josie stone, rn cpnp crni © josie stone consulting llc 2011
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© Josie Stone Consulting LLC 2011
Josie Stone, RN CPNP CRNI
Clinical Update:Risk of Particulate Contamination
In Infusion Therapy
© Josie Stone Consulting LLC 2011
Disclosure
Independent clinical education consultant for PALL Medical.
© Josie Stone Consulting LLC 2011
Objectives
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
Areas for Discussion
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
Particulates
“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.
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What Are Particulates?
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)
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Particulate Size Reference
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Nanotechnology Just for interest: 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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Particulates in our Environment
Dust Pollen Bacteria Mold spores Attached viruses Animal dander Radon progeny
(Radon daughters) Pollen magnified 25,000x 0.2micronPhoto courtesy of University of Minnesota
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Significance of Particulates in our Immediate Environment
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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Respiratory System and Particulates
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
Particulates in IV Solutions
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)
5. Entrapped air emboli
Esketamin precipitate in IV lineCourtesy of F. Schröder
© Josie Stone Consulting LLC 2011Slide content courtesy © Pall Corporation 2011
© Josie Stone Consulting LLC 2011
Predisposing Factors
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
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Circulatory System and Particulates
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
Particulate Matter Transport
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Illustration courtesy of Heart.org.in
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Capillaries
• 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 blood-stream.
• Occlusion of blood flow restricts efficiency.
The micro-capillary system of solid organs is specifically vulnerable . Several mechanical and biological mechanismscan lead to capillary damage.
The effect they have depends upon their size, quantity, shape and composition
Particulate Size Comparison
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Drug incompatibility reactions are among the most frequent problems of infusion therapy
Esketamin
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Clinical Particle Origin
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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Clinical Particle Origin (cont.)
1. Drug incompatibility reactions
Drug A Drug CDrug B Drug ...Buffers
Stabilisers
Solvents
Infusate
Chemical reactionsOxydation, Reduction, Substitution, Addition,
Decarboxylation, Complex formation
Physical reactionsAssociation, Aggregaation, Crystallisation
Phase Separation, Precipitation
EnhancerspH shift, light, high temperature
Trace elements, oxygen
Formation of particles and loss of pharmacological activity
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Clinical Particle Origin (cont.)
Clinical Particle Origin (cont.)
Drug incompatibility reactions
Drug application errors 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
1. K. Taxis K, Barber N. Eur J Clin Pharmacol. (2004) 59: 815–72. Vogel Kahmann I. et al. Anaesthesist (2003) 52: 409–4123. Wirtz V. et al. Pharm World Sci (2003) 25: 104-1114. Valentin A. et al. Brit Med J (2009) 338: 8145. Shay DK et al. Infect Control Hops Epidemiol (1997) 18: 814–817
6. Hill S.E. JPEN (1996) 20: 81–877. McNeary T. et al. Digestive Diseases Sciences (2003)
48: 1352–13548. Marimbert J, AFSSAPS warning letter, Nov. 30, 20069. Arzneimittelkommission d.dt.Aärzteschaft,(2007) Deutsches Ärzteblat 36: A2445
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Clinical Particle Origin (cont.)
Particle load of components and systems
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
Particulate contamination isolated from clot in catheter1
– Presumably plastic materials
Abrasion of silicone particles during pump-controlled infusion therapy2
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1. Lehr H.-A. et al. Am J Respir Crit Care Med (2002) 165: 514–5202. Oie S and Kamiya A. Biol Pharm Bull (2005) 28: 2268 - -22703. Yorioka K. et al. Biol. Pharm. Bull. (2006) 29: 2321-2323
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Particle content in clinically used PN solutions
Unadmixed solutions Admixed solutions
Base particle contamination from components and systems
Generic formulations of antibiotics have been found to be heavily contaminated with particles1
Admixing increased the amount of particles found by more than 10 fold2
Glass ampoules contained 379 – 3890 particles >1.3µm/ml3
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Clinical Particle Origin (cont.)
Generic Drugs and Solutions
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)
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
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1. Generic Pharmaceutical Association2. Hans-Anton Lehr et. al. Am J. Respir. Crit. Care Med., Vol. 165, Number 4, Feb 202, 514-520
The Problem
“The number of small particles (2–10µm in diameter) was 30 times higher in antibiotics B and C, as compared with antibiotic A.”
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Antibiotic brand
Particulate contamination
>2µm >10µm >25µm
(Lehr et al. 2002)© Josie Stone Consulting LLC 2011
Slide content courtesy © Pall Corporation 2011
Embolisation
Particles
Micelles
Gas emboli
Thrombogenic
effects
Inflammation
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Particle Embolization
Clinical Effects of Particles
2. Direct embolisationGlass 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© Josie Stone Consulting LLC 2011
Slide content courtesy © Pall Corporation 2011
Clinical Effects of Particles (cont.)
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Clinical Effects of Particles (cont.)
1. Driscoll DF and Bistrian BR Clinical Nutrition (2005) 24: 699-700
2. USP, Chapter 729 Pharm Forum (2005) 31: 1448 –53
3. Driscoll DF et al Clinical Nutrition (2006) 25(5): 842-50
Lipid macro micelles 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
Phase separation
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Clinical Effects of Particles (cont.)
Embolisation
Particles
Micelles
Gas emboli
Thrombogenic
effects
Inflammation
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Clinical Effects of Particles (cont.)
1. Wald M. et al. Intensive Care Medicine (2003) 29: 630 -633
2. Muth CM, Shank ES. NEJM (2000) 342: 476 – 482
3. Barak M & Katz Y Chest (2005) 128: 2918 – 2932
4. Eckmann DM, Diamond SL Anesthesiology (2004) 100: 77 – 84
Entrapped air emboli 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
© Josie Stone Consulting LLC 2011Slide content courtesy © Pall Corporation 2011
Clinical Effects of Particles (cont.)
Embolisation
Particles
Micelles
Gas emboli
Thrombogenic
effects
Inflammation
Slide content courtesy © Pall Corporation 2011© Josie Stone Consulting LLC 2011
Clinical Effects of Particles (cont.)
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 Solubility limits
Jack T et al. Intensive Care Medicine Online publication 18th Feb. 2010 Slide content courtesy © Pall Corporation 2011© Josie Stone Consulting LLC 2011
Aggravating Factorsfor Particle Formation
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Today’s Complex IV Therapy
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Infusion Particulate Standards
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.
Incomplete reconstitution of drugs Reconstituted Amphotericin B contained particle counts beyond the threshold limits of
the USP, originating from un-dissolved drug and particles released from the vial1
Particle content (> 5µm) in 5ml-solution pre and post filtration
Filtration reduced the rate of particulate contamination from reconstituted drugs2
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1. Sendo T. et al. J Clin Pharmacy and Therapeutics (2001) 26: 87 – 912. Kuramoto K. et al. Yakagaku Zasshi (2006) 126: 289 - 295
Outside Acceptable LimitExample
Particle Toxicology
Physiochemical particle characteristics determine toxicity
Size
Size distribution
Agglomeration state
Shape
Crystal structure
Oberdörster, G. et al. Particle and Fibre Toxicology (2005) 2: 8 - 43
Chemical composition
Surface area
Surface chemistry
Surface charge
Porosity© Josie Stone Consulting LLC 2011
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Potential Clinical Outcomes
1. Thrombogenicity, thrombophlebitis
2. Direct embolisation – respiratory distress
3. Inflammation
4. Impairment of micro-circulation and endothelial function
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Underlying Mechanisms and Pathways
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 balance3. Direct actions upon the vasculature of particle
constituents capable of reaching the central circulation
Brook R D Clin Spec. 2008 115-175
From: Brook RD Clin.Sci (2008) 115: 175
Underlying Mechanisms and Pathways Algorithm
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High Risk PatientsPatients 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)
ARDS COPD Atherosclerosis Infarction (heart,
brain) Trauma, Polytrauma Peripheral arterial
occlusive disease Diabetic angiopathie Sepsis
Hemostasis disorders- Sepsis- SIRS
Organ transplant- Kidney- Liver- Lung- Heart
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Systemic Inflammatory Response Syndrome (SIRS)
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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Pathophysiology of SIRS
A self-defense mechanism Inflammation is the body’s response to
non-specific insults The inflammatory cascade is a complex
process that involves humoral and cellular responses, complement and cytokine cascades
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Stages of Response 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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Is Filtration a Consideration
?
The Potential Benefits of Filtration
Retention of particles Reduction of thrombophlebitis rate Prevention of functional capillary loss Reduction of SIRS rate Reduction of overall complication rate
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The Effect of Filtration
Retention of particles Particles retained on filter media from clinically
administered IV solutions
Brent B. et al. Eur Heart J. e-pub 1st Dec. 2006
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Particles on a filter membrane
25 µm
17 µm
The Effect of Filtration (cont)
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Why does the filter clog? Is there something wrong with it?
Without a filter in place, the elements that cause filter clogging would pass to the patient 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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Clogged Filter
Ref Author Year Patient Blinded Phlebitis rate
Number (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
The Effect of FiltrationStudies
Reduction of phlebitis rate
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Falchuk: Thrombophlebitis
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Filter No Filter
Reduction of thrombophlebitis rate 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, Peterson, McNeil (1985) NEJM 312: 78© Josie Stone Consulting LLC 2011
Slide content courtesy © Pall Corporation 2011
The Effect of FiltrationStudies
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Studies on the Effect of Inline Filtration on Thrombophlebitis Rate
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The Effect of FiltrationStudies
Prevention of deep vein thrombosis Sudden upswing of deep vein
thrombosis rate in a University hospital PICU triggers search for root cause (2002)
Problem ceases upon the introduction of a 0.22 micron filter
Investigation reveals that quality problems with IV tubing used lead to particle release, which was the most likely cause for deep vein thrombosis cases
Danschutter D. et al. Pediatrics 2007;119;742-753)
Introduction of a 0.22 micron filter
Control tubeDisintegrating tube
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The Effect of FiltrationStudies
Reduction of overall complication rate with the use of in-line intravenous filters in sick newborn infantsResults: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
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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The Effect of FiltrationStudies
(http://www.clinicaltrials.gov/ct/show/NCT00209768?order=9)
The Effect of FiltrationEuropean Study 2009
Reduction of SIRS rate
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© Josie Stone Consulting LLC 2011Slide content courtesy © Pall Corporation 2011
Summary
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- Reducing organ failure rate - Lowering complication rate- Lowering intensity of medical treatment- Reducing cost
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Recommendations andGuidelines
Infusion Nurses Society - Standards of Practice 2011
28. Filters- 28.1 The use of bacteria and particulate-retentive, air-
eliminating, 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 used11. Infusion Nursing Standards of Practice – Journal of Infusion Nursing (2011) 34, No 1S: S33-S34
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Infusion NursingAn Evidence Based Approach
“While the immediate clinical benefit of filters has eluded researchers and clinicians, there is a growing trend in recent literature to support their use.”
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Focus On EvidenceParticulate Matter and Filtration
Ref: INS Infusion Nursing An Evidence Based Approach, 3rd Edition, Pg 419
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QUESTION
S