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 Filtration and Infection Control
  Filtration and Infection Control

J A Roe BSc, PhD and D Smith RGN, Cert Ed.


Introduction
The incidence of hospital acquired (nosocomial) infections has been estimated by the World Health Organisation to vary between 3 and 21% of hospital admissions1. Development of these infections can lead to further patient treatment and increased hospital stay resulting in increased costs and nursing time. Methods to prevent these infections occuring are therefore of obvious interest.

There are numerous infection control measures that can be employed to decrease the incidence of nosocomial infections in patients. The use of filters is one approach that can be adopted. Filtration technology can be applied to numerous areas in the hospital environment to aid infection control. These areas include anaesthetic and intensive care unit (ICU) breathing systems, pulmonary function equipment, gas lines, intravenous fluid therapy, blood transfusion and administration of crystalloid cardioplegia during cardiac surgery. This booklet reviews the benefits and use of filters in infection control in each of these areas.


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Filtration in Anaesthetic and ICU Breathing Systems
There is now a wealth of clinical papers demonstrating that breathing circuits used during anaesthesia or ICU can become contaminated during use2-4. Contamination of breathing systems can arise either via medical gases or through the patient. Several studies have shown that medical gases are not sterile5, 6 and it has been observed that these gases can act as vectors transporting organisms around the circuit7. However, it is the patient that is the major source of initial contamination in a breathing circuit2, 8, 9.

With regard to anaesthetic circuits, both non-rebreathing10 and rebreathing or circle systems11-13 can become contaminated with microbes during use. Studies have shown that the spread of organisms can take place against the gas flow (retrograde flow)2, 14. Work investigating circle system contamination is interesting from several points of view. In the past many people believed that colonisation and growth of bacteria in circle systems was not a problem as it was thought that soda lime had a bacteriocidal effect and thus “sterilised” the system. However, it has been found that bacteria can be rapidly spread and recovered from all components of a circle system15 and that organisms can pass through a soda lime cannistor and remain viable13, 16. Another point of interest with these systems is that the reaction between soda lime and CO2 is highly exothermic, leading to the generation of heat and moisture. Considerable condensation can therefore occur with these systems, particularly during long operations. Microbes may colonize this condensed water and proliferate.

Biofilm formation at the end of endotracheal tubes has been noted, allowing bacterial proliferation to occur17, 18. Particles can be projected from the biofilm into the breathing circuit thus allowing this contamination to be easily disseminated. Work has also shown that anaesthetic endotracheal tubes harbour viruses19 and that viral replication is unaffected by volatile anaesthetic agents such as halothane or isoflurane20, 21. Furthermore, studies have shown that 76-86% of endotracheal tubes have some degree of blood contamination (either visible or subvisible) after use22, 23. In Australia recently, five patients who all used the same anaesthetic circuit were found to have contracted Hepatitis C24, 25. It is believed that a patient carrying Hepatitis C may have coughed up blood stained respiratory secretions into the anaesthetic circuit. Four other patien ts who used this circuit are believed to have subsequently become infected.

Nosocomial infections acquired via the respiratory tract are an expensive, time consuming and potentially fatal complication of anaesthesia and respiratory therapy. Several groups have recommended use of individually clean anaesthesia or regular tubing change practices in the ICU as a potential means of reducing the incidence of these infections2, 3, 11, 26-29. There are several ways in which breathing systems can be decontaminated. However, sterilisation and disinfection methods can be time consuming, expensive and may also be environmentally unfriendly30. In addition, there have been a number of reports in the literature that show that these methods are not always completely effective31-34. In some of these studies patients actually acquired infections from equipment following defective decontamination regimes. Recently disposable circuits and filters have become very popular in anaesthesia and intensive care.

Incorporating a filter into the breathing system is an increasingly popular way of providing individually clean anaesthesia or allowing ICU circuits to remain free of patient microflora. In a recent editorial in the British Journal of Anaesthesia, Snowdon35 stated that there is an argument for using a microbial filter for every anaesthetic, as the anaesthetist will not always be aware that the patient may be carrying a high risk infectious disease. As the patient is the most likely source of initial contamination of a circuit probably the most logical place to position the filter is as near to the patient as possible. Hedley and Allt-Graham36 have proposed that the “ideal patient end” filter should totally retain contaminated liquids, have a high airborne microbial removal efficiency, a low resistance during clinical use and be able to be left in place during nebulisation. In addition the device showed also act as a heat and moisture e xchanger (HME). Currently there are a whole range of different devices that have been proposed for use at the “patient end” of a breathing circuit and it is extremely difficult to know whether or not a device possesses these attributes. Fortunately things can be simplified to some extent as all of the available products can be divided into three groups37 (Fig. 2).


Figure 1: Categories of Heat and Moisture Exchanging Devices and Scanning Electron Micrographs of Typical Layers from:-
  1. Hygroscopic HMEs (first generation);
  2. Hygroscopic HMEs (second generation);
  3. Hydrophobic Heat and Moisture Exchanging Membrane Filters. (Bar = 100µm)





Devices falling into groups (b) and (c), which combine both filtration and HME properties, are often referred to as heat and moisture exchanging filters (HMEFs). Some breathing systems filters incorporate only an electret felt material within them. As these devices have no HME element they are unsuitable for “patient end” use. Their use is limited to a “machine end” application ie. between the ventilator and the circuit.

A breathing systems filter must have both a high airborne and a high waterborne microbial removal capability. The latter is, however, the most important as the vast majority of microbes arriving at a filter during clinical use will be in the form of contaminated secretions38. To prevent passage of waterborne microbes a filter material needs to be truly hydrophobic. If liquid water is placed on a solid hydrophobic material a bead of water results, (Fig 2a) since the forces of attraction between the liquid water molecules are much stronger than the attraction between the solid hydrophobic material and the liquid water. However, a hydrophobic material can still, under certain circumstances, allow liquid penetration. A breathing systems filter must possess pores to allow passage of gases but if the pores are too large the pressures that are exerted in the circuit are sufficient to force contaminated liquids into the pores and through to the other side (Fig. 2b). This is obviously not true hydrophobicity. True hydrophobicity occurs when there is a combination of a hydrophobic material with pores that are so small that they will not allow liquid penetration during clinical use (Fig. 2c). Furthermore, the truly hydrophobic nature of the material allows liquids to “run off” leaving the pores open and allowing gas flow through the device to be maintained.

Figure 2: Hydrophobicity/Pore Size Relationship

Airborne particles are removed from gas flows by three filtration mechanisms37:-

(1) Direct Interception:- This sieving mechanism removes particles such as dust and large bacteria that are physically too big to enter the pores of the filter material. (Fig. 3a).

(2) Inertial Impaction:- Most bacteria are small enough to enter the pores of the filter medium. Bacteria, when travelling in a gas flow, possess both mass and velocity and thus have a momentum associated with them. As the gas and particles pass through the filter medium, the gas takes the path of least resistance to flow and passes around the filaments. The bacteria, however, because of their momentum, tend to travel in a straight line and will therefore eventually impact on the filter medium and be held by Van der Waal’s (electrostatic) forces (Fig. 3b). The efficiency of inertial impaction depends on the flow rate and particle size. The higher the gas flow, the higher the particle velocity and thus the greater the momentum. Similarly, the larger the particle size the greater its mass is likely to be, again increasing its momentum.

(3) Diffusional Interception:- Viruses can be prevented from passing through a gas filter by this mechanism. As viruses have a very small mass, they undergo considerable Brownian motion. When lineated by a gas flow, these viruses will randomly move up and down such that their apparent diameter is increased. Eventually they will hit the filter medium and be held by electrostatic-type forces. (Fig. 3c).

Figure 3: Mechanisms of Gas Filtration

As mentioned previously most of the first generation hygroscopic HMEs were designed solely to act as HMEs. They were not generally marketed as filters and consequently they have low microbial removal efficiencies even when impregnated with bacteriostatic or bacteriocidal chemicals36, 38-42. Second generation hygroscopic HMEs and electret felt only containing filters tend to have an improved airborne microbial removal capability and may typically remove 86-99.999% of airborne bacteria and viruses36, 43-45. The exact removal efficiency of a particular device will depend upon factors such as the number of layers present and the density of the felt. As mentioned earlier, however, the majority of bacteria and viruses arriving at a breathing systems filter will be waterborne rather than airborne. It is essential that if a device is to act as an effective infection control measure that waterborne microbes are completely retained38. Numerous studies ha ve now demonstrated that large pore electret felt containing devices allow the passage of liquids and microbes at pressures typically seen in breathing circuits during clinical use4, 36, 44-47. In fact one study showed that 6ml of artificial saliva was able, in some instances, to penetrate these devices after only 14 minutes of simulated ventilation36. In addition, a number of recent reports have described how liquid passage into the large pore hygroscopic devices has occurred, resulting in an increase in device resistance and patient safety being compromised48-51. Several authors have concluded that electret felt containing filters are unsuitable for clinical use4, 36, 44-47. In contrast truly hydrophobic membrane filters have:

  1. complete (ie. 100%) waterborne microbial retention36, 45, 46,
  2. a high airborne microbial removal capability (>99.999%)36, 43, 45, 52-54,
  3. and offer a low resistance under all clinical conditions36, 55, 56.

The hydrophobic filter membrane has extremely small pores and a large surface area. This membrane is pleated to allow dead space to be kept to a minimum. Hydrophobic membrane filters will keep ICU circuits, used for the duration of mechanical ventilation56, 57, and the interior of anaesthetic tubing4, 15 free of patient microbes.

In the ICU, heated waterbaths may be used to provide humidification to intubated patients during mechanical ventilation. These have been viewed as a potential source of contamination. Either the waterbath itself may become contaminated or alternatively the condensate within the system becomes colonised2, 58, 59. In addition to acting as a bacterial and viral filter a hydrophobic membrane filter will also act as an efficient HME thereby negating the need to use heated waterbaths55, 56, 60, 61. Saline instillation or nebulization may be required prior to suctioning to help loosen tracheal secretions and replace the lavage effect given by condensed water generated from hot water baths. Saline instillation and suctioning should be performed using strict aseptic techniques. Hydrophobic membrane filters have been found to decrease the incidence of respiratory colonization and infection in ICU compared to when hot water baths are included in the circu it thus proving a valuable infection control tool56, 60, 62.


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Pulmonary Function Testing and Filtration
A wide variety of potentially pathogenic organisms have been isolated from unsterilized tubing and equipment in the pulmonary function laboratory (Table 1). Houston et al63 observed that, during four one week periods when 1,000 patients used a Vitalograph spirometer, on average over 10,000 million micro-organisms per week were recovered from the breathing circuits. Various authors have expressed concern that pulmonary function equipment can transmit infection and have therefore recommended that the connections between the patient and pulmonary function testing apparatus are changed between patients and cleaned or disinfected before re-use64-68. This includes tubing, rebreathing valves and mouthpieces. However, this approach was already being used in a report by Hazaleus et al69 in which a case of tuberculosis was attributed to contaminated pulmonary function equipment. In this in stance the reservoir of infection was believed to be within the spirometer and valve section of the apparatus itself.

Table 1
Micro-organisms Isolated from
a Vitalograph Spirometer:-
    Acinetobacter calcoaceticus (var Anitratus)
    Acinetobacter calcoaceticus (var Lwoffi)
    Achromobacter xylosoxidans
    Alkaligenes denitrificans
    Alkaligenes spp
    Citrobacter freundii
    Aerobic spore bearing bacillus
    “Coliform” Gram negative bacilli
    Enterobacter agglomerrans
    Flavobacterium spp
    Klebsiella pneumoniae
    Pseudomonas fluorescens
    Pseudomonas spp
    Staphylococcus aureus
    Staphylococcus albus
    Streptococcus spp (haemolytic)
    Xanthomonas spp
    Penicillium spp
From Houston et al (1981)63

Depledge and Barrett70 state that some patients may be reluctant to undergo pulmonary function testing if they believe that the equipment may have been used previously by infected patients. For example, concerns may arise when pulmonary function testing equipment is used with immuno-incompetent patients, such as those infected with the human immunodeficiency virus (HIV)71, 72 or patients with cystic fibrosis73. This latter group reported Pseudomonas cepacia infection in 500 patients with cystic fibrosis and also observed contamination of pulmonary function equipment and spirometers.

Elimination of the organism from the apparatus was achieved with the introduction of decontamination techniques. The group recommended that bacteriological surveillance and appropriate hygiene measures should be adopted in other respiratory laboratories to prevent nosocomial transmission of organisms such as Pseudomonas cepacia.

Spread of infection via pulmonary function testing equipment is a two-stage process. The initial stage involves contamination of the equipment by an infected person. In the next stage a second patient becomes colonized via the previously contaminated equipment. Unfortunately in many pulmonary function laboratories decontamination of all equipment between patients is impractical due both to the high through-put of patients and the difficulty of apparatus disassembly and disinfection. An alternative approach is to incorporate a microbial filter into the circuit between the patient and the equipment66, 72, 74.

A pulmonary function filter containing a supported pleated filter media has been extensively tested75, 76. This filter has been shown to have a unidirectional microbial removal efficiency of greater than 99.9%. As the device is bi-directional this means that the probability of cross contamination is one in a million ie. negligible. Furthermore the filter has a minimal resistance and thus does not result in any clinically significant changes in lung function measurements, even in paediatrics77, 78.


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Filtration and Endoscopic Surgery
Endoscopic (or keyhole) surgery is a rapidly expanding, innovative and alternative approach to conventional surgery. After the patient has been premedicated and anaesthetised the body cavity is injected with gas (insufflation). However, the medical gas cylinders used have been found to be contaminated with bacteria and particulates (eg rust, metal filings)79, 80. In addition backflow of gases containing microbes and body fluids can cause machine contamination and, during desufflation, aerosols and particles may be released into the environment81, 82. Various groups have recommended that during the insufflation procedure a hydrophobic filter is used81, 82, 83.

A hydrophobic insufflator gasline filter has now been developed. This device prevents bacterial and particulate contamination during insufflation and prevents the contamination of other patients and healthcare workers. Additionally, as desufflation can be carried out through the filter, environmental contamination can also be prevented.


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Filtration and Intravenous Fluid Therapy
Intravenous (IV) therapy is an integral part of modern patient care and is used in the clinical management of more than a quarter of hospitalized patients. IV systems offer numerous benefits including rapid delivery of drugs and fluids to the patient and haemodynamic monitoring. Unfortunately IV systems also provide a direct route for micro-organisms to enter the blood stream. Despite excellent aseptic techniques and practices, nosocomial infections still occur in hospitalized patients, particularly those in critical care environments. It has been estimated that 8.5% of nosocomial infections can be attributed to intravenous catheter sepsis84.

IV related septicaemia may be catheter associated or non-catheter associated and can arise from various sources eg. intrinsic catheter contamination, contaminated disinfectants, hands of medical personnel and the patient’s own skin microflora. Catheter hub manipulations have been acknowledged as an important contributor of IV related septicaemia particularly with central lines85. Various approaches, including the use of strict aseptic techniques, can be used to minimise IV related septicaemia.

Septicaemia can also result from the delivery of contaminated fluids to the patient. Microbiological contamination of intravenous infusions can be either intrinsic or extrinsic in origin. Intrinsic contamination, where contamination occurs during manufacture, transport or storage, is a rare occurrence now-a-days, due to the excellent quality control procedures carried out by the pharmaceutical industry. However, in the early 1970s a number of cases of hospital acquired septicaemia, as a result of intrinsic microbial contamination, were reported86. In one of these outbreaks seven patients became septic and five died postoperatively after receiving 5% dextrose contaminated with Gram-negative bacteria. Contamination was traced to faulty maintenance of autoclaving equipment at the Company’s manufacturing plant. Following these incidents, Departments of Health around Europe formulated hospital guidelines to minimise the clinical consequences should a similar event occur dur ing administration of IV infusions87. One of these guidelines was that IV administration sets and the fluid flowing through them should, wherever possible, be changed every 24 hours.

Extrinsic microbial contamination is that which arises due to in-use manipulations of the IV system. Every manipulation of this system, including initial set up, subsequent addition of new solutions, the attachment of three-way taps, addition of medication to the hanging solution and CVP measurements increase the risk of introducing bacterial or fungal contaminants88.

The many areas of potential microbial contamination in the IV system are shown in Figure 4. When a needle pierces an injection port a tiny meniscus of fluid remains. This damp, warm environment is ideal for microbial proliferation thus resulting in an innoculum culture when further injections are made89. It has been reported that in-use contamination of infusion fluids exceeded 30% when additions were injected on the ward compared to a “background” rate of 14%90. Marshall and Lloyd91 carried out a review of the literature and reported that the rate of in-line contamination of IV fluids ranges from 0-30% with an average value of 3%. Basically the more manipulations that are made to the system the greater the likelihood that inadvertent microbial contamination of the IV line will occur. Patients in critical care settings are likely to have a large number of manipulations to their comp lex systems. These patients are obviously particularly susceptible to infection.

Figure 4: Potential Mechanisms for contamination of Intravenous Infusion Systems

Many Gram-negative bacteria are able to proliferate in simple solutions. It has been reported that even when small, washed innocula of various Gram-negative bacteria, such as members of the tribe Klebsiella, were injected into 5% dextrose, rapid microbial proliferation at room temperature occurs with more than 105 organisms per ml being detected after 24 hours92. Several reports in the last few years have been published highlighting cases of septicaemia where contamination of a variety of infusions has been implicated93-101 (Table 2). It is interesting to note that many of these reports involve paediatrics or neonates and that the majority of organisms responsible for these cases of septicaemia are Gram-negative bacteria.

Table 2
Cases of Septicaemia Where IV
Infusions Have Been Implicated
Nature of
Contaminated
Infusion		 Organism
Responsible		 Author(S)
Parenteral Nutrition
& Glucose-electrolyte + KC1		 K. pneumoniae Twum-Danso et al (1989)93
Methotrexate Ps. aeruginosa Leprat et al (1989)94
Parenteral Nutrition A. calcoaceticus Ng et al (1990)95
Parenteral Nutrition Mucor sp. Todd et al (1990)96
Intravenous Fluid K. pneumoniae Bin Ibrahim & Ghaznawi
(1990)97
“Sterile Water” Ps. picketti Roberts et al (1990)98
Lacey & Want (1991)99
RATG-anti-rejection drug O. anthropi Ezzedine et al (1994)100
Parenteral Nutrition S. odorifera Frean et al (1994)101

The introduction of a filter into the IV line offers a simple way of preventing inadvertent microbial contamination of IV fluids from reaching the patient. Positioning the filter end-line (ie. proximal to the cannula) offers maximum patient protection, although some IV filters are used mid-line. Some authors have proposed that 72 hour set life is safe and effective102. However, many of these studies are of patients in general wards rather than in intensive care units and peripheral lines are used rather than central lines. Patients in general wards tend to have less manipulations made to their IV systems.

Certain types of bacteria have been shown to be able to penetrate IV filters with a 0.45µm membrane103. Therefore for complete bacterial, fungal and yeast retention a 0.2µm filter membrane is required. A study at the University Hospital in Heidelberg has shown that approximately 34% of filters used in an adult ITU had microbial contamination on their upstream surface after 72 hours indicating that there was microbial contamination in a third of IV systems in use and that the filter had protected patients against this104. In 1986, Quercia et al105 published the results of a double-blind study in which 70 surgical ICU patients were randomly assigned to receive IV fluids and medications via either a 0.2µm filter set or a filter housing without membrane (“filter-blank”). Clinically significant hospital-acquired bacteraemia was documented in ten patients in the “filter-blank” group compared to only three in the group with real filter sets. Furthermore, a recent study demonstrated that use of extended life IV filters resulted in a reduction in the amount of catheter hub contamination85.

Now-a-days there are a number of 0.2µm IV filters available. However, Holmes et al103 demonstrated that a continuous infusion of endotoxin can originate solely from a population of Gram-negative bacteria present in an in-line filter set. Therefore, if the filter and IV set life are to be safely extended beyond twenty four hours the retention of these endotoxins has to be considered. Endotoxins are negatively charged, high molecular weight complexes that form part of the outer membrane of Gram-negative bacteria. These endotoxins are sometimes referred to as pyrogens or lipopolysaccharides. Small amounts of endotoxins are constantly being shed from these bacteria, however, when the bacteria divide or lyse a large burst of endotoxin is suddenly released.

Inadvertent infusion of endotoxin into a patient results in several adverse effects ranging from fever and hypotension to multiple organ failure and, in extreme cases, death106 (Figure 5).

Figure 5: Spectrum of Adverse Effects Associated With Endotoxins

It is very difficult to remove endotoxins by conventional microfiltration. However, advances in filtration technology have developed a 0.2µm nylon membrane called Posidyne which is surface modified so that it is positively charged over a wide range of clinical pH values. Therefore, endotoxins, which have a high density of negative charges on their surface due to their phosphate groups, will be retained by the filter membrane. Several authors have carried out laboratory investigations whereby various types of IV infusion are deliberately contaminated with up to 108 Gram-negative bacteria103, 107-113. A simulated clinical infusion through an IV filter is then performed and the resulting effluent is monitored for the presence of endotoxins. Only IV filters containing a 0.2µm Posidyne nylon membrane have been found to completely retain high levels of bacteria and their associated endotoxins for periods of at least 96 hours (Table 3) and that th is retention is unaffected by the type of fluid or medication passing through the filter. Even cell bursting antibiotics such as Ampicillin do not affect the retention of endotoxins by Posidyne nylon IV filters108. In contrast, IV filters with other types of membrane have been observed to leak endotoxins as little as five minutes after the start of the infusion113. It is important to note that, when testing IV filters for their ability to retain endotoxin, infusions are contaminated with viable Gram-negative bacteria, which will proliferate and release natural endotoxin with time. This represents what may happen clinically. Purified endotoxin, which is extracted using heat and solvents, has different physical characteristics (it has a smaller aggregate size, is less charged and more soluble) to natural endotoxin, is never encountered in the clinical environment and is therefore unsuitable for testing IV filters for their ability to retain endotoxin. Purified endotoxin is, however, suitable for standardising endotoxin tests because it is more homogenous and soluble.

Table 3
Ability of Different IV Filter
Membranes to Reliably Retain
Natural Endotoxin for 96 Hours
  Membrane Material
P
O
S
I
D
Y
N
E

N
Y
L
O
N		 C
E
L
L
U
L
O
S
E		 P
O
L
Y
A
C
R
Y
L
A
T
E		 P
O
L
E
T
H
Y
L
E
N
E		 P
O
L
Y
S
U
L
P
H
O
N
E		 P
O
S
I
T
I
V
E
L
Y

C
H
A
R
G
E
D		 P
O
L
Y
S
U
L
P
H
O
N
E
Holmes et al
(1980)103		   NO         
Baumgartner et al
(1986)107		 YES NO NO NO NO  
Ball & Saunders
(1987)108		 YES          
Horibe et al
(1990)109		 YES NO        
Richards & Thomas
(1990)110		 YES NO        
Wilkins & Kendall
(1991)111		 YES NO       NO
Richards & Grassby
(1994)112		 YES NO       NO
Kendall et al
(1994)113		 YES         NO

The bacterial and endotoxin retention capabilities of Posidyne filters means that, from a microbiological point of view, they and all administration equipment upstream of the filter can be safely used for periods of up to 4 days. This means that cost and nursing time savings may result114-122 but, more importantly from the infection control point of view, the number of catheter hub manipulations is dramatically decreased85 - further reducing the risk of septicaemia.

The vast majority of drugs and solutions given intravenously are fully soluble in their carrier fluids as this is often the best way that the body can make use of them. These can all be filtered. The only IV drugs that cannot pass through 0.2µm filters are the small number formulated as emulsions or suspensions, or where the drugs are not totally dissolved in the carrier fluid. In addition cellular blood products and lipids cannot be administered via these types of filters. It is well documented that lipid emulsions support microbial growth123-127. Filters for removal of contaminants such as microbes from emulsions have now been developed and should prove a useful addition to infection control procedures in parenteral nutrition. The development of these filters, however has been a very challenging area as the lipid/emulsion micelles are very similar in size to the contaminants one wishes to remove.

A further practical issue related to IV filter use concerns pressure monitoring. For example Maki and Hassemer128 reported that 12% of transducer domes were contaminated and that four definite, and another four possible, cases of septicaemia were due to contaminated intra-arterial infusions. More recently it has been suggested that 33% of CDC-investigated outbreaks of nosocomial bacteraemia can be traced to arterial infusions used for pressure monitoring129. Posidyne IV filters have been used on arterial and central venous pressure monitoring lines without significantly damping the readings that are obtained and allowing, from a microbiological point of view, extended equipment life122, 130, 131.

Although this review has concentrated on the infection control aspects of IV filters several other clinical advantages associated with their use have been documented. These include the prevention of air embolism, patient protection against the systemic effects of particulates, such as lung granuloma and a reduction in the incidence of phlebitis91. With regard to this latter point it was once thought that infection was the most significant factor affecting the development of post-infusion phlebitis. However, in more recent years it has been shown that micro-organisms can be cultured from less than 1% of catheter tips removed from patients with infusion-related phlebitis86, 88, 132. Phlebitis can be attributed to several factors including particle contamination and IV filters have been reported to decrease the incidence of phlebitis by approximately a half133-141 (Table 4).

Table 4
Studies Comparing the Incidence of
Infusion Phlebitis in Patients
Receiving Infusions Either With or
Without End-Line Filtration
Author(S) Number Of
Patients		 % PHLEBITIS
FILTER		 % PHLEBITIS
NO FILTER
Ryan et al (1973)133 100 2 45
De Luca et al (1975)134 146 12 61
Evans et al # (1976)135 49 8 56
Maddox et al # (1977)136 120 20 60
Rusho & Bair (1979)137 150 6 27
Bivins et al # (1979)138 146 25 62
Allcutt et al # (1983)139 194 31 51
Falchuk et al # (1985)140 541 25 57
Francombe (1988)141 56 29 57
# = double blind studies

Finally, the role of filtration in IV therapy should be seen as an economical method of providing additional safety whilst potentially decreasing the work load of health care workers. It should not be seen as a replacement for strict hygiene methods employed during catheter insertion, the application of entry side dressings and all other manipulations of the IV system, rather as a useful aid to infection control.


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Infection Control and Leucocyte Depleting Filters During Blood Transfusion
There are two main areas where the use of leucocyte depleting filters during blood transfusion may play a role in infection control:- removal of bacteria and viruses harbored in contaminating leucocytes (white blood cells) and prevention of transfusion induced immuno-suppression resulting in a reduced incidence of bacterial infection.(a) Removal of Bacteria and Viruses

Transfusion reactions caused by bacterial contamination of blood and blood products were common in the early years of transfusion therapy with septicaemia occuring in up to 25% of transfusion recipients. Today, with improvements in the way that blood is donated, processed and stored transfusion associated sepsis is perceived to be a rare complication. However, bacterial contamination of blood products, if it does arise, can cause serious complications to recipients. Of 81 cases of bacterial infection attributed to contaminated blood products between 1975-1989, 35% resulted in death142.

Many of the red blood cell units that have been implicated have been found to be contaminated with Yersinia enterocolitica. This organism is psychrophilic and iron dependent and may be present in donor blood during the incubation and recovery phases of gastroenteritis. Platelet concentrates may be contaminated with a wide variety of normal skin or environmental microflora. It is worthy of note that the ability to grow an organism from a contaminated blood product does not automatically mean that the patient will experience a transfusion reaction as the organism may be present in low concentration or may be non-pathogenic in nature.

Högman et al143 proposed that phagocytic leucocytes ingest bacteria such as Yersinia species present in blood during the first few hours of storage. Some of these ingested bacteria, however, may remain viable. Therefore, when the phagocytic white cells disintegrate the bacteria are re-released and proliferate. It has been shown that blood from donors infected with Yersinia species has a significant level of contamination after 3 weeks of storage144. In the early 1990s several reports were published showing that leucocyte depleting filters removed Yersinia enterocolitica from contaminated units of red blood cells143-149. It has been suggested that the timing of the filtration could be critical ie. if leucocyte depletion is carried out too early not all of the bacteria will have been ingested. Conversely if filtration is performed too late white cells will have begun to disintegrate re-releasing viable or ganisms back into the blood150. The optimum length of the “holding period” prior to filtration is currently the subject of much debate and research. It has been suggested that leucocyte depletion may also be beneficial when units of blood and platelet concentrates are contaminated with other types of bacteria although further work is required to confirm this151. Interestingly, preliminary data shows that in previously leucocyte depleted red blood cell units a second filtration step was able to remove spiked contaminating bacteria (Staphylococcus xylosus 100cfu/ml) directly152. This suggests that leucocyte depleting filters may be able to remove contaminating bacteria either by removal of bacteria ingested by white cells or by direct trapping of free microbes.

Leucocyte depletion can also decrease the risk of transmission of certain blood-borne viruses. Most work has centred on the prevention of Cytomegalovirus (CMV) transmission. This virus is a member of the human herpes family of viruses and is present in approximately 50% of the adult population. Some areas of the world, however, have rates considerably higher than this whilst others may be lower. In healthy individuals the virus is usually latent and the subject is therefore asymptomatic. However, CMV can cause severe problems in immuno-compromised (eg. patients with haematological malignancies, those having solid organ or bone marrow transplantation (BMT), AIDS patients) and immuno-naive patients (eg. very low birth weight (VLBW) neonates). There are principally three routes of CMV infection related to blood transfusion - primary infection, secondary infection (ie. transmission of a second strain of the virus) and activation of latent virus caused by the immunosuppressive effects of blood transfusion. ( see (b) below). With the ever increasing list of patients claimed to benefit from CMV negative blood products, transfusion services are being placed under increasing strain to provide products designated “CMV safe” by conventional serological testing methods. In normal donor blood CMV is confined to contaminating leucocytes and numerous studies have shown that leucocyte depleting filters will prevent transfusion - transmitted CMV infection in high risk patients153-159 (Table 5). A major clinical trial in the United States has just been completed showing that leukodepletion by filtration is equivalent to serological testing for CMV to reduce CMV transmission via blood products158.

Table 5
Leucocyte Depletion of Red Cells and Platelets Prevents
Transmission of Cytomegalovirus (CMV) to
Immunocompromised CMV Seronegative Recipients
AUTHOR(S) No & NATURE OF INITIALLY SERO-NEGATIVE PATIENTS RESIDUAL WBCs LEUCOCYTE-DEPLETED GROUPS CMV INFECTION POST TRANSFUSION
RBCs PLATELETS CONTROL LEUCO-
DEPLETED
Verdonck et al (1987)153 29 BMT <1X106/Unit CMV Seronegative NA 0/29
de Graan Hentzen et al
(1987)154		 61 Acute Leukaemics <2x107/Unit <2x108/6 Unit pool NA 0/61
Murphy et al
(1989)155		 20 Acute Leukaemics <8x106/Unit Mean 2x108/PC
(Centrifugation) or mean
1x108/PC (Dual stage harvesting)		 2/9
(22.2%)		 0/11
Gilbert et al
(1989)156		 72 Neonates 94-99% Removal Not Administered 9/24
(37.5%)		 0/30
de Grann Hentzen et al
(1989)157		 55 High Dose Chemo-Radiotherapy & BMT 1x106/Unit Seroneg NA 0/55
59 Remission Induction <1x106/Unit 1x107 NA 0/59
192 Cardiac Surg 1.1x109 Not Given 14/80
(17.5%)		 9/112
(8%)
Bowden et al
(1993)158		 501 BMT Not Stated Not Stated 2/251*
(0.8%)		 3/250
(1.2%)
Van Prooijen et al
(1994)159		 60 BMT 0.8x106/Unit 0.7x106/6 Unit pool NA 0/60

Leucocytes may act as vectors for other types of blood borne viruses (eg. HIV, HTLV, Hepatitis B virus and Epstein - Barr virus). It has been suggested that the bioburden of these viruses may also be reduced by leucocyte depletion160-162. However, these viruses are not solely leucocyte associated being often found free in plasma. As yet, removal of free viruses by leucocyte depleting filters has not been reported.

(b) Transfusion induced immunosuppression

It has been recognised for several years that blood transfusions can cause a general immunosuppressive effect163. In some instances this transfusion-induced immunosuppression may prove beneficial, for example, improved survival of renal allografts and decreased recurrence rates after surgery for Crohn’s disease. In other instances however, the immunosuppressive effect of blood transfusion may be detrimental, for example, the possibility of increased frequency or earlier recurrence of solid tumours, increased frequency of bacterial infection and increased severity of viral infection. These two latter areas are relevant to infection control issues.

The relationship between perioperative homologous (ie. foreign) transfusion and an increased incidence of bacterial infection is well established from both animal and clinical studies. In humans this relationship has been observed in abdominal surgery, cardiac surgery, orthopaedic surgery, burns and trauma patients. These studies have generally shown a bacterial infection rate of approximately 20-30% in patients receiving homologous blood transfusions compared to 0-10% in non-transfused patients or those receiving their own (ie. autologous) blood products in similar clinical settings164-171. (Table 6). The majority of studies on this subject have shown that, even after accounting for factors such as shock, duration of surgery, type or extent of surgery and degree of wound contamination, transfusion remained a statistically significant predictor of infection. Indeed, in most of these studies transfusion was the single most significant predictor of infec tion. The role of transfusion as an independent prognostic factor is supported by the increased incidence of distant as well as local infections. In addition there is evidence to show that there is a dose-dependent effect of homologous blood transfusion and bacterial infection172-175.

The component in blood responsible for this immunosuppressive effect has been the subject of much debate over the last few years. Some workers have proposed that the agent is humoral (eg. plasma proteins, cytokines, immunoglobulins). However, an increasing number of studies favour a cellular component implicating contaminating white cells as the aetiological agent176. A prospective, randomized clinical study has recently demonstrated that the use of leucocyte depleting filters results in a statistically significant decrease in the incidence of post-operative infection171.

Table 6
Evidence of Transfusion-Mediated Bacterial Infection
Author(S) Type of
procedure		 Homologous
Transfusion		 Autologous
Transfusion		 No
Transfusion		 Leucocyte
Depleted
Transfusion
Dellinger et al
(1984)164		 Abdominal
Surgery		 28% - 9% -
Ottino et al
(1987)165		 Cardiac
Surgery		 Significant Transfusion Effect
Tartter
(1988)166		 Gut
Surgery		 24.6% - 4.3% -
Tartter et al
(1988)167		 Crohn’s
Disease		 26% - 8% -
Graves et al
(1989)168		 Burns Significant Transfusion Effect
Murphy et al
(1991)169		 Hip
Replacement		 32% 3% - -
Triulzi et al
(1992)170		 Spinal
Surgery		 20.8% 3.3% 4% -
Jensen et al
(1992)171		 Gut
Surgery		 23% - 2% 2%

Bacterial infections may not be the only type of infection potentiated by homologous transfusion. It has been shown that blood transfusion can cause activation of latent CMV177. In addition it has recently been shown that HIV-1 infected patients receiving homologous blood transfusion have an increased death rate and increased frequency of CMV, wasting and bacterial infection compared to non-transfused HIV-1 patients178. Busch et al179 have reported that homologous lymphocytes but not homologous red cells or platelets, increase HIV-1 replication and transmission in vitro. Therefore, it is possible that transfusion of leucocyte depleted blood to these patients may slow down progression to “full blown” AIDS.

There are numerous other clinical advantages associated with the use of filters to remove microaggregates (leucocyte, platelet and precipitated fibrin “clumps”) and leucocytes from transfused blood products. These include decreasing the incidence of pulmonary dysfunction and respiratory distress, post transfusional thrombocytopenia, fibronectin depletion, Histamine release, non-haemolytic febrile transfusion reactions and alloimmunisation and subsequent platelet refractoriness. However, detailed discussions of these areas is beyond the scope of this booklet and the reader’s attention is drawn to other reviews on these subjects180, 181.


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Filtration of Clear Fluids Used During Cardiopulmonary Bypass
Inadvertent bacterial contamination of clear fluids used during cardiopulmonary bypass may arise during storage or manipulation of equipment. Although reports of inadvertent contamination of clear fluid cardioplegia and priming solutions are rare, if this does occur it can have potentially fatal consequences. There have been several cases which have documented inadvertent contamination of crystalloid cardioplegia with Enterobacter cloacae. Talbot et al182 noted that 4 out of 14 patients undergoing cardiac surgery in Philadelphia developed otherwise unexplained intra-operative and/or immediate post-operative hypertension. E. cloacae contaminated cardioplegic solution was discovered to be responsible. In another hospital in Sydney crystalloid cardioplegia inadvertently contaminated with E. cloacae was used in 11 patients. Five of the patients died and another six had respiratory and renal complications183. In 1990 reports appeared in the A merican press which stated that four people had died and four others were being treated after receiving E. cloacae contaminated cardioplegia solution during open heart surgery184.

E. cloacae is a Gram negative bacterium. As discussed in the review of IV filters filtration, these organisms can shed endotoxins which can cause clinical complications. Endotoxins have been identified in cardioplegic fluids, prebypass fluids and ice for cooling. They have been described as a possible source of endotoxaemia in cardiopulmonary bypass185, 186. Nilsson et al187 demonstrated a rise in endotoxins in patients undergoing cardiopulmonary bypass and suggested that these probably originate from the bypass equipment. Winter188 states that since mortality rates associated with endotoxin production during surgery are high, novel attempts to overcome the problem are welcome. 0.2µm endotoxin-retentive cardioplegic and prebypass filters have now been developed. In addition to removing microbial and associated endotoxin contamination from clear fluids used during cardiopulmonary bypass these filters al so remove gaseous microemboli and particulates. Removal of these contaminants is useful in protecting the patient’s myocardium and systemic circulation189.


Top

Conclusion
Technological advances in the field of medical filtration have produced a variety of products which have been shown to be clinically beneficial in minimising several types of hospital acquired infection. As further research is conducted and more clinical studies are published the application of filtration in the hospital environment continues to expand.

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