particulate contamination

Risk Prevention in Infusion Therapy

Particulate Contamination

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CausesSeveral causes of particulate contaminations of IV fluids are known. This is because drugs are available in various containers (for example vials, ampoules, pre-filled containers and premixed solutions) and their usage and manipulations are highly diversified.Consequently, many types of particle contamination can occur (Fig. 2):nGlassnPlasticnRubbernUndissolved particles/drugs

DefinitionParticulate contamination describes the unin-tended presence of extraneous, mobile and undissolved particles in a parenteral solution. These particles can be of various size, defining them as detectable by visual inspection (in general ≥ 50 µm) or as sub-visible with a range of 2-50 µm in size in general. Especially the sub-visible sized particles demand specific analytical tests for their detection (BSP 2009; USP 2009).

Glass ampoules especially pose a high risk of particulate conta-mination, as glass fragments may enter the ampoule when it is opened (Fig. 1) [Douglas et al. 2001].If a needle (for example 18G) is used for removing a glass am-poule’s content, small glass particles can pass through the needle into the syringe and easily be injected into patients. This risk remains if drugs are routinely administered via the injection port of the intravenous cannula, which is a safety measure designed to decrease sharps injuries to the medical staff [Lye 2003].Plastic contamination occurs frequently due to particles from the infusion container’s raw material itself and from the injection port due to its usage with sharp items [Walpot et al. 1989]. The insertion of a needle through the stopper of a medication vial or infusion con-tainer can shear off a small piece of the stopper. This particle may float in the medication or IV solution. If the particle is small or masked (e.g. by the label, a matching background or a colored vial), the contamination may be unnoticed. The particle may then be aspirated into a syringe and injected into a patient [Roth 2007].

Undissolved solids in drugs or parenteral solutions can also be an origin of particulate contamination [Durgan et al. 2004].

A further frequent cause of particles occurs as a consequence of incompatibilities. This is an undesirable reaction between an admixtured drug and the carrier solution, the container or further drugs added to the IV solution itself. Incompatibilities can also be present when various solutions are mixed in infusion lines and catheters for parenteral administration. As one consequence of an incompatibility, precipitations can occur leading to the particulate contamination [Josephson 2006, RCN 2005, Douglas et al. 2001].

The occurrence of contamination was shown by Preston et al. [2004], who identified glass particles bigger than 130 µm in 57 % of the controlled injectable solutions. Additionally, Lye [2003] found in a number of more than 500 glass ampoules an average of 0.22 glass particles per unit. The injection of such particles into the body of the patient is therefore a prominent risk.

DefinitionCauses

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Fig. 1: Glass fragments may enter the ampoule when it is opened.

Size 15 μmFig. 2: Electronmicroscopy of various particles found in samples of IV preparations prior to use.

Size 33 μm Size 36 μm Size 40 μm

Defi nition

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Fig. 3: Overview of parts and organs of the human body mainly a� ected by particulate contamination of IV � uids.

Organsn Brain n Spleenn Eye n Intestinen Lung n Kidneyn Livern Heart

Blood vessels

Consequences

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Symptoms and clinical signsAll types of particles present in the intraluminal compartment which are not eliminated by a fi lter are directly entering the human body (Fig. 3). These particles from plastic, glass or rubber can have unfavorable eff ects, especially in patients who are already ill. Particles as small as 1.5 µm can cause blockages in patients, whereas particles of 6 µm can cause blockages in healthy subjects [Lehr et al. 2002; Anonymous 2004]. Damage to various organs, such as the lungs, kidneys, liver and spleen are described in general [Yorioka et al. 2006, Lye 2003, Puntis et al. 1992, Walpot et al. 1989, Turco et al. 1971], but particularly aff ected are severely ill patients [Jack et al. 2009, Oie et al. 2005, DeLuca et al. 1975, Schroeder et al. 1976, Turco et al. 1971]. Patients with prior organ damage are especially sensitive, as particles can exacerbate their impaired blood micro-circulation [Anonymous 2004, Lehr et al. 2002]. A fur-ther clinical sign that can be caused by glass particles from glass ampoules is phlebitis [Yorioka et al. 2006, DeLuca et al. 1975, Schroeder et al. 1976]. Phlebitis is evident as local warmth, with pain, swelling and reddening at the aff ected site of parenteral ad-ministration [Grünewald et al. 2004].The infusion of glass particles can lead to pulmonary silicotic changes and nodular fi brosis of the liver, spleen and small intestines as a result of foreign body reaction [Lye 2003, Sabon et al. 1989]. Also, glass fragments in drugs have been shown to induce an adult respiratory distress syndrome and pulmonary artery granuloma in immature infants [Yorioka et al. 2006, Puntis et al. 1992, Walpot et al. 1989]. Contamination with silicone particles can lead to granu-lomatous lung disease [Bowen et al. 1981]. Other complications

recorded in association with plastic migration include lung disease [Rodríguez et al. 1989], myocarditis [Kossovsky et al. 1990], and skin rash [Ellenbogen et al. 1975]. These contaminations have been reported after migration of large volumes of plastic. Little is known about the eff ect of silicone in humans over a long period. Animal studies demonstrated minimal reactions in the brain [Dewan et al. 1995a] and lungs [Dewan et al. 1995b; publications ex Dewan et al. 2002]. Rubber complications range from clinically occult pulmo-nary granulomas to local tissue infarction and pulmonary infarc-tion. [Roth 2007, Lehr et al. 2002].

Particles from plastic, glass or rubber can cause phlebitis and also damage the lungs, kidneys, liver and spleen. Apart from harming patients, this may lead to additional treatment costs as well as ex-tended duration of hospital stays.

Prominent risks

nimpairement of microcirculation

nblockages of blood vessel

ndamages of various organs

nphlebitis

Prominent risks

nimpairement of microcirculation

nblockages of blood vessels

ndamage to various organs

nphlebitis

Consequences

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Risk related costs for the healthcare institutionGiven the wide spectrum of patient complications causedby the various particles from plastic, glass and rubber found ascontamination, it has to be assumed that particulate contaminationcan lead or contribute to extended duration of hospital stay as wellas additional treatment costs.A cost evaluation of the risk can be done by assigning costs to their related clinical treatment and resulting extended length of stay. The cost can be calculated using the average daily cost [Gianino 2007, Bertolini 2005] of the expected clinical treatment. Fig. 4 shows the results of such a calculation for selected examples of complications.

Consequences

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ConclusionAccording to the severity of its direct and indirect complications, preventing the entrance of foreign particles into the patients circulatory system can result in signifi cant budget savings for the healthcare provider. In the case of health complications such as severe organ dysfunctions requiring full ICU treatment, a hospital may save up to 56,670 € per single case.

Consequences

Fig. 4: Estimation of possible additional costs as a consequence of complications caused by particulate contamination. In order to facilitate the attribution of each complication to the cost calculation, severity levels were introduced. ARDS: Acute Respiratory Distress Syndrome. RICU: Respiratory Intermediate Care Unit

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Fig. 5: Open ampoule or vial according to standards of care.Use � lter straw for withdrawal of the infusion.

Fig. 6: In-line � lter and infusion set � lter prevent the infusion of particles into the patient.

Preventivestrategies

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Preventive strategiesThe strategy to prevent particle contamination at the point of origin is based on many aspects, such as using quality products to avoid the generation of particles (e.g. stopper of vials) or using products with a low intrinsic particle load (e.g. plastic containers instead of glass ampoules). Another important factor is the avoidance of drug incompatibilities.

If a particulate contamination has occurred, the usage of in-line fi l-ters provides an important safety benefi t. In addition, fi lters function as an early warning system, providing optical control of the infusate and stopping the infusion when the fi lter becomes gets obstructed [Kuramoto et al. 2006, Anonymous 2004].

Particle contamination may be reduced by using an in-line fi lter and fi lter needle to withdraw drugs from glass ampoules prior to administration [Panknin 2007, Heiss-Harris et al. 2004, Preston 2004, Lye 2003]. The in-line fi lter devices can remove particulate contamination, micro-biological contamination and air from infusion solutions (not all devices used can remove all three types of conta-mination).It is, however, not standard practice to perform fi ltration [Jack et al. 2009, Ball 2003]. Filters in the intravenous line may be positioned close to the patient access. Dispensing pins (spikes) also provide protection against particles in solution [Ohgke et al. 1997].

In-line fi lters are recommended for:nNon lipid-containing solutions (0.2 µm fi lter) [Ball 2003, Lehr et al. 2002, Bethune et al. 2001] nLipid infusions or total nutrient preparations (1.2 µm fi lter) [Ball 2003, Bethune et al. 2001]

The ISO 8536-4 norm (for infusion sets) recommends fi ltration forpatient protection. Generally, the fl uid fi lter used has a nominal pore size of 15 μm [ISO 8536-4].

Preventive strategies

navoid glass ampoules

nuse fi lter straws or fi lter needles

nincorporate appropriate fi lters into IV administrations

Preventivestrategies

The British Pharmaceutical Nutrition Group (BPNG) has issued a guideline about how to avoid contaminating the body with insoluble particles [Ball 2003, Bethune et al. 2001]:

nSolutions being added to parenteral nutrition taken from glass ampoules or vials should be added to the fi nal parenteral nutrition admixture through a fi lter with a maximum pore size of 5 µm. Filter needles and dispensing pins (spikes) with particle fi lter minimize the risk of injecting glass particles into patients (Fig. 5).n Appropriate fi lters should be used during the administration of parenteral nutrition to patients who require intensive or prolonged parenteral therapy, namely immunocompromised patients, neonates and children, and patients receiving home parenteral nutrition.nWhen used, in-line fi lters should be placed as close to the patient as possible (Fig. 6).nThe 1.2 µm fi lters should be used for the admini stration of solutions containing lipids, including all-in-one admixtures, and changed every 24 hours.

Several associations and offi cial bodies recommend the incorporationof a fi lter in the intravenous line: - British Pharmaceutical Nutrition Group (BPNG) - Royal College of Nursing [RCN 2005] - National Coordinating Committee on Large Volume

Parenterals (NCCLVP) - Intravenous Nurses Society (INS) - Food and Drug Administration (FDA)

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Ecoflac® plus The state of the art IV solution container that off ers safe and convenient application of all IV procedures from drug admixture to drug delivery.n The superior properties of the resealable port membrane prevent coring of elastomeric particles when punctured with a needle or an infusion set.

Intrafi x® SafeSetIV set for safe and convenient infusions.nA 15 μm particle fi lter prevents the infusion of particles. nUsing 15 μm particle fi lter in IV sets is recommended in the international standards for infusion sets for single use in ISO 8536-4 (gravity) and in ISO 8536-8 (infusion equipment for use with pressure infusion apparatus).

Intrapur® and Sterifix® Infusion FiltersA whole range of fi lters for safe infusion therapy.nMembranes of 0.2 µm and 1.2 µm separate particles and lipid macro micelles larger than the pore size of the fi lter.

Safefl ow / Ultrasite®Capless valves for safe and convenient access to the infusion line.nB. Braun’s needle-free infusion systems reduce the risk of particulate contamination by preventing coring of membranes.

cross-section

Riskprevention

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Sterifi x® fi lter strawsFilter straws for particle free withdrawal and fi ltration of fl uids from ampoules.n A 5 µm fi lter prevents the administration of glass particles, which can occur when ampoules are opened. The fi lter is already integrated in the hub of the straw.

Mini-Spike®Vented dispensing pins for safe and convenient fl uid transfer with syringes.n Particles such as undissolved lyophilisates in the fl uid are retained due to the inbuilt 5 µm fi lter.

Mini-Plasco® connect / Mini-Plasco®The plastic ampoule off ers small volumes of IV solution for drug preparations.nLow intrinsic particle load as Mini-Plasco® plastic material does not produce such particles.nCan easily be opened without particle creation.

Risk

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LiteratureAnonymous. Risks due to particles in infusion therapy – experts promote use of infusion filters (Transl.: Gefahren durch Partikel in der Infusionstherapie – Experten fordern Einsatz von Infusions-filtern). Krankenpfl J 2004; 42(3-4): 97

Ball PA. Intravenous in-line filters: filtering the evidence. Curr Opin Clin Nutr Metab Care 2003; 6(3): 319-25

Bertolini G, Confalonieri M, Rossi G, Rossi, Simini B, Gorini M and Corrado A. Costs of the COPD. Differences between intensive care unit and respiratory intermediate care unit. Respiratory Medicine 2005; 99: 894–900

Bethune K, Allwood M, Grainger C, Wormleighton C. British Phar-maceutical Nutrition Group Working Party. Use of filters during the preparation and administration of parenteral nutrition: position paper and guidelines prepared by a British pharmaceutical nutrition group working party. Nutrition 2001; 17(5): 403-8

Bowen JH, Woodard BH, Barton TK, Ingram P and Shelburne JD. Infantile pulmonary hypertension associated with foreign body vasculitis. Am J Clin Pathol 1981; 75(4): 609-14

BSP: British Pharmacopoeia, 2009

Carbone-Traber KB and Shanks CA. Glass Particle Contamination in Single-Dose Ampules. Anesth Analg 1986; 65: 1361-3 DeLuca PP, Rapp RP, Bivins B, McKean HE and Griffen WO. Filtrati-on and infusion phlebitis: a double-blind prospective clinical study. Am J Hosp Pharm 1975; 32(10): 1001-7

Dewan PA, Ehall H, Edwards GA, Middleton DJ, Terlet J. Plastic particle migration during intravenous infusion assisted by a peristal-tic finger pump in an animal model. Pediatr Surg Int 2002; 18(5-6): 310-4

Dewan PA, Owen AJ, Byard RW. Histological response to injected Poly-tef and Bioplastique in the sheep brain. Br J Urol 1995a; 75(5): 666-9

Dewan PA, Stefanek W, Byard RW. Long-term response to intrave-nously injected Teflon and Silicone in a rat model. Pediatric Surgery International 1995b; 10(2,3): 129-133 Douglas JB, Hedrick C. Pharmacology. In: Perucca R. Infusion therapyequipment: types of infusion therapy equipment. In: Infusion therapy in clinical practise. Philadelphia: Saunders 2001; 176-208 Durgin JM, Hanan ZI. Thomson Delmar Learning's Pharmacy Practice for Technicians 2004; 227

Ellenbogen R, Rubin L. Injectable fluid silicone therapy. Human morbidity and mortality. JAMA 1975; 234(3): 308-9

Gianino MM, Vallino A, Minniti D, Abbona F, Mineccia C, Silvaplana P and Zotti CM. A method to determine hospital costs associated with nosocomial infections (transl). Ann Ig 2007; 19(4): 381-92

Grünewald M, Kobbert E, Terodde H. Pflege von Patienten mit Erkrankungen des Herz-Kreislauf- und Gefäßsystems. In: Kellnhauser E, Schewior-Popp, et al. Thiemes Pflege. Stuttgart, New York: Thieme 2004; 316-317 Heiss-Harris GM, Verklan MT. Maximizing patient safety: filter needle use with glass ampules. J Perinat Neonatal Nurs 2005; 19(1): 74-81 ISO 8536-4: 2004. Infusion equipment for medical use – Part 4: Infusion sets for single use, gravity feed

Jack T, Boehne M, et al. In-line filtration reduces the incidence of SIRS in critically ill children. Poster presentation, ISICEM 2009

Josephson DL. Risks, complications, and adverse reactions associated with intravenous infusion therapy. In: Josephson DL. Intravenous infusion therapy for medical assistants. The American association of Medical Assistants. Clifton Park: Thomson Delmar Learning 2006; 56-82


Literature

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Kossovsky N, Cole P, Zackson DA. Giant cell myocarditis associated with silicone. An unusual case of biomaterials pathology discovered at autopsy using X-ray energy spectroscopic techniques. Am J Clin Pathol 1990; 93(1): 148-52

Kuramoto K, Shoji T, Nakagawa Y. Usefulness of the fi nal fi lter of the IV infusion set in intravenous administration of drugs - conta-mination of injection preparations by insoluble microparticles and its causes. Yakugaku Zasshi 2006; 126(4): 289-95

Lehr HA, Brunner J, Rangoonwala R and Kirkpatrick CJ. Particulate matter contamination of intravenous antibiotics aggravates loss of functional capillary density in postischemic striated muscle. Am J Respir Crit Care Med 2002; 165(4): 514-20

Lye ST, Hwang NC. Glass particle contamination: is it here to stay? Anaesthesia 2003; 58(1): 93-4

Ohgke H, Krauß R. Senkung des Kontaminationsrisikos bei der Entnahme von Medikamenten aus Mehrdosisbehältern. Die Schwester Der Pfl eger 1997

Oie S, Kamiya A. Particulate and microbial contamination in in-use admixed parenteral nutrition solutions. Biol Pharm Bull 2005; 28(12): 2268-70

Panknin HT. Particle release from infusion equipment: etiology of acute venous thromboses. Kinderkrankenschwester 2007; 26(10): 407-8

Preston ST, Hegadoren K. Glass contamination in parenterally administered medication. J Adv Nurs 2004; 48(3): 266-70

Puntis JW, Wilkins KM, Ball PA, Rushton DI and Booth IW. Hazards of parenteral treatment: do particles count? Arch Dis Child 1992; 67(12): 1475-7

RCN. Royal College of Nursing. Standards for infusion therapy. 2005

Rodríguez MA, Martínez MC, Lopez-Artiguez M, Lusia M, Bernier F. and Repetton M. Lung embolism with liquid silicone. J Forensic Sci 1989; 34(2): 504-10

Roth JV. How to enter a medication vial without coring. Anesth Analg 2007; 104(6): 1615

Sabon RL Jr, Cheng EY, Stommel KA and Hennen C. Glass particle contamination: infl uence of aspiration methods and ampule types. Anesthesiology 1989; 70(5): 859-62

Schroeder HG, DeLuca PP. Particulate matter assessment of aclinicalinvestigation on fi ltration and infusion phlebitis. Am J Hosp Pharm 1976; 33(6): 543-6

Turco SJ, Davis NM. Detrimental eff ects of particulate matter on thepulmonary circulation. JAMA 1971; 217(1): 81-2 Walpot H, Franke RP, Burchard WG, Agternkamp C, Müller FG, Mittermayer C, Kalff G. The fi lter eff ectiveness of common 15-micron fi lters (DIN 58362). II: Scanning electron microscopy and roentgen analysis. Infusionstherapie 1989; 16(3): 133-9

Yorioka K, Oie S, Oomaki M, Imamura A and Kamiya A. Particulate and microbial contamination in in-use admixed intravenous infusi-ons. Biol Pharm Bull 2006; 29(11): 2321-3


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Notes

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Notes

Nr. 6069091 Edition: 03/2011

B. Braun Melsungen AG | Hospital Care | 34209 Melsungen | GermanyTel. +49 5661 71-0 | www.bbraun.com | www.safeinfusiontherapy.com

The summarized scientifi c information in this document has been prepared for healthcare professionals. It is based on an analysis of public literature and guidelines. The intention is to give an introduction to the risks commonly associated with infusion therapy and to increase the awareness of healthcare workers to these kinds of problems. Due to its summary nature, this text is limited to an overview and does not take into account all types of local conditions. B. Braun does not assume responsibility for any consequences that may result from therapeutical interventions based on this overview.

particulate contamination

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