Josie Stone, RN CPNP CRNI © Josie Stone Consulting LLC 2011.

© Josie Stone Consulting LLC 2011

Josie Stone, RN CPNP CRNI

Clinical Update:Risk of Particulate Contamination

In Infusion Therapy


Disclosure

Independent clinical education consultant for PALL Medical.


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.


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


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.


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)


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


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


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


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


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


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


Illustration courtesy of Heart.org.in


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


Drug incompatibility reactions are among the most frequent problems of infusion therapy

Esketamin


Clinical Particle Origin

Incompatibility reactions may be avoided through review of the drug regime with clinical pharmacists and reference to drug incompatibility charts.

Diazepam


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




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



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


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

1,3 µm 5µm10µm

50µm

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Particles larger than

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



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


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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Claforan (A) Cefantral (B) Taxim C)

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


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.


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


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

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


Embolisation

Particles

Micelles

Gas emboli

Thrombogenic

effects

Inflammation



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



Embolisation

Particles

Micelles

Gas emboli

Thrombogenic

effects

Inflammation



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


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 > 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


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


Potential Clinical Outcomes

1. Thrombogenicity, thrombophlebitis

2. Direct embolisation – respiratory distress

3. Inflammation

4. Impairment of micro-circulation and endothelial function



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


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



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.


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


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.


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


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


Particles on a filter membrane

25 µm

17 µm

The Effect of Filtration (cont)


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


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


Falchuk: Thrombophlebitis

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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




Studies on the Effect of Inline Filtration on Thrombophlebitis Rate

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Filter No Filter


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



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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(http://www.clinicaltrials.gov/ct/show/NCT00209768?order=9)

The Effect of FiltrationEuropean Study 2009

Reduction of SIRS rate

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


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


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.”


Focus On EvidenceParticulate Matter and Filtration

Ref: INS Infusion Nursing An Evidence Based Approach, 3rd Edition, Pg 419


QUESTION

S

Josie Stone, RN CPNP CRNI © Josie Stone Consulting LLC 2011.

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