must be performed at the
same time as tip cultures or blood cultures via the catheters.
There are limited data on risk factors contributing to AC-CRI. Previous studies have found
that insertion via the femoral artery and catheterisation time are possible risk factors92 93 141.
This is also supported by a recent multi-centre study139, but could not been verified in another
study140. We could not verify these findings, possibly because of the infrequent use of the
femoral artery and the low AC-CRI incidence in our study. Multivariate analysis identified
immunosuppression, CVC colonisation, and CVC-CRI as risk factors in our study. Microbial
growth or coexisting infections on AC and CVC needs clinical attention. It is impossible to
determine which catheter was colonised or infected first, and whether or not crosscontamination is important pathogenetically. However as CVC colonisation and CRI were
risk factors for AC-CRI, we suggest that both the AC and CVC should be considered for
removal if one is found to be colonised and suspected as being a source of infection.
In accordance with other studies we found that CoNS was the dominating agent for
colonisation. Furthermore CoNS was the only microorganism responsible for AC-CRI. Other
studies have found a more heterogeneous microbiology causing AC-CRBSI92 93 137 140. This
could reflect differences in hospital microbiological flora, patient characteristics and
adherence to hygiene routines.
Transmission of pathogenic bacteria between patients on an ICU is well documented but the
role of Candida spp. in this mechanism has not fully been explored and previous studies have
shown conflicting results111-118.
One of the main problems with studies on Candida transmission is the selection of a
representative reference group. Genotype variations within specific populations and
geographical areas is poorly documented127. Furthermore, ICU patients are not comparable
with a normal population since they are often severely ill and exposed to antibiotics prior to
their ICU stay, and this influences the microbial ecology. Thus, a reference group showing
57
Candida genotypes found in the local population might not be the best choice. In this study,
we included blood culture isolates from severely ill patients in the same region, but not from
our ICU, as a reference group, since they represent Candida isolates from a similar patient
population. As a complement, we performed a temporal cluster analysis to evaluate genotype
distribution with no relation to a reference.
The colonisation rate of Candida spp. among ICU patients varies significantly in different
reports, depending on several factors such as diagnosis, type of surgery, length of ICU stay as
well as selection of culture sites and sampling techniques118. The colonisation rate of twelve
per cent in our study is low118. A possible explanation for this could be that we have included
all patients regardless of length of ICU stay, and that a limited number of throat cultures were
performed118. This could also be explained by a high antifungal prescription rate between
2004 and 2009 compared to other Swedish ICUs (unpublished data, Swedish Institute for
Communicable Disease Control) or different patient characteristics. The patients harbouring
Candida spp. were older, had a higher Apache II score, longer ICU stay, and were more often
operated on compared to other ICU patients, which is in accordance with other studies109. We
found only two blood cultures positive for Candida spp. on the ICU, of which both of which
were C. glabrata. The proportion of patients not cultured was 14%, predominately patients
with a short ICU stay and no infection. Hence, these patients presumably have a low impact
on transmission.
Seventy-five per cent of the ICU patients from whom Candida spp. was isolated had a prior
negative Candida culture. The switch from negative to positive Candida culture during an
ICU stay could be the result of promoted growth of endogenous strains or of transmission.
However, certain genotypes were more frequently isolated than others among the ICU
patients, and the distribution of some genotypes gave the impression of temporal clustering
indicating transmission. Furthermore, two genotypes were significantly more frequently
isolated from the ICU patients compared to the reference group, and genotypes found in more
than one patient were significantly more often seen on the ICU. These results suggest that
some genotypes may have a greater tendency to be transmitted between patients on the ICU.
This is supported by the temporal cluster analysis using a time interval of 21 days after the
first positive Candida culture.
The DiversiLab system has been shown to be useful for local studies on Candida
epidemiology123. A recent study, however concluded that DiversiLab has a moderate
discriminatory power, which may lead to clustering of isolates not closely related
genetically124. In the present study, this could have influenced the number of accumulations
and led to an overestimation of transmissions. However, the use of a standardised and easy-touse commercially available method enables rapid tracking of isolates and may indeed have the
potential to detect on-going outbreaks. Furthermore, knowledge of local Candida
epidemiology may enhance the possibility to prevent nosocomial transmission, identify more
virulent strains and could predict infection rates enabling optimised anti-fungal treatment and
better patient outcome as a result. In cases of inconclusive discrimination a second method at
a reference laboratory could be used to strengthen the clinical conclusions regarding
nosocomial spread.
There are possible explanations other than transmission for the Candida genotype distribution
seen in this study. Firstly, these genotypes could be more common in the general population.
However, we do not think that this is a likely explanation since these genotypes were
58
infrequent in the reference group. Secondly, these genotypes could have been selected, as a
result of antibiotic treatment. This is also unlikely since the majority of patients in the
reference group had also received antibiotics. Thirdly, patients harbouring a frequently
occurring genotype could be more predisposed to ICU treatment. This is contradicted by the
fact that there was no difference in the distribution of these genotypes between ICU patients
colonised or those infected with Candida spp.
Previous studies, predominately from ICUs and neonatal wards, have stated that transmission
of Candida spp. may occur111-114 116 117 120. However, this has only been supported by
simultaneously occurring genetically indistinguishable isolates, with a limited reference
groups or cluster analysis, not including time as a variable112 115.
Invasiveness and tendency to be transmitted are two important virulence traits of microorganisms, but these two properties are not always linked127. Two of the genotypes in this
study may have had a greater tendency to be transmitted but we could not demonstrate
increased invasiveness.
Since other studies have found indistinguishable genotypes in both healthcare workers and
patients, a role of healthcare workers in transmission is likely111 112 121. Growth of Candida in
the environment has seldom been studied and the significance of the inanimate environment
as a source of C. albicans transmission on the ICU is not known142.
59
CONCLUSIONS

Low incidences of CVC-colonisation and CVC-infections, compared to international
studies, were found in an entire hospital patient population after implementing
evidence-based routines for insertion and care of CVCs.

Low incidences of AC-colonisation and AC-infections, compared to international
studies, were found after implementing evidence-based routines for insertion and care
of ACs.

Sustained low incidence rates for CVC-colonisation and CVC-infections were found
in an entire hospital patient population over a six-year follow-up period after
implementing evidence-based routines for insertion and care of CVCs.

Microorganisms responsible for CVC colonisation and infections were similar to those
found in international studies. However, Candida spp. were found more often than in
most other studies. There was no difference in catheterisation time for CVCs
associated with CRI/CRBSI caused by Candida spp. as compared to CRI/CRBSI
caused by bacteria.

Only CoNS were responsible for CRI related to ACs.

Risk factors for CVC colonisation in Study 1 were; catheterisation time and chronic
haemodialysis and in Study 4; no antibiotics on removal, use of the internal jugular
vein as apposed to the subclavian vein, and of the femoral vein as apposed to the
subclavian and internal jugular veins.

Risk factors for CRI associated with CVCs were catheterisation time (Studies 1 and
4), chronic haemodialysis (Study 1), haemodialysis in general (Study 4) and CVCs
inserted in the internal jugular vein compared to the subclavian vein (Study 4).

Risk factors for AC colonisation were colonisation or CRI of a simultaneous CVC.

Risk factors for AC-CRI were colonisation or CRI of a simultaneous CVC, and
immunosuppression.

Transmission of Candida spp. between ICU patients is possible.
60
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ACKNOWLEDGEMENTS
I would like to express my gratitude and appreciation to all who, in one way or another, have
contributed to this work. I thank you all, and especially:
Bo-Eric Malmvall, my supervisor, for guiding me through this thesis, and always believing
in what we did, for all your support and never ending patience.
Sören Berg, my co-supervisor, for your precision and the laughs we have had together.
Håkan Hanberger, my co-supervisor for always posing the difficult questions.
Gerd Wallén and Karin Landén-Johansson, “CVC nurses”, for such excellent collaboration
over the years. This work would not have been possible without you.
Sara Mernelius, Sture Löfgren and Andreas Matussek for guiding me in the mysterious
world of DNA and microbiology.
Knut Taxbro, colleague and friend, for sharing the world of intravascular catheters with me.
Birgit Ljungquist, for multivariate analysis and for putting up with my never-ending
questions on statistics.
Roland Andersson and Max Petzold, for introducing me to cluster analysis.
Peter Kammerlind, for introducing me to statistical process control.
My former and present heads of the Department of Anaesthesia and Intensive Care, Jan
Lundberg for luring me into anaesthesia and intensive Care, Mats Persson for giving me
rock n´roll, and Martin Holmer for support and friendship.
Peter Nordlund, my ICU companion, for all your support and companionship on the ICU.
Göran Lindskog, my clinical tutor for teaching me anaesthesia and intensive care.
All colleagues and personnel at the Department of Anaesthesia and Intensive Care for your
patience with me, my protocols and cultures, but most of all, the stringent adherence to our
hygiene routines.
Peter Cox, for converting my texts from “Swinglish” to English and for never ceasing to
teach me English prepositions.
Ulla Strand and her colleagues at the patient records archive, for finding me thousands and
thousands of medical notes.
Susanne Karlsson, my computer-mentor, for helping me with all the partially functioning
computer-systems at the hospital.
Carl Hildebrand and other colleagues at neighbouring hospitals for retrieving insertion data
on CVCs inserted outside Ryhov.
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Alf and Britt, my parents-in-law, for making daily-life possible.
Göran and Birgit, my parents for all support and love in life. Magnus, for our brotherly
love.
Anneli, my beloved wife and dearest friend, for your never-ending love and support. And yes,
we will travel to beautiful, weird and dangerous places in the coming future.
Jakob, Sara, Sofie and Ella, my children, for understanding why Dad has been so busy and
tired. I love you!
The thesis was financially supported by Futurum the Academy for Health Care, Jönköping
County Council, Jönköping.
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