Over the past years and with the progress in medical treatment, infusion therapy has become increasingly complex, particularly in intensive care units. An increasing number of patients are undergoing complex and intense treatment, during which they encounter critical phases of impaired vital function, frequently accompanied by reduced microcirculation in vital organs.
Against this background, the micro-particulate contamination of the bloodstream of patients undergoing infusion therapy is a growing problem, since these particles can also seriously impair the microcirculation.
During intravenous infusion therapy, up to 10 million particles > 2 µm may enter the patient’s blood system every day via infusion solutions.
1,2
Infused particles originate from various sources. During the manufacturing of infusion solutions and infusion systems, particles may be shed from containers, bottles or reservoirs. Most Pharmacopoeias define a threshold limit to which particles are tolerated as “unavoidable contamination caused by manufacturing and transportation”. An additional influx of particles may occur as a result of the handling of infusion systems in clinical practice, e.g. by turning three-way taps or preparing disposable syringes. If no preventive measures are taken, these particles can get infused with the infusion solutions into the patient's circulatory system.

Drug incompatibility reactions are a further and very significant source of particles. These reactions occur when a drug is mixed with one or several other drugs, which have the potential to react with each other chemically or physically. As a consequence, precipitates, crystals, or aggregates may form which then contain the pharmacologically active substance in particle format. Drug incompatibility reactions may not only generate a large number of particles in the infusate but also transform the drug into an inactive form. Therefore, they may not only present a serious risk for extensive particulate contamination of the patient’s infusion solutions, but also have deleterious effects on the patient’s prescribed drug regime. A recently published study showed that drug incompatibility reactions represent one of the most common drug errors in infusion therapy.
3
Drug incompatibility reactions can be predicted and minimized by using the available literature on this subject during the planning process of infusion therapy.
The size of the particles found in standard infusion therapy can vary considerably. Several studies have determined their size distribution.
1,2 It has been shown that most particles are below
5 µm in size. However, the largest particles have been found to reach a size of 100 µm, representing a particular risk to the microcirculation in vital organs.
Larger particles which are sharp-edged or pointed may cause direct trauma to the vascular endothelium upon entering the bloodstream, resulting in inflammation.
Infused particles are recognised as foreign matter by the body’s immune system. This may trigger defense reactions resulting in encapsulation and the formation of a thrombus around the foreign matter.
7 Thrombi formed around a foreign particle may directly block blood vessels in its vicinity or it may dislodge and cause blockage with the corresponding effects on the microcirculation of the affected organs. Particles released from the infusion system have been identified as the likely cause for a series of deep vein thromboses.
9
If particles contaminate the human bloodstream, they can cause various clinically significant negative effects.
Particles which are larger in diameter than the blood vessel into which they are infused can directly embolize the affected blood vessel. This considerably reduces the oxygen and nutrient supply to the tissue surrounding the vessel, which then may progress to tissue ischaemia and can cause further reactions.
Particles have been shown to trigger inflammatory reactions.
10 The mechanical irritation of the endothelium leads to the release of inflammatory mediators, which stimulate local inflammation. In addition, free radicals can form on the complex surface of the particle, triggering oxidative stress on the adjacent cell surfaces.
This, in turn, causes the release of inflammatory mediators in the endothelial cells, leading to local inflammation.
11,12 Whether oxidative stress triggered by particles is involved in the development of atherosclerosis is still a matter of debate.

Lipid emulsions for parenteral nutrition may get destabilized by certain conditions of storage or during application. In destabilized emulsions the size of lipid micelles may exceed 5 µm.
13 If large lipid micelles are infused into the patient's bloodstream, they can cause oxidative stress to the organs of the reticuloendothelial system.
14
Fat emboli may have the same negative effects on he microcirculation of the affected tissue as emboli caused by particles or gas bubbles.
In addition to particles, a large number of gas bubbles may enter the patients’ circulatory system during infusion therapy. These air bubbles can arise from the degassing of infusion solutions, leakages in the system or may be injected inadvertently with drug additions into the system. Once in the patient's bloodstream, air bubbles can lead to air embolism. A local inflammation may result from this with the known negative impact on tissue and organ perfusion.
15
As a result of local inflammation or tissue ischaemia, endothelial cells are deprived of oxygen, which is needed to generate the fuel to drive energy requiring processes in the cell, like the transport of ions across the cell membrane. If the proper function of ionic pumps deteriorates, water can flow into the cells in an uncontrolled manner and cause the cells to swell. Swollen endothelial cells will further reduce the internal diameter of the blood vessels affected and lead to further reduction in local microcirculation. Therefore, tissue which has been stressed by respective insults, reacts far more sensitively to particle contamination than healthy tissue.
16
Particulate contamination of systems and solutions used in infusion therapy may therefore have its most detrimental effects on patients who suffer from pre-existing microcirculatory disorders due to their primary disease, medical treatment or clinical condition (trauma, major surgery, systemic inflammatory reactions, sepsis, burns, heart attack, stroke etc.). In these patients, particles may lead to a further and serious reduction in microcirculation.
16
The above mentioned clinical effects of particles ultimately cause tissue ischaemia, i.e. a reduction in supply of blood to the affected tissue, which is associated with a reduced supply of oxygen and nutrients and an impaired discharge of metabolic end products. A reduction in microcirculation, especially in major organs such as the lungs or liver, is always associated with a reduced organ function and may progress to organ damage, organ failure and multi-organ failure, leading the patient into clinical situations which are associated with an extremely high mortality rate.
Infusion filters (pore size rating 0.2 µm) can be integrated in a point-of-care infusion system and provide effective protection against particles. Several studies have shown that the use of infusion filters considerably reduced complications associated with particles.
17, 18
Infusion filters have an integrated hydrophobic membrane which enables them to remove gas bubbles from infusion solutions, significantly minimizing the risk of gas emboli.
www.pall.com/medical

Lipid filters (pore size 1.2 µm) safely prevent the infusion of oversized lipid droplets, preventing fat emboli and minimizing particle contamination.
Infusion filters with positively charged 0.2 µm membranes retain bacteria and their associated endotoxins. This feature is not highlighted in this presentation, which is focused on the role of particulate contamination.
1. Backhouse et al. (1987): Particulate contaminants of intravenous medications and infusions. J Pharm Pharmacol, 39 : 241 – 245
2. Kirkpatrick (1988): Particulate matter in intravenous fluids the importance for medicine. Krankenhauspharmazie, 9 (12): 487 – 490
3. Taxis and Barber (2004): Incidence and severity of intravenous drug errors in a
German hospital. Eur J Clin Pharmacol, 59 : 815 – 817
4. Puntis et al . (1992): Hazards of parenteral treatment: do particles count? Arch
Dis Child, 67 : 1475 –1477
5. Oie and Kamiya (2005): Particulate and microbial contamination in in-use admixed parenteral nutrition solutions. Biol Pharm Bull, 28 (12) : 2268 – 2270
6. Kuramoto et al. (2006): Usefulness of the final filter of the IV infusion set in intravenous administration of drugs-contamination of injection preparations by insoluble microparticles and its causes. Yakugaku Zasshi, 126 (4) : 289 – 295
7. Gatti et al . (2004): Detection of micro-and nano-sized biocompatible particles in blood. J Mater Sci Mater Med, 15 : 469 –472
8. Walpot et al . (1989): Partikuläre Verunreinigung von Infusionslösungen und
Medikamentenzusätzen im Rahmen einer Langzeit-Intensiv-Therapie, Teil 1 Der
Anaesthesist, 38 : 544 –548
9. Danschutter et al . (2007) Di-(2-ethylhexyl)phthalate and deep venous thrombosis in children: A clinical and experimental analysis. Pediatrics 119: 742 – 753
10. Peters et al . (2004): Effects of nano-scaled particles on endothelial cell function in vitro: studies on viability, proliferation and inflammation.J Mater Sci Mater Med,
15 : 321 – 325
11. Donaldson et al . (2001): Ambient particle inhalation and cardiovascular system: potential mechanisms. Environ Health Perspect, 109 Supp. 4 : 523 –527
12. Stoeger and Schulz (2006) Micro- bzw. Nanopartikel im Blutkreislauf? Journal für
Anästhesie und Intensivbehandlung, 2 / 2006
13. Driscoll et al . (2005): Pathological consequences from the infusion of unstable lipid emulsion admixtures in guinea pigs. Clinical Nutrition, 24: 105 -113
14. Driscoll et al . (2006): Pathological consequences to reticuloendothelial system organs following infusion of unstable all-in-one mixtures in rats. Clinical Nutrition,
25 : 842 - 850
15. Muth and Shank (2000): Gas embolism. N Engl J Med, 342 : 476 – 482
16. Lehr et al . (2002): Particulate matter contamination of intravenous antibiotics aggravates loss of functional capillary density in postischaemic striated muscle.
Am J Respir Crit Care Med, 165 (4) : 514 – 520
17. van Lingen et al . (2004): The use of in-line intravenous filters in sick newborn infants. Acta Paediatr, 93 : 658 – 662
18. Schaefer et al . (2006): Partikel in der Infusionstherapie - das unterschätzte Risiko-
Nierenersatztherapie und HLM? Journal für Anästhesie und Intensivbehandlung,
2 / 2006
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