Josie Stone, RN CPNP CRNI

Josie Stone, RN CPNP CRNI
Clinical Update: Risk of Particulate Contamination In Infusion Therapy Josie Stone, RN CPNP CRNI © Josie Stone Consulting LLC 2011

Disclosure Independent clinical education consultant for PALL Medical.
© Josie Stone Consulting LLC 2011

Objectives To identify the type and source of particulates in IV solutions today. To understand the relationship between infusion-related particulates and their effect on the patient. © Josie Stone Consulting LLC 2011

Areas for Discussion The problem What do we know about particles?
What clinical effects do they have? Which patients are especially vulnerable? 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. © Josie Stone Consulting LLC 2011

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) © Josie Stone Consulting LLC 2011

Particulate Size Reference

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 Nanotechnology in medicine currently being developed involves employing nanoparticles to deliver drugs, heat, light or other substances to specific types of cells (such as cancer cells). © Josie Stone Consulting LLC 2011

Particulates in our Environment
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

Significance of Particulates in our Immediate Environment
Size of particles directly linked to their potential for causing health problems and defined as “coarse inhalable” ( 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 © Josie Stone Consulting LLC 2011

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 © Josie Stone Consulting LLC 2011

Particulates in IV Solutions
Where do particles come from in IV solutions? Drug incompatibility reactions Incomplete reconstitution of drugs Particle contamination from components and systems Lipid macro micelles (ultra- microscopic units of protoplasm) Entrapped air emboli Esketamin precipitate in IV line Courtesy of F. Schröder © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 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 © Josie Stone Consulting LLC 2011

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 © Josie Stone Consulting LLC 2011

Particulate Matter Transport
Illustration courtesy of Heart.org.in Introduced into the vein and travel to the (R) atrium of the heart , through the tricuspid valve , and into the (R) ventricle Pumped to the pulmonary artery and on through branches of arteries that decrease in size until trapped in massive capillary beds of the lung Particles of 5µm potentially dangerous as can become lodged Particles of 300µm can pass through an 18-gauge catheter and even greater in size through an indwelling catheter with larger lumen Ref: Plumer’s principles of practice intravenous therapy/Sharon Weinstein 8th Ed. © Josie Stone Consulting LLC 2011

Capillaries The micro-capillary system of solid organs is specifically vulnerable . Several mechanical and biological mechanisms can lead to capillary damage. 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. Capillaries, the smallest, most numerous and thinnest walled blood vessels in the human body, range from 5 to 10 µm in diameter and number around 10 billion. An inner diameter of 5 µm is just wide enough for an erythrocyte to squeeze through. It is estimated there are 25,000 miles of capillaries in an adult, each with an individual length of about 1 mm. Most capillaries are little more than a single cell layer thick, consisting of a layer of endothelial cells and a basement membrane. This minimal wall thickness facilitates the capillary's primary function permitting the exchange of materials between cells in tissues and the blood. Any interruption/occlusion of the flow of blood from particulates through this network will restrict its efficiency. © Josie Stone Consulting LLC 2011

Particulate Size Comparison
The effect they have depends upon their size, quantity, shape and composition © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Clinical Particle Origin
Esketamin Drug incompatibility reactions are among the most frequent problems of infusion therapy © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Clinical Particle Origin (cont.)
Incompatibility reactions may be avoided through review of the drug regime with clinical pharmacists and reference to drug incompatibility charts. Diazepam © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

1. Drug incompatibility reactions Solvents Drug A Drug B Drug C 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 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Drug incompatibility reactions Drug application errors % 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 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: Valentin A. et al. Brit Med J (2009) 338: 814 Shay DK et al. Infect Control Hops Epidemiol (1997) 18: 814–817 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 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Particle load of components and systems Particulate contamination isolated from clot in catheter1 Presumably plastic materials Abrasion of silicone particles during pump-controlled infusion therapy2 Ball, P.A., Bethune K., Fox, J., Ledger, R. Barnett , M.I. Nutrition (2001) 17: Dewan P.A. et al. Pediatr Surg Int (2002) 18: 310–314 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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 Lehr H.-A. et al. Am J Respir Crit Care Med (2002) 165: 514–520 Oie S and Kamiya A. Biol Pharm Bull (2005) 28: Yorioka K. et al. Biol. Pharm. Bull. (2006) 29: © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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 Generic Pharmaceutical Association Hans-Anton Lehr et. al. Am J. Respir. Crit. Care Med., Vol. 165, Number 4, Feb 202, © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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.” All cephalasporins (cefotaximine) © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 (Lehr et al. 2002)

Particle Embolization
Embolisation Particles Micelles Gas emboli Thrombogenic effects Inflammation © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Clinical Effects of Particles
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: © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Clinical Effects of Particles (cont.)
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. © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Turco S, Davis NM. Glass particles in intravenous injections. N Engl J Med. 1972;287:

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 Driscoll DF and Bistrian BR Clinical Nutrition (2005) 24: USP, Chapter 729 Pharm Forum (2005) 31: 1448 –53 Driscoll DF et al Clinical Nutrition (2006) 25(5): © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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 Wald M. et al. Intensive Care Medicine (2003) 29: 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 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Aggravating Factors for Particle Formation
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 © Josie Stone Consulting LLC 2011 Jack T et al. Intensive Care Medicine Online publication 18th Feb. 2010 Slide content courtesy © Pall Corporation 2011

Today’s Complex IV Therapy

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 > 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. © Josie Stone Consulting LLC 2011

Outside Acceptable Limit Example
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 Sendo T. et al. J Clin Pharmacy and Therapeutics (2001) 26: 87 – 91 Kuramoto K. et al. Yakagaku Zasshi (2006) 126: © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Particle Toxicology Physiochemical particle characteristics determine toxicity Size Size distribution Agglomeration state Shape Crystal structure Chemical composition Surface area Surface chemistry Surface charge Porosity © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Oberdörster, G. et al. Particle and Fibre Toxicology (2005) 2:

Potential Clinical Outcomes
1. Thrombogenicity, thrombophlebitis 2. Direct embolisation – respiratory distress 3. Inflammation 4. Impairment of micro-circulation and endothelial function © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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: Instigation of systemic inflammation and/or oxidative stress Alterations in autonomic balance Direct actions upon the vasculature of particle constituents capable of reaching the central circulation Brook R D Clin Spec © Josie Stone Consulting LLC 2011

Underlying Mechanisms and Pathways Algorithm
© Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 From: Brook RD Clin.Sci (2008) 115: 175

High Risk Patients 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) 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 Filtration to follow © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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. © Josie Stone Consulting LLC 2011

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 © Josie Stone Consulting LLC 2011

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. © Josie Stone Consulting LLC 2011

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 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

The Effect of Filtration (cont)
Particles on a filter membrane 25 µm 17 µm © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Clogged Filter 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 © Josie Stone Consulting LLC 2011

The Effect of Filtration Studies
Reduction of phlebitis rate 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 DeLuca et al. 1975 146 12 61 3 Evans et al. 1976 49 Y 8 56 4 Maddox et al. 1977 120 20 60 5 Rusho & Blair 1979 150 6 27 Bivins et al. 25 62 7 Allcut et al. 1983 194 31 51 Falchuk et al. 1985 541 57 9 Francombe 1988 29 10 Chee & Oh 1997 200 23 11 Chee & Tan 2002 394 28 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

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) © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Falchuk, Peterson, McNeil (1985) NEJM 312: 78

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 Introduction of a 0.22 micron filter Disintegrating tube Control tube © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Danschutter D. et al. Pediatrics 2007;119; )

Reduction of overall complication rate with the use of in-line intravenous filters in sick newborn infants Results: Overall complication rate in the filter group significantly lower than in the control group without filter (8 vs 21 cases, p<0.05). 14% of filters in the study group contaminated on upstream side 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” © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 RA van Lingen et al. Acta Paediatrica (2004) 93: 658

The Effect of Filtration European Study 2009
Reduction of SIRS rate Josie Stone Consulting LLC 2011 Slide 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 Next INS Guidelines © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Recommendations and Guidelines
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 used1 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Infusion Nursing Standards of Practice – Journal of Infusion Nursing (2011) 34, No 1S: S33-S34

Infusion Nursing An Evidence Based Approach
Focus On Evidence Particulate Matter and Filtration “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 © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011

Clinical Effects of Particles
1. Thrombogenicity Micro- and nano-scale inorganic particles have been isolated from thrombi on 12 out of 14 explanted vena cava filters. These particles are the likely cause for the thrombi1 Birefringent – refracting the light Post-mortem analysis of lung tissue from ARDS patients revealed foreign bodies as the nucleus for thrombi formation. Analyses show glass from ampoules, rubber from stoppers of infusion bottles, and plastic from infusion sets2 2Walpot H et al, Particulate contamination of infusion solutions and drug additives within the scope of long-term intensive therapy. 1. Energy dispersion electron images in the scanning electron microscope-REM/EDX] Anästhesist( 1989 ) 38: © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Gatti A, Montanari S. Retrieval Analysis of Clinical Explanted Vena Cava Filters. Appl. Biomaterial (2006) 77B: 307 –

Appendix 1 Recommendations & Guidelines
American College of Cardiology (ACC) and American Heart Association (AHA) 2008 Guidelines for the Management of Adults with Congenital Heart Disease Therapy of infective endocarditis (IE): … Recognizing that initial therapy is usually parenteral and usually intravenous, one should recall that cyanotic patients with right-to-left shunts have the possibility of “paradoxical” systemic embolization and, as such, risk of stroke. Air retention filters should be used on the line with meticulous attention to avoiding injection of air bubbles. Atrial Septal Defects … Paradoxical embolism from peripheral venous or pelvic vein thromboses, atrial arrhythmias, unfiltered intravenous infusions, or indwelling venous catheters is a risk for all defects regardless of size. … Table 10 Ref. Key Issues to Evaluate and Monitor in Adults With Atrial Septal Defects: Paradoxical embolus; avoid ... ● Unfiltered IV lines ● … © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Circulation (2008) 118; e714 – e833

Appendix 1(cont) Recommendations & Guidelines
American College of Cardiology (ACC) and American Heart Association (AHA) 2008 Guidelines for the Management of Adults with Congenital Heart Disease Recommendations for Medical Therapy of Eisenmenger Physiology “Risk of right-to-left embolization warrants avoidance of bubbles, and consideration of the use of air- eliminating filters on all venous catheters still tends to be advocated, although controversy exists regarding the relative benefit obtained compared with meticulous guarding of all intravenous administration systems. …” © Josie Stone Consulting LLC 2011 Slide content courtesy © Pall Corporation 2011 Circulation (2008) 118; e714 – e833

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