Josie Stone, RN CPNP CRNI
© Josie Stone Consulting LLC 2011
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Independent clinical education consultant for
PALL Medical.
© Josie Stone Consulting LLC 2011
1.
To identify the type and source of particulates
in IV solutions today.
2.
To understand the relationship between
infusion-related particulates and their effect on
the patient.
© Josie Stone Consulting LLC 2011
1.
The problem
2.
What do we know about particles?
3.
What clinical effects do they have?
4.
Which patients are especially vulnerable?
5.
The value of filtration on particle related risks
© Josie Stone Consulting LLC 2011
“The mobile, undissolved substances
unintentionally present in parenterals.” 1
S K Singhal - 2010, J Anaesthesiol Clin Pharmacol. 2010 Oct-Dec; 26(4): 564–565.
1. Lim Y S, Turco S, Davis N M. Particulate matter in small-volume parenterals as determined by two methods. Amer J Hos Pharm. 1973;30:518–525.
© Josie Stone Consulting LLC 2011
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Made up of “particles” which are “very small
pieces or parts of matter: tiny fragments or
traces” (Taber’s Cyclopedic Medical Dictionary)
Particulates are measured in microns (µm) or
micrometers (= 0.001mm) interchangeable
units of size measurement)
© Josie Stone Consulting LLC 2011
© Josie Stone Consulting LLC 2011
Just for interest:
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Uses a basic unit of measure called a "nanometer"
(abbreviated nm). “Nano" is a metric prefix and
indicates a billionth part (10-9).
There are one billion nm's
to a meter. Each nm is only
three to five atoms wide.
~40,000 times smaller than
the width of an average
human hair.
Evolving application in
medicine
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Dust
Pollen
Bacteria
Mold spores
Attached viruses
Animal dander
Radon progeny
(Radon daughters)
Pollen magnified 25,000x 0.2micron
Photo courtesy of University of Minnesota
© Josie Stone Consulting LLC 2011
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Size of particles directly linked to their potential for causing health
problems and defined as “coarse inhalable” (2.5-10 µm) and
“fine” (< 2.5 µm )
Particles, especially “fine” particles, contain microscopic solids or
liquid droplets that can penetrate deep into the lungs, alter the
bodies defense mechanisms and can also pass from the lungs to
the bloodstream
Scientific studies have linked particle pollution to respiratory
compromise, decreases lung function, immunosuppression, cardiac
irregularities and premature death
People most likely to be affected are those with heart and lung
disease, children and older adults
Standards set by United States Environmental Protection Agency
(EPA) most recently regulated in 2006 but detrimental health
effects from environment particulates remain a serious issue
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Lungs are easy targets for atmospheric pollutants
A relatively primitive system of nasal hair and mucous
is all that stands between a toxin and delicate alveoli
Humans inhale and
exhale about 10,000
litres of air every day,
hence lungs will
eventually be exposed
to fairly significant
amounts of toxins
even if they are only
in low concentrations
in the atmosphere
moonchalice.com
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Where do particles come from in IV solutions?
1. Drug incompatibility
reactions
2. Incomplete reconstitution
of drugs
3. Particle contamination from
components and systems
4. Lipid macro micelles (ultra-
microscopic units of protoplasm)
Esketamin precipitate in IV line
Courtesy of F. Schröder
5. Entrapped air emboli
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Varying levels ph (acid/base) values and
osmolarity/osmolality
Varying concentrations
Irritating or vesicant nature
Potential for contamination (TPN, glucose solutions,
lipids)
Susceptible to precipitation if infused simultaneously
May be compounded from powder formulas
Require reconstitution
May be dispensed in glass ampules, vials etc.
Note: All properties may have effect on tissue interaction and
potential for particulate development
© Josie Stone Consulting LLC 2011
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Average adult has 5 litres of blood in their
circulation
Three vascular systems, pulmonary, coronary and
systemic
Systems must be working independently for them
all to work together
Compromise of function in one will lead to
compromise in another
Optimal exchange of oxygen and CO2 occurring at
the alveoli/capillary level essential for health and
well being
Compromise of capillary integrity will affect
outcomes i.e. particulate obstruction
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Illustration courtesy of Heart.org.in
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The micro-capillary system of solid organs is specifically
vulnerable . Several mechanical and biological mechanisms
can lead to capillary damage.
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Range from 5 to 10 µm in diameter and number around 10 billion.
Estimated 25,000 miles of capillaries in an adult, averaging 1 mm
in length.
Single cell wall thickness.
Facilitates exchange
of materials between
the wall and the bloodstream.
Occlusion of blood
flow restricts efficiency.
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The effect they have depends upon their size, quantity,
shape and composition
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Esketamin
Drug incompatibility reactions are among the
most frequent problems of infusion therapy
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Incompatibility reactions
may be avoided through
review of the drug regime
with clinical pharmacists
and reference to drug
incompatibility charts.
Diazepam
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1. Drug incompatibility reactions
Drug A
Drug B
Drug C
Solvents
Drug ...
Buffers
Stabilisers
Infusate
Enhancers
pH shift, light, high temperature
Trace elements, oxygen
Chemical reactions
Oxydation, Reduction, Substitution, Addition,
Decarboxylation, Complex formation
Physical reactions
Association, Aggregaation, Crystallisation
Phase Separation, Precipitation
Formation of particles and loss of pharmacological activity
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Drug incompatibility reactions
Drug application errors
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15 - 28% of drugs given clinically without knowing incompatibility
pattern or in spite of known incompatibilities1,2,3
Medication errors occurred in 9% of bolus, 6% of continuous and
6% of subcutaneous drug applications4
Calcium phosphate precipitates in IV solutions have been reported
as the cause for ARDS, granulomatous interstitial pneumonia,
pulmonary embolisation and death5,6 and pulmonary arterial
occlusion7
Ceftriaxone precipitating in the presence of calcium salts caused
death of neonate8,9
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1.
2.
3.
4.
5.
K. Taxis K, Barber N. Eur J Clin Pharmacol. (2004) 59: 815–7
Vogel Kahmann I. et al. Anaesthesist (2003) 52: 409–412
Wirtz V. et al. Pharm World Sci (2003) 25: 104-111
Valentin A. et al. Brit Med J (2009) 338: 814
Shay DK et al. Infect Control Hops Epidemiol (1997) 18: 814–817
6.
7.
8.
9.
Hill S.E. JPEN (1996) 20: 81–87
McNeary T. et al. Digestive Diseases Sciences (2003)
48: 1352–1354
Marimbert J, AFSSAPS warning letter, Nov. 30, 2006
Arzneimittelkommission d.dt.Aärzteschaft,(2007) Deutsches Ärzteblat 36: A2445
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Particle load of components and systems
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Particulate
contamination isolated
from clot in catheter1
– Presumably plastic
materials
Abrasion of silicone
particles during pumpcontrolled infusion
therapy2
1. Ball, P.A., Bethune K., Fox, J., Ledger, R. Barnett , M.I. Nutrition (2001) 17: 933-936.
2. Dewan P.A. et al. Pediatr Surg Int (2002) 18: 310–314
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Base particle contamination from components and systems
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Generic formulations of antibiotics have been found to be
heavily contaminated with particles1
Admixing increased the
Particle content in clinically used PN solutions
amount of particles found
1000
by more than 10 fold2
900
800
Glass ampoules contained
700
600
379 – 3890 particles
500
>1.3µm/ml3
400
Number of particles
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300
200
100
0
1,3 µm
5µm
10µm
50µm
Particles larger than
Unadmixed solutions
1. Lehr H.-A. et al. Am J Respir Crit Care Med (2002) 165: 514–520
2. Oie S and Kamiya A. Biol Pharm Bull (2005) 28: 2268 - -2270
3. Yorioka K. et al. Biol. Pharm. Bull. (2006) 29: 2321-2323
Admixed solutions
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U.S. brand pharmaceutical manufacturer sales for 2007: $228
billion1 U.S. generic pharmaceutical manufacturer sales: $58.5
billion (source: IMS National Sales Perspective, Moving Annual Total,
Nov. 2007)
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10,072 of the 12,571 drugs listed in the FDA’s Orange Book have generic
counterparts (source: FDA, MedAd News)
The FDA requires the bioequivalence of the generic product to
be between 80%-125% of that of the innovator product
Bioequivalence does not mean that generic drugs must be
exactly the same (“pharmaceutical equivalent” ) as chemical
differences may exist (e.g. different salt or ester)
The possible deleterious effects of [particulate matter] contaminants have
become all the more clinically relevant, as generic products are being
increasingly used because of economic pressures on health resources.2
1. Generic Pharmaceutical Association
2. Hans-Anton Lehr et. al. Am J. Respir. Crit. Care Med., Vol. 165, Number 4, Feb 202, 514-520
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Particulate contamination
16000
Number of particles/ 1g of drug
“The number of small
particles (2–10µm in
diameter) was 30 times
higher in antibiotics B
and C, as compared
with antibiotic A.”
18000
14000
12000
10000
8000
6000
4000
2000
0
Claforan (A)
Cefantral (B)
Taxim C)
Antibiotic brand
>2µm
(Lehr et al. 2002)
>10µm
>25µm
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Embolisation
Particles
Micelles
Gas emboli
Thrombogenic
effects
Inflammation
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2. Direct embolisation
Glass fragments embedded in lung tissue in post
mortem specimens from the lung of neonates
Puntis JWL, Wilkins KM, Ball PA, Rushton DI, Booth IW. Hazards of parenteral treatment: do particles
count ? Archives of Disease in Childhood 1992;67:1475-1477.
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Glass ampules have been responsible for the injection of
thousands of glass particles into the circulation. Turco and
Davis1, in a classic study prompted by the frequency of
high-dose administration of furosemide, showed that a dose
of 400 mg, which at that time required that breaking of 20
ampules, could add 1,085 glass particles >5 µm to the
injection. A dose of 600 mg, requiring 30 ampules, could
result in 2,387 particles >5µm.
1.
Turco S, Davis NM. Glass particles in intravenous injections. N Engl J Med. 1972;287:1204-1205
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Lipid macro micelles
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1.
2.
3.
Phase separation
Enlarged lipid droplets arise in
admixtures due to instability and the
use of plastic bag containers1.
The USP suggests that the proportion
of lipid present as droplets >5 μm
should not exceed 0.05% of total fat2
Infusion of unstable AIO (all in one
IVFE) admixtures has been shown to
cause tissue injury and oxidative
stress to reticuloendothelial system
organs3
Driscoll DF and Bistrian BR Clinical Nutrition (2005) 24: 699-700
USP, Chapter 729 Pharm Forum (2005) 31: 1448 –53
Driscoll DF et al Clinical Nutrition (2006) 25(5): 842-50
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Embolisation
Particles
Micelles
Gas emboli
Thrombogenic
effects
Inflammation
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Entrapped air emboli
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1.
2.
3.
4.
Degassing or mixing of solutions, administration set leaks or gas
residues in injection syringes and connectors1
Air bubbles may transfer into the arterial circulation and cause end
arterial obstruction (paradoxical embolism)2
Air bubbles as small as 30 – 60µm may cause an embolization of small
arteries followed by tissue ischemia2
Air bubbles have been shown to
trigger inflammatory responses,
activate the complement system
and to induce the formation of clots
in human blood3, 4
Wald M. et al. Intensive Care Medicine (2003) 29: 630 -633
Muth CM, Shank ES. NEJM (2000) 342: 476 – 482
Barak M & Katz Y Chest (2005) 128: 2918 – 2932
Eckmann DM, Diamond SL Anesthesiology (2004) 100: 77 – 84
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Embolisation
Particles
Micelles
Gas emboli
Thrombogenic
effects
Inflammation
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Complexity of IV therapy today
Lack of incompatibility information for
complex mixtures
Lack of incompatibility information for the
entire formulation including buffers,
emulsifiers, additives, etc.
Liquid volume constraints
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Solubility limits
Jack T et al. Intensive Care Medicine Online publication 18th Feb. 2010
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The USP (United States Pharmacopoeia) sets the
acceptable limit of particles for single-dose
infusion at not more than 50 particles/mL that
are > 10.0 µm and not more than 5
particles/mL that are > 25.0 µm in effective
linear dimension.
Over the years, manufacturers have made great
efforts to produce high-quality products, but
these efforts may be negated by manipulating
the products before their infusion.
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Incomplete reconstitution of drugs
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Reconstituted Amphotericin B contained particle counts beyond the
threshold limits of the USP, originating from un-dissolved drug and
particles released from the vial1
Filtration
reduced
the rate
Particle content
(> 5µm)
in 5ml-solution
pre of particulate
and post filtration
contamination from reconstituted drugs2
1. Sendo T. et al. J Clin Pharmacy and Therapeutics (2001) 26: 87 – 91
2. Kuramoto K. et al. Yakagaku Zasshi (2006) 126: 289 - 295
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Physiochemical particle characteristics determine
toxicity
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Size
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Chemical composition
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Size distribution
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Surface area
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Agglomeration state
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Surface chemistry
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Shape
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Surface charge
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Crystal structure
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Porosity
Oberdörster, G. et al. Particle and Fibre Toxicology (2005) 2: 8 - 43
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1. Thrombogenicity, thrombophlebitis
2. Direct embolisation – respiratory distress
3. Inflammation
4. Impairment of micro-circulation and
endothelial function
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Particulate matter inhaled into the pulmonary tree
or introduced into the central circulation may
instigate cardiovascular health effects by three
general pathways:
1. Instigation of systemic inflammation and/or
oxidative stress
2. Alterations in autonomic balance
3. Direct actions upon the vasculature of particle
constituents capable of reaching the central
circulation
Brook R D Clin Spec. 2008 115-175
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From: Brook RD Clin.Sci (2008) 115: 175
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Patients with an impaired micro-circulation are at an especially
high risk from particulate contamination both in solutions and
the environment
Highest likelihood to profit from the removal of particulate
contamination (solid particles, oversized lipid micelles, air
bubbles)
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ARDS
COPD
Atherosclerosis
Infarction (heart, brain)
Trauma, Polytrauma
Peripheral arterial
occlusive disease
Diabetic angiopathie
Sepsis
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Hemostasis disorders
Sepsis
- SIRS
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Organ transplant
Kidney
- Liver
- Lung
- Heart
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Systemic Inflammatory Response to a variety of severe
clinical insults (pancreatitis, ishcemia or reperfusion,
multiple trauma, tissue injury, hemorrhagic shock and
immune-mediated organ injury) in the presence or
absence of infection.
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A self-defense mechanism
Inflammation is the body’s response to nonspecific insults
The inflammatory cascade is a complex process
that involves humoral and cellular responses,
complement and cytokine cascades
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Stage 1: Local cytokine is produced to initiate
inflammatory response to promote wound repair an
activation of the reticular endothelial protective system
(RES)
Stage 2: Small quantities of cytokines released into
circulation to improve the local response leading to
growth factor stimulation and recruitment of
macrophages and platelets. This phase is well
controlled by a decrease in pro-inflammatory
mediators and the release of endogenous antagonists
(homeostasis)
Stage 3: If homeostasis is not restored, a systemic
reaction occurs; cytokine release leads to destruction
rather than protection causing numerous humoral
cascades, activation of the RES and subsequent loss of
circulatory integrity, leading to end organ dysfunction.
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Retention of particles
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Reduction of thrombophlebitis rate
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Prevention of functional capillary loss
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Reduction of SIRS rate
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Reduction of overall complication rate
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Retention of particles
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Particles retained on filter media from clinically
administered IV solutions
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Particles on a filter membrane
25 µm
17 µm
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Why does the filter clog?
Is there something wrong with it?
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Without a filter in place, the elements that cause
filter clogging would pass to the patient
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Infusates should be checked for issues that could
cause precipitates such as pH, temperature, time,
drug interactions, etc.
Correct filter size for infusates must be used
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Reduction of phlebitis rate
Ref
Author
Year
Number
Patient
Blinded
Phlebitis rate
(n)
(Y/N)
(% of patients)
Filter
No Filter
1
Ryan et al.
1973
100
N
2
45
2
DeLuca et al.
1975
146
N
12
61
3
Evans et al.
1976
49
Y
8
56
4
Maddox et al.
1977
120
Y
20
60
5
Rusho & Blair
1979
150
N
6
27
6
Bivins et al.
1979
146
Y
25
62
7
Allcut et al.
1983
194
Y
31
51
8
Falchuk et al.
1985
541
Y
25
57
9
Francombe
1988
56
N
29
57
10
Chee & Oh
1997
200
N
5
23
11
Chee & Tan
2002
394
N
8
28
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Reduction of thrombophlebitis rate
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Prospective, randomized, double blind clinical study on
541 patients
25% of patients with filter developed thrombophlebitis vs.
57% of patients w/o filter (p< 0.001)
Falchuk: Thrombophlebitis
% of patients w.thrombophl.
35
30
25
20
15
10
5
0
1
2
3
Day
Filter
Falchuk, Peterson, McNeil (1985) NEJM 312: 78
No Filter
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Studies on the Effect of Inline Filtration on
Thrombophlebitis Rate
% of thrombophl. pat.
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9
10
11
Ref. Number
Filter
No Filter
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Prevention of deep vein thrombosis
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Sudden upswing of deep vein
thrombosis rate in a University
hospital PICU triggers search
for root cause (2002)
Introduction of a 0.22 micron filter
Problem ceases upon the
introduction of a 0.22 micron filter
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Investigation reveals that quality problems with IV tubing used
lead to particle release, which was the most likely cause for deep
vein thrombosis cases
Disintegrating tube
Danschutter D. et al. Pediatrics 2007;119;742-753)
Control tube
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Reduction of overall complication rate with the use of
in-line intravenous filters in sick newborn infants
25
Results:
1. Overall complication rate in
the filter group significantly
lower than in the control
group without filter (8 vs 21
cases, p<0.05).
2. 14% of filters in the study
group contaminated on upstream side
3. Cost for disposable products reduced by 24% in the filter group
No. of patients (n)
20
15
10
5
0
Total
Sepsis
no filter
Clinical
Sepsis
Thrombi
NEC
Filter (ELD96)
Conclusion:
“The use of this in-line filter leads to a significant decrease in
major complications and substantial cost savings”
RA van Lingen et al. Acta Paediatrica (2004) 93: 658
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Reduction of SIRS rate
(http://www.clinicaltrials.gov/ct/show/NCT00209768?order=9)
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 Particles induce pathological processes, which lead to
tissue ischemia
 Depending on clinical conditions ischemia may
progress to loss of organ function
 Further particle contamination will aggravate ischemia
 Ischemia may progress to organ failure and multi
organ failure
 Particle filtration contributes to
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Reducing organ failure rate
Lowering complication rate
Lowering intensity of medical treatment
Reducing cost
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Infusion Nurses Society - Standards of Practice 2011
28. Filters
- 28.1 The use of bacteria and particulate-retentive, aireliminating, and blood and blood component filters shall be
established in organizational policies, procedures, and/or
practice guidelines.
- 28.2 For non-lipid containing solutions that require filtration, a
0.2-micron filter containing a membrane that is bacteria- and
particulate-retentive and air eliminating shall be used
- 28.3 For lipid infusions or total nutrient admixtures that
require filtration, a 1.2-micron filter containing a membrane
that is particulate-retentive and air eliminating shall be used1
1. Infusion Nursing Standards of Practice – Journal of Infusion Nursing (2011) 34, No 1S: S33-S34
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Focus On Evidence
Particulate Matter and Filtration
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“While the immediate clinical benefit of filters has
eluded researchers and clinicians, there is a growing
trend in recent literature to support their use.”
Ref: INS Infusion Nursing An Evidence Based Approach, 3rd Edition, Pg 419
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