One of the fundamental principles guiding the pharmaceutical quality of parenteral products is to prevent injecting contaminants from microbiological, chemical or physical sources. It is just as difficult to ensure the absence of chemical and particulate contaminants in injectable products as it is to weigh up the microbiological risk. The problem of particulate matter is mainly related to the preparing and administrating of injectable drugs rather than through the contamination of marketed products. Particulate contamination also arises in situ during the simultaneous intravenous (IV) infusion of incompatible drugs. A complete overview of these problems in the context of IV infusion was carried out to assess their clinical impact. Many studies had already been performed on this theme, but the majority date from the 1970s and 1980s. Clinicians have expressed a renewed interest since the early 2000s, focusing on the impact of particles on patients.
The quality required for injectable preparations is based on the non-administration of contaminants whether biological, chemical or physical. Particulate matter in injections can be a serious health problem with potentially severe consequences for patients, especially if particles are infused in a precipitate. Such consequences may include CVC obstruction, occurrence of potentially fatal embolism , deposits of calcium phosphate crystals in various organs during total parenteral nutrition  or systemic inflammatory response syndromes (SIRS) . The United States Pharmacopoeia (USP) defines injectable drug particulate matter as “foreign particles, undissolved, mobile, other than gas bubbles, which are involuntary in these solutions (parenteral formulations)” . The European Pharmacopeia (EP) has a corresponding chapter on particulate contamination . There are two tests to determine particulate matter in preparations : (1) the light obscuration particle count test and (2) the microscopic particle count test. These two procedures test count the particles that are larger than 10 and 25 µm with limits according to the particle size and the volume of the preparation (Table 1).
|Nominal content||Maximum number of particles ≥ 10 µm||Maximum number of particles ≥ 25 µm|
|More than 100 mL*||25 per mL||3 per mL|
|Less than 100 mL||6 000 per container||600 per container|
It is just as difficult to assess the risk of microbiological contamination in injectable products as it is to ensure the absence of particulate contamination in these same products . Contamination of fluids with bacteria, endotoxins and/or particles has been observed with intravenous (IV) infusion therapy. It is difficult to control particulate contamination during drug infusion, especially when several different drugs are administered simultaneously. Particulate contamination of IV fluids can result from drug incompatibilities, especially frequent in intensive care unit (ICU) patients who may receive numerous drugs simultaneously through a limited number of venous access sites. When many IV therapies have to be administered through the same central venous catheter, the risk of drug incompatibilities and thus particle formation increases.
The aim of our review is to define the sources of particulate matter infused to the patient and their clinical consequences.
Causes of particulate contamination of IV fluids
There are several causes of particulate contamination of IV fluids. There are two types of injectable drug particulate matter according to its source : 1) intrinsic particles, defined as those initially associated with the solution which have not been eliminated either by filtration or by precipitation from the solution, and 2) extrinsic particles, defined as those that contaminate the container or solution during manufacture or preparation of drug solutions. Some of these have been described , including, for example, fibres, dust, rubber or silicone and have been known for some years, which explains the limited use of glass ampoules today in favour of plastic bottles or pods to ensure patient safety .
Particles from glass containers
Traditionally, glass was the most widely used container for the primary packaging of parenteral products because it is relatively inert, non-porous, impermeable to gas and moisture, transparent, resistant, rigid, easy to reclose and economical. Pharmacopeias describe the glass to be used for pharmaceutical containers [13, 14] as its composition is varied. “It is either borosilicate glass or soda-lime-silica glass. Borosilicate glass contains significant amounts of boric oxide, aluminum oxide, and alkali and/or alkaline earth oxides and has high hydrolytic resistance and high thermal shock resistance due to its chemical composition; it is classified as type I glass. Soda-lime-silica glass is a silica glass containing alkaline metal oxides (mainly sodium oxide) and alkaline earth oxides (mainly calcium oxide). It has moderate hydrolytic resistance due to its chemical composition; it is classified as type III glass. Suitable treatment of the inner surface of type III soda-lime-silica glass containers will raise hydrolytic resistance from a moderate to a high level, changing the classification of the glass to type II”. Type I glass containers are reusable unlike Type II.
However, despite the neutral property of glass, interactions between the packaging components and the formulation ingredients are possible with the release of glass particles. The presence of such particles in primary containers for pharmaceutical liquids has concerned health authorities in recent years due to claims leading to product recalls. Manufacturers must ensure the absence of any contaminants such as glass fragments to respect the rules of Good Manufacturing Practices (GMPs) to obtain quality products . A working group was set up at the French medical drug agency (ANSM) between December 2006 and September 2007 in partnership with pharmaceutical manufacturers to identify preventive measures which all manufacturers must apply to avoid the introduction or generation of glass particles and to detect their possible presence .
Glass ampoules are a high-risk source of particulate contamination. Glass fragments can be introduced into the ampoule when it is opened by the operator . If a needle (for example 18G) is used to withdraw the contents, small glass particles can pass through the needle into the syringe and easily be administered to patients. This risk remains if drugs are administered via the injection port of the IV cannula which is a safety measure to limit sharp injuries to the medical staff .
An attempt has been made to optimise the opening of glass ampoules: in partnership with an industrialist, Lee et al.  developed a vacuum machine to reduce glass particulate contamination when glass ampoules are opened. Sabon et al.  showed that various types of aspirating techniques and ampoules have no effect on glass particle contamination. Other studies demonstrated the effectiveness of filter needles and in-line filters to reduce glass particle contamination [21, 22]. Preston et al.  recovered glass particles larger than 130 µm in size in 57 % of controlled injectable solutions. Additionally, Lye et al.  identified an average of 0.22 glass particles per unit in more than 500 glass ampoules analyzed. The injection of these particles into the patient is therefore a major risk. Preston et al.  therefore recommended the use of filtered needles when administering injectable drugs to patients.
Pre-filled syringes have increasingly been used instead of glass vials and ampoules in recent years . Yorioka et al.  showed that pre-filled syringes helped to decrease glass particles in IV admixtures. The number of particles in the residual IV solution was significantly higher for fluids prepared from drugs packaged in glass ampoules than for those obtained by mixing drugs in pre-filled syringes. Nevertheless, microscopic observation of the residual IV admixture solutions in glass ampoules revealed glass fragments.
Particles from plastic containers
Plastic contamination frequently occurs due to particles from the plastic infusion container or from the use of sharp items through the injection port . The insertion of a needle through the septum or stopper of a medication vial or infusion container may detach a small fragment from the septum or stopper. This particle may float in the IV solution. If it is small or masked (e. g. by the label or a coloured vial), contamination may go undetected. The particle may then be aspirated into a syringe and injected into the patient .
Infusion containers must be manufactured to prevent contamination from particles . For empty containers, the requirements are the following: the number of particles having a diameter ≥ 10 µm per mL of nominal container capacity of the container should not be > 25 and the number of particles with a diameter ≥ 25 µm per mL of nominal container capacity of the container should not be > 3. Ready-to-use parenteral solutions in infusion containers must meet the requirements of the pharmacopoeia specifying the particle content of finished products (Table 1). A study revealed that handling and storage influenced the initial amount of particles found in the plastic bags . Several materials are used for different types of containers, such as polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate (EVA), combined or not. The relative merits of each, especially in terms of particulate contamination, are discussed by Petrick et al. .
Non-electrically driven portable infusion devices include a particulate matter filter on the fluid path of the solution . Filter pore-size of ≤ 15 µm does not retain the smaller particles. Two commonly-used elastomers (silicone and polyisoprene) in diffusers present different mechanical characteristics which have an impact on infusion flow rate . However, there is no data concerning their impact on the presence of particulate matter in IV solutions or on the effectiveness of elastomeric diffuser filters on particulate contamination.
Particles from infusion sets
Particles in medical devices used in infusion sets (e. g. tubings or catheters) may cause problems for the health of patients who can be exposed to a risk of contamination by a release of particles from the devices themselves during infusion. Mastering particulate contamination in the manufacture of devices is a major concern for all manufacturers if they are to ensure the safe use of their devices, and more especially as standards stipulate virtually no particulate contamination. The FDA has established acceptance criteria of a minimum of 90 % recovery for 10–25 µm particles and a minimum of 80 % recovery for ≥ 25-µm particles . Pavanetto et al.  analysed the level of particulate contamination of different tubings for infusion and hemodialysis. To do so, they injected particle-free water into the tubes and particle contamination was measured at different sampling times. Particle-free water was passed through filters of different porosity (0.8 µm, 0.45 µm and 0.22 µm). An initial particle contamination of the devices was observed, but which had an only limited impact on the particulate contamination of the drug solutions infused. However, the authors recommended vigilance, through visual inspection, especially when flushing devices. Indeed, particles larger than 50 µm could thus be detected.
Some manufacturers are setting their own acceptance limits or using the limits specified in USP 788, « Particulate Matter in Injections ». However, USP 788 is specific for injections and parenteral infusions and may not always be appropriate for medical devices but manufacturers may use the acceptance criteria specified therein as a general guide . The standards for infusion devices include thresholds for particle contamination. Infusion devices must therefore be manufactured under conditions reducing this contamination, for example the standard ISO 8536-4: 2010 standard. ‘Infusion equipment for medical use – Part 4: Infusion sets for single use, gravity fed’ defines a method to determine an index for particulate contamination for gravity administration sets.
Particulate contamination of IV solutions arises from incomplete reconstitution of drugs, drug incompatibility reactions during IV therapy, or components of the infusion systems [35, 36]. Analysis of samples from the terminal connection of infusion tubings identified plastic particles .
Lubricant (silicone oil) in pre-filled glass syringes can cause an aggregation of proteins and therefore generate particles . The reconstitution of L-Asparaginase in siliconised syringes induces protein aggregation . Various technologies may be used to measure particle numbers in protein formulation but they are inadequate to characterise particles in a variety of protein solutions . The siliconisation process may have an impact on the generation of particles in protein formulations in pre-filled syringes . The addition of surfactants at certain concentrations to antibody formulations reduces particle formation in pre-filled glass syringes .
Undissolved solids in drug solutions
Undissolved solids in drug solutions are another source of particulate contamination.
In a neonatal ICU, a piece of research work demonstrated that the dosing variability of vancomycin syringes was mainly due to the solvent used to reconstitute the powder and the non-systematic practice of stirring for complete dissolution of the powder . Reconstitution of IV medications by a centralized intravenous admixture service (CIVAS) ensures the microbiological quality and chemical stability of ready-to-use injectable drugs and thus contributes to the quality and efficient management of the patient in hospital [44, 45].
Therapeutic protein products may also contain particulates that are inherent to the product. These inherent “proteinaceous” particulates are generally different from traditional “foreign” particles and are more difficult to detect and count . The need to monitor all (foreign as well as inherent) particulates in therapeutic protein products has led to the developing of measurement techniques . A flow cytometer equipped with forward- and side-scattering as well as fluorescent detectors, is able to determine the number of subvisible particles in monoclonal antibody formulations . Moreover, industry case studies have illustrated how strategies for subvisible particle analysis are being developed to assess the nature and amount of particulate matter for better drug product development or stability studies .
Drug incompatibilities: a problem in clinical practice
A further frequent cause of particles is drug incompatibility. Drug incompatibilities are chemical and physical reactions between drugs and/or with the carrier fluid during their IV administration through the same venous access. Drug physico-chemical incompatibilities can lead to precipitate formation, responsible for particulate contamination of the infusion [50–52].
Such drug incompatibilities can potentially harm the effectiveness and safety of drugs administered during IV therapy, especially in ICUs where several drugs may be simultaneously infused through the same catheter, contributing to an increase in the the risk of drug incompatibilities. The mechanisms of drug incompatibility were well described by Newton , who drew a distinction between physical and chemical reactions. Physical incompatibilities include visible (precipitation, turbidity or color change) and subvisible (pH change, subvisible particles, decrease in drug concentration) reactions. Special care should be given to subvisible incompatibilities, whih can lead to a significant decrease in drug amount administered to the patient. Chemical drug incompatibilities are often subvisible reactions, leading to redox, complexation or racemization reactions. This kind of drug incompatibility may reduce the effectiveness of the drug administered, or create toxicity. In general, medications with different pH (high risk of precipitation) should not be administered through the same port of a venous access device. Knowledge of healthcare professionals is limited in this field. Tissot et al.  detected 14.4 % of nursing errors related to drug incompatibilities in an adult ICU and Gikic et al.  3.4 % in a paediatric ICU. Serious consequences have been described due to drug incompatibility, such as obstruction of catheter, therapeutic failure, or the occurrence of embolism [56, 57] of fatalities [58, 59].
A number of practical measures can reduce the risks. Contact time between incompatible drugs can be limited by using multilumen catheters . Some hospitals have implemented strategies to avoid mixing incompatible drugs. For example, in Switzerland, a colour coding system according to drug pH was adopted over five years, resulting in a reduction in incompatibilities between acid and alkaline drugs . Double-entry tables, or lists of drugs commonly used, can be drawn up . Although a number of publications and databases deal with the subject [63–65], discrepancies exist among available references, data is often non-existent or incomplete, and usually describe only one mixture. In-line filters can also be an effective solution for blocking particles generated by a drug-drug incompatibility and potentially administered to the patients, especially in neonatal and paediatric care. Two types of filter porosity can be distinguished: 0.22 µm and 1.2 µm in-line filters for aqueous drug solutions and lipid mulsions, respectively. When using filters during drug infusion, drug particles are captured by the filter membrane and can be analysed by electronic microscopy. In the study by Jack et al. , microscopic analysis showed particles of approximatively 40 × 20 µm in size. In another study performed by Foinard et al. , particles trapped by the filter membrane were also analysed, with a particle size of about 30 × 30 µm. These authors also showed that particulate contamination could be present downstream from the in-line filter, with particles greater than 10 µm. Nevertheless, the benefits of these filters have been challenged by several authors [3, 67, 68]. A meta-analysis did not provide specific justification for using in-line IV filters to prevent morbidity and mortality  and there may be a problem in clinical practices due to the ineffectiveness of the therapeutic management. Indeed, filters are characterised by the presence of different types of membranes used (polycarbonate, polytetrafluoroethylene (PTFE), or cellulose) and in health care they usually contain Posidyne® (Nylon 6.6) or Supor® (polyethersulfone (PES)) membranes, whose electrical charge may have an effect on drug retention. Gasch et al.  showed that a positively charged PES membrane filter could increase the retention of several drugs, especially when infusing no-ionic drugs (i. e. furosemide and potassium canrenoate). Several active drugs, such as antibiotic (gentamicin) and anticancer drugs (dactinomycin, vincristine) can be retained and are therefore not administered to the patient . The use of IV filters, when infusing proteinaceous drugs, has increasingly become a major, particularly because of the lack of data available in the scientific literature .
Elements determining particulate risk
Particles administered to patients through IV infusion may lead to complications, as well as an increased risk of venous thromboembolism. Rare cases of fatal pulmonary embolism have even been reported. The age-profile of patients is important and young patients especially seem to be at risk .
Postnatal development provides a partial explanation for risk differences between adult and paediatric populations. These populations do not have the same cardiovascular characteristics : although the pulmonary capillary diameter of neonates is the same as that of adults, the number and diameter of blood vessels are smaller in infants. This physiological condition could contribute to the more drastic effect of injecting particulate matter into paediatric patients .
The neonate population is particularly at risk, especially in neonate ICUs, not only because of their age but also because of therapeutic management. This concerns mainly the simultaneous administration of injectable drugs. Very low volumes of liquids given to this type of patient may lead to the incomplete dissolution of injectable drugs and increase the risk of drug-drug incompatibilities.
Route of administration
Adverse reactions can take place depending on the administration route of particles.
The IV administration route is the main entry point for particles into the bloodstream. Particles diffuse to the lungs through the venous system because of the increasing size of veins. Jack et al.  showed that most particles have mean sizes within the range of 5 to 50 µm resulting in considerable particulate retention in the pulmonary capillaries of particles ranging from 5–10 µm in diameter. All particles smaller than the diameter of pulmonary capillaries pass through the lungs and diffuse into the different organs, including the liver and spleen, where particles can be phagocytised by the reticuloendothelial system.
The cardiovascular system is usually considered to be one of the major routes affected by particulate contamination and is associated with a high level of morbidity and mortality. Indeed, blood circulation is linked to the respiratory route; inhaled fine particles (<100 nm) migrate from lungs into the bloodstream and are therefore distributed to all organs. Many studies have investigated the impact of these inhaled particles on the body. Takenaka et al.  exposed rats to 50 µg fine silver particles through intratracheal instillation for a few hours. They showed concentrations of particulate in the lungs, blood circulation and many organs (liver, spleen, heart and brain). After inhalation, particles accumulate in the different organs, especially in the liver [75–77]. In a study conducted on healthy mice, Khandoga et al.  reported that ultrafine carbon particles, when translocated after inhalation, went through the microcirculation of extrapulmonary organs, leading especially to platelet accumulation in the hepatic microvasculature. This accumulation was associated with prothrombotic complications.
Other routes of administration used during epidural and spinal anesthesia, or the intraocular route may also constitute potential sources of particulate contamination, because of direct delivery of particles to specific areas of the body. However there is a low risk of systemic reaction via the intrathecal, epidural and intraocular routes due to the negligible risk of particulate migration from these injection sites. The risk of injecting particles via these routes should nevertheless be anticipated during drug development .
Number and characteristics
Every day millions of particles may be infused into patients during hospitalisation, especially in ICUs and are likely to worsen pathogenetic effects in vulnerable patients. Most particles range from 1 to > 100 µm in size (even up to > 500 µm), with the majority at around 2 µm . The present authors opted for a detection limit of 1 µm suggesting that particulate contamination has so far been underestimated. Particles may also come from the particulate contamination of medical devices used during drug infusions. This is in addition to the initial particulate matter specific to all drug preparations. However, some studies have shown that particulate contamination from infusion sets and drug preparations is relatively low compared with the number of particles contained in parenteral solutions, implying that other explanations have to be found [79, 80]. Different methods for evaluating the particle load administered to patients during IV infusion have been applied. Most studies have controlled it through the presence of in-line filters in infusion sets, leading to an imprecise estimation of the number of particles administered to paediatric and adult patients [66, 81]. A visual examination method based on the Tyndall effect has recently been assessed , but the authors concluded that an evaluation of drug compatibility and parenteral nutrition could not be obtained only through the visual detection of particles. Recently, Perez et al.  directly analysed overall particulate contamination exposure during IV therapy in children by connecting the infusion sets to a dynamic analyser system which showed that patients may receive up to millions of particles per day.
As already stated, sources of particulate contamination and the nature of particles are numerous. The main sources of contaminants include glass, which can be intrinsic or extrinsic. Clinical consequences attributed to glass particles are many and varied, including peripheral (phlebitis) and systemic (pulmonary granulomas, SIRS) effects . Despite the fact that glass containers offer excellent properties in terms of chemical and thermal resistance, a high softening point and large-size particle-forming tendency, studies suggest that glass particles may be found in infusions and lead to clinical damage after several years [18, 25].
Other secondary sources are silicone particles which could be shed from the silicone tubing used to fill containers  or could migrate directly from infusion sets into infusion solutions . Environmental exposure to silicone and/or the pH of some infused drugs (alkaline drugs) can account for silicone plastic particles found in animals. Plastic particle migration during IV infusion is linked to infantile pulmonary hypertension . Other particulate contaminants, such as metallic particles, can be found during IV infusion, e. g. aluminum particles detected in premature babies during total parenteral nutrition resulted in death [86, 87]. Indeed, many commonly used IV solutions, especially parenteral nutrition solutions, may be contaminated by traces of aluminum, leading to a high risk of aluminum intoxication in exposed infants. Traces of lead and chromium are other forms of metal contamination [88, 89].
It is difficult to show a clear link between the electrical charge of particles and clinical impact because no studies have been conducted to date on patients. Only Wilkins et al.  studied the relationship between the electric properties of particles and their blood clearance and organ distribution in animals. Polystyrene latex was injected into rats. The surface charge of these particles was modified by the adsorption of macromolecules to obtain negatively- (i. e. gum arabic) and positively- (i. e. gelatin) charged particles. The authors showed that 99 % of all injected particles were cleared from the blood 15 minutes after injection with a considerable uptake by the lungs, particularly of positive colloids. These led to a decrease in hepatic uptake and a later accumulation in the spleen. The liver largely took up negatively- charged colloids and their distribution was maintained. This study showed that the surface charge of particles plays a major role in terms of interactions with the reticuloendothelial system.
Size and shape
Particle size and shape are two factors to consider as they may have effects on particle positioning in the human body, and the consequences of this. In this assessment, spherical particles are used as a model, which is a major limit to all studies. These particles do not adequately reflect real conditions of particulate contamination during infusion because most particles are fibrous.
An initial work was conducted by Kanke et al. . Radiolabelled spherical particles with a mean diameter of between 3 and 12 µm were injected into dogs. The study demonstrated that the distribution of particles was size-dependent with larger particles rapidly clearing from the bloodstream (i. e. 12 µm spheres) but being retained in the lungs, while smaller ones were retained in the liver and spleen.
Ilium et al.  investigated the effects of particle size, shape and nature on blood clearance and organ positioning by injecting spherical particles into animals. Two kinds of particles were used: small (1.27 µm diameter) and large (15.80 µm diameter) polystyrene microspheres and cellulose particles (from 5 to 30 µm). A total of 106 radiolabelled particles were injected via the ear vein of rabbits. The technique of gamma scintigraphy was used to investigate the particulate distribution in dynamic and static modes. It was shown that small microspheres circulated through the lungs but were taken up by the liver, whereas the larger particles were trapped in the lungs, whatever their nature. The shape of particles is very important: fibres were entrapped in the lungs, but also in other organs. Pulmonary vessels were obstructed by larger fibres, leading to the death of several rabbits.
In conclusion, this preclinical data performed with animal models shows that all particle characteristics (size, shape) are important, especially when assessing the overall particulate matter potentially administered during IV injections. Relevance to human is not totally reliable as comparison is difficult, especially with paediatric patients. However, some clinical studies have demonstrated that drug particulates could be responsible for fatal cases in neonates, due to the presence of precipitates in the lungs .
Clinical effects of particulate matter in IV fluids
Physico-chemical drug incompatibilities can lead to the IV administration of particles to patients, with potentially serious clinical consequences. Clinicians often misunderstand this aspect.
Peripheral clinical effects
The effects of the IV administration of particles were studied in a prospective and double- blind investigation, where particles were found to be responsible for phlebitis. In blood circulation, particles diffuse through the vascular endothelium and can result in blood clots. Peripheral IV administration is commonly associated with the occurrence of phlebitis and poses a 70 % risk for longer-term infusions . This relationship has been indirectly evaluated in several outdated studies by comparing patient groups with and without in-line filters [93–97].
Studies on this subject are discordant. In a prospective double-blind study, Maddox et al.  analysed the effect of IV particles on post-infusion phlebitis (PIP). 195 men were randomised in two groups: a filter was present in the infusion set for the experimental group versus no filter for the control group. In both groups, IV fluids and medications were administered at 40 mL/h. There were no significant differences as to the incidence of PIP from one group to the other. Despite the unwarranted reduction in the incidence of PIP, this study reveals that the presence of IV filters prevented the infusion of microorganisms. Falchuk et al.  implemented a prospective study on the impact of particles on the occurrence of phlebitis during a 3-day IV infusion on 541 patients. Patients were randomised into two groups (with 0.22 µm in-line filters versus without filters). In the filter group, there was a 66 % decrease in the occurrence of phlebitis. A systematic review of randomized controlled trials assessed the effects of particulate matter on infusion-related phlebitis by using in-line filters in peripheral IV catheters. The authors indicated that the risk of phlebitis was reduced through the use of in-line filters but the outcome remained uncertain because of the methodological weakness of the studies. Their conclusion was that in-line filters could not be recommended routinely in clinical practice with peripheral IV catheters.
Systemic clinical effects
During IV infusion, the administration of drug particles may cause inflammatory response, with the formation of granuloma. Studies have shown that foreign objects such as talc or cotton fibre could be injected into patients and lead to granuloma [98–100]. In a study based on children receiving parenteral fluids, Puntis et al.  confirmed that pulmonary granulomata could be found in small proportions, related to particulate contamination of IV solutions. More than 30,000 particles of between 2 and 100 µm in size were detected during a one-day infusion.
The IV administration of high amounts of particles to patients with organ failure can have deleterious effects on microcirculation. Some preclinical studies have tried to explain the action mechanism of such contamination in animal models [102–104] but none have managed to highlight the deleterious effects on the microcirculation of the striated muscle because healthy animals were used. In hospital, IV fluids are not usually administered to healthy patients, but rather to ill patients (polytrauma, major surgery, microvascular blood affections, etc.). Lehr et al.  investigated whether particulate contamination could affect the microvascular bed, using different IV solutions of cefotaxime. Functional capillary density (FCD) was analysed in non-ischemic and ischemic-reperfused muscle tissues; it was found that loss of FCD induced by particles was particularly significant in the post-ischemic tissue. Indeed, no loss of FCD after the injection of particles was observed in normal muscle tissue. Furthermore, histological sections of the tissues showed particles within arterioles and capillaries adjacent to the muscle tissue, and infiltration by inflammatory cells in response to the post-ischemic reperfusion injury.
Drug incompatibilities, such as precipitate, can occur during IV infusion, leading to SIRS. SIRS can be observed in many clinical conditions of infectious and non-infectious pathological causes. Dorris et al.  studied the inflammatory potential of infused particles by subcutaneous (SC) and IV injections. Dogs were randomised in control (with in-line filtration) and experimental (without in-line filtration) groups, and received concentrated solutions of particles. When particles were injected by the SC route, no inflammatory response was observed in either group. The IV route however has been implicated in venous thrombosis, phlebitis and systemic sepsis. It was shown that the longer the IV infusion, the greater the risk of endothelium reactions. These studies performed on animal models deserve deeper investigation and reference to human patients, especially paediatric patients. For children, the clinical consequences of particulate matter have been reported in several studies, leading to severe complications  or death [58, 108].
Several clinical studies have demonstrated that the IV injection of particles can result in inflammatory responses. Jack et al.  designed a prospective study with more than 800 children who were randomly assigned to two groups (with and without in-line filters). This study showed that the occurrence of SIRS was reduced when using 0.22 µm and/or 1.2 µm in-line filters. They continued their investigation on a subgroup of patients in a paediatric ICU, so confirming their previous results that the filter group was associated with a significant reduction in the risk of SIRS .
Particulate contamination during IV therapy constitutes a non-negligible risk for patients (thrombosis, impaired microcirculation or modulated immune response). Recently, studies have investigated the impact of particulate contamination on organ failure in critically ill children. Boehne et al.  evaluated the clinical impact of particulate contamination on different organs, as defined by the International Pediatric Sepsis Conference 2005 . They concluded that the infusion of particles may cause alteration to the microcirculation, inducing systemic inflammatory reactions with adverse effects on organs. On the other hand, a similar study was performed in adult critically ill adult patients and did not indicate any impact of in-line filters in reducing SIRS or organ complications . Nevertheless, it should be noted that the study concerned a mixed ICU population, which probably makes it impossible to conclude any significance.
IV infusions are extensively used in clinical wards, exposing patients to the risk of particulate contamination as well as drug incompatibility when several drugs have to be administered simultaneously through a limited number of venous accesses. Preventing both contamination and drug incompatibility are therefore essential to the safe administration of injectable drugs to polymedicated patients. Clinical pharmacists have an important role to play here: they must inform and educate the nursing staff on choices to be made and ways of preventing drug incompatibilities in ICUs (research in literature and databases, double-entry tables, use of multi-lumen infusion devices, in-line IV filters, identification of drugs by colour-code according to pH, etc). Medical devices (e. g. plastic materials, silicon oil, sterilisation process) or drug handling (e. g. infusion rate, shaking) have also a significant impact on particle formation on which it is difficult to adress.
The measures mentioned above are essential if IV therapy is to be improved and severe complications avoided.
Conflict of interest statement: Authors state no conflict of interest. All authors have read the journal’s Publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.
1. Schneider MP, Cotting J, Pannatier A. Evaluation of nurses’ errors associated in the preparation and administration of medication in a pediatric intensive care unit. Pharm World Sci PWS 1998 Aug;20(4):178–82.10.1023/A:1012087727393Search in Google Scholar
2. Reedy JS, Kuhlman JE, Voytovich M. Microvascular pulmonary emboli secondary to precipitated crystals in a patient receiving total parenteral nutrition: a case report and description of the high-resolution CT findings. Chest 1999 Mar;115(3):892–5.10.1378/chest.115.3.892Search in Google Scholar PubMed
3. Jack T, Boehne M, Brent BE, Hoy L, Köditz H, Wessel A, et al. In-line filtration reduces severe complications and length of stay on pediatric intensive care unit: a prospective, randomized, controlled trial. Intensive Care Med 2012 Jun;38(6):1008–16.10.1007/s00134-012-2539-7Search in Google Scholar PubMed PubMed Central
4. <788>Particulate matter in injections. United States Pharmacopeial. Rockville, Md: The United States pharmacopoeia, 35th revision. Rockville, MD: The United Stated Pharmacopoeial Convention, 2012:339–42.Search in Google Scholar
5. Ph. Eur., General, particulate contamination: sub-visible particles, in: The European Pharmacopoeia, eighth ed., 2016 (Chapter 2.9.19).Search in Google Scholar
6. Tran T, Kupiec TK, Trissel LA. Quality-control analytical methods: particulate matter in injections: what is it and what are the concerns? Int J Pharm Compd 2006 Jun;10(3):202–4.Search in Google Scholar
7. Foinard A, Perez M, Barthélémy C, Lannoy D, Flamein F, Storme L, et al. In vitro assessment of interaction between amino acids and copper in neonatal parenteral nutrition. JPEN J Parenter Enteral Nutr 2015 Feb 23.10.1177/0148607115571967Search in Google Scholar PubMed
8. Perez M, Décaudin B, Abou Chahla W, Nelken B, Barthélémy C, Lebuffe G, et al. In vitro analysis of overall particulate contamination exposure during multidrug IV therapy: impact of infusion sets. Pediatr Blood Cancer 2015 Jun;62(6):1042–7.10.1002/pbc.25442Search in Google Scholar PubMed
9. Perez M, Décaudin B, Foinard A, Barthélémy C, Debaene B, Lebuffe G, et al. Compatibility of medications during multi-infusion therapy: A controlled in vitro study on a multilumen infusion device. Anaesth Crit Care Pain Med 2015 Apr;34(2):83–8.10.1016/j.accpm.2014.06.003Search in Google Scholar PubMed
10. Bukofzer S, Ayres J, Chavez A, Devera M, Miller J, Ross D, et al. Industry perspective on the medical risk of visible particles in injectable drug products. PDA J Pharm Sci Technol PDA 2015 Feb;69(1):123–39.10.5731/pdajpst.2015.01037Search in Google Scholar PubMed
11. Groves MJ. The formulation of parenteral products. In: Parenteral Products, The preparation and Quality Control of Products for Injection. London: William Heineman Medical Books, Ltd, 1973.10.1016/B978-0-433-12640-9.50006-7Search in Google Scholar
13. <660> Containers-Glass. United Stated Pharmacopeia-National Formulary (USP-NF). Rockville, MD: The United Stated Pharmacopeial Convention, Inc.Search in Google Scholar
14. Ph. Eur. 8.4, Chapter 3.2. Containers, European Pharmacopeia, 2014.Search in Google Scholar
15. European Commission of Glass, “Good Manufacturing Practices, Medicinal Products for Human and Veterinary Use”, 2010.Search in Google Scholar
16. Afssaps Form n°2 – Complaints “glass particles in injectable products”. Elements of investigation to be taken into account and preventive measures. Afssaps – juin 2009.Search in Google Scholar
17. Douglas JB, Hedrick C. Pharmacology. In: Perucca R, editor. Infusion therapy equipment: types of infusion therapy equipment. In: Infusion therapy in clinical practise. Philadelphia: Saunders, 2001:176–208.Search in Google Scholar
19. Lee K-R, Chae Y-J, Cho S-E, Chung S-J. A strategy for reducing particulate contamination on opening glass ampoules and development of evaluation methods for its application. Drug Dev Ind Pharm 2011 Dec;37(12):1394–401.10.3109/03639045.2011.580349Search in Google Scholar PubMed
20. Sabon RL, Cheng EY, Stommel KA, Hennen CR. Glass particle contamination: influence of aspiration methods and ampule types. Anesthesiology 1989 May;70(5):859–62.10.1097/00000542-198905000-00024Search in Google Scholar
21. Joo GE, Sohng K-Y, Park MY. The effect of different methods of intravenous injection on glass particle contamination from ampules. SpringerPlus 2016;5:15.10.1186/s40064-015-1632-0Search in Google Scholar PubMed PubMed Central
22. Heiss-Harris GM, Verklan MT. Maximizing patient safety: filter needle use with glass ampules. J Perinat Neonatal Nurs 2005 Mar;19(1):74–81.10.1097/00005237-200501000-00015Search in Google Scholar PubMed
25. Yorioka K, Oie S, Oomaki M, Imamura A, Kamiya A. Particulate and microbial contamination in in-use admixed intravenous infusions. Biol Pharm Bull 2006 Nov;29(11):2321–3.10.1248/bpb.29.2321Search in Google Scholar PubMed
26. Walpot H, Franke RP, Burchard WG, Agternkamp C, Müller FG, Mittermayer C, et al. [The filter effectiveness of common 15-micron filters (DIN 58362). II: Scanning electron microscopy and roentgen analysis). Infusionstherapie Basel Switz 1989 Jun;16(3):133–9.10.1159/000222364Search in Google Scholar
28. NF EN ISO 15747 « Norm & Standard [Internet]. [cited 2016 Apr 12]. Available at: http://www.norm-standard.com/tag/nf-en-iso-15747/Search in Google Scholar
29. Stokes TF, Sumner ED, Needham TE. Particulate contamination and stability of three additives in 0.9 % sodium chloride injection in plastic and glass large-volume containers. Am J Hosp Pharm 1975 Aug;32(8):821–6.10.1093/ajhp/32.8.821Search in Google Scholar
31. NF ISO 28620 « Norme et standard [Internet]. [cited 2016 Apr 12]. Available at: http://www.norme-standard.com/tag/nf-iso-28620/Search in Google Scholar
32. Guiffant G, Durussel J-J, Flaud P, Vigier J-P, Dupont C, Bourget P, et al. Mechanical performances of elastomers used in diffusers. Med Devices Auckl NZ 2011;4:71–6.10.2147/MDER.S18633Search in Google Scholar
33. Lunceford R, Reynolds S Analyzing Particulate Matter on Medical Devices. Medical Diagnostic Industruy (MD&DI), 2009 May.Search in Google Scholar
34. Pavanetto F, Conti B, Modena T, Genta I, Ponci R. Particulate contamination in parenteral type medical devices. Int J Pharm 1988 Dec 1;48(1):255–65.10.1016/0378-5173(88)90270-0Search in Google Scholar
35. Foroni LA, Rochat MH, Trouiller P, Calop JY. Particle contamination in a ternary nutritional admixture. J Parenter Sci Technol Publ Parenter Drug Assoc 1993 Dec;47(6):311–14.Search in Google Scholar
36. Schröder F. [Compatibility problems in intensive care medicine]. Infusionsther Transfusionsmed 1994 Feb;21(1):52–8.Search in Google Scholar
37. Ball PA, Bethune K, Fox J, Ledger R, Barnett M. Particulate contamination in parenteral nutrition solutions: still a cause for concern? Nutr Burbank Los Angel Cty Calif 2001 Dec;17(11–12):926–9.10.1016/S0899-9007(01)00708-0Search in Google Scholar
38. Gerhardt A, Mcgraw NR, Schwartz DK, Bee JS, Carpenter JF, Randolph TW. Protein aggregation and particle formation in prefilled glass syringes. J Pharm Sci 2014 Jun;103(6):1601–12.10.1002/jps.23973Search in Google Scholar PubMed
39. Uchino T, Miyazaki Y, Ohkawa T, Yamazaki T, Yanagihara Y, Yoshimori T, et al. Reconstitution of L-asparaginase in siliconized syringes with shaking and headspace air induces protein aggregation. Chem Pharm Bull (Tokyo) 2015;63(10):770–9.10.1248/cpb.c15-00242Search in Google Scholar PubMed
40. Demeule B, Messick S, Shire SJ, Liu J. Characterization of particles in protein solutions: reaching the limits of current technologies. AAPS J 2010 Dec;12(4):708–15.10.1208/s12248-010-9233-xSearch in Google Scholar PubMed PubMed Central
41. Gerhardt A, Nguyen BH, Lewus R, Carpenter JF, Randolph TW. Effect of the siliconization method on particle generation in a monoclonal antibody formulation in pre-filled syringes. J Pharm Sci 2015 May;104(5):1601–9.10.1002/jps.24387Search in Google Scholar PubMed
42. Gerhardt A, Mcumber AC, Nguyen BH, Lewus R, Schwartz DK, Carpenter JF, et al. Surfactant effects on particle generation in antibody formulations in pre-filled syringes. J Pharm Sci 2015 Dec;104(12):4056–64.10.1002/jps.24654Search in Google Scholar PubMed PubMed Central
43. Foinard A, Décaudin B, Simon N, Barthélémy C, Storme L, Odou P. Vancomycin syringe study shows significant reduction in dosing variability after introducing a revised protocol. Acta Paediatr Oslo Nor 1992 2014 Mar;103(3):e93–4.10.1111/apa.12484Search in Google Scholar PubMed
44. Bonnabry P, Stucki C, Sadeghipour F, et al. La préparation centralisée de médicaments injectables. Le Moniteur Hospitalier 2011;237:19-29.Search in Google Scholar
47. Wuchner K, Büchler J, Spycher R, Dalmonte P, Volkin DB. Development of a microflow digital imaging assay to characterize protein particulates during storage of a high concentration IgG1 monoclonal antibody formulation. J Pharm Sci 2010 Aug;99(8):3343–61.10.1002/jps.22123Search in Google Scholar PubMed
48. Mach H, Bhambhani A, Meyer BK, Burek S, Davis H, Blue JT, et al. The use of flow cytometry for the detection of subvisible particles in therapeutic protein formulations. J Pharm Sci 2011 May;100(5):1671–8.10.1002/jps.22414Search in Google Scholar PubMed
49. Corvari V, Narhi LO, Spitznagel TM, Afonina N, Cao S, Cash P, et al. Subvisible (2–100 μm) particle analysis during biotherapeutic drug product development: Part 2, experience with the application of subvisible particle analysis. Biol J Int Assoc Biol Stand 2015 Nov;43(6):457–73.10.1016/j.biologicals.2015.07.011Search in Google Scholar PubMed
50. Royal College of Nursing. Standards for Infusion Therapy. RCN, London. 2005.Search in Google Scholar
51. Josephson DL. Risks, complications, and adverse reactions associated with intravenous infusion therapy. In: Josephson DL, editor. Intravenous infusion therapy for medical assistants. The American association of Medical Assistants. Clifton Park: Thomson Delmar Learning, 2006:56–82.Search in Google Scholar
52. Nouvel M, Lepape A. Administration of parenteral drugs: Drug physicochemical incompatibilities. Nurses Congress. Intensive Care Nurses. SFAR 2015.Search in Google Scholar
54. Tissot E, Cornette C, Demoly P, Jacquet M, Barale F, Capellier G. Medication errors at the administration stage in an intensive care unit. Intensive Care Med 1999 Apr;25(4):353–9.10.1007/s001340050857Search in Google Scholar PubMed
55. Gikic M, Di Paolo ER, Pannatier A, Cotting J. Evaluation of physicochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit. Pharm World Sci PWS 2000 Jun;22(3):88–91.10.1023/A:1008780126781Search in Google Scholar
56. McNearney T, Bajaj C, Boyars M, Cottingham J, Haque A. Total parenteral nutrition associated crystalline precipitates resulting in pulmonary artery occlusions and alveolar granulomas. Dig Dis Sci 2003 Jul;48(7):1352–4.10.1023/A:1024119512162Search in Google Scholar
57. Knowles JB, Cusson G, Smith M, Sitrin MD. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. JPEN J Parenter Enteral Nutr 1989 Apr;13(2):209–13.10.1177/0148607189013002209Search in Google Scholar PubMed
58. Bradley JS, Wassel RT, Lee L, Nambiar S. Intravenous ceftriaxone and calcium in the neonate: assessing the risk for cardiopulmonary adverse events. Pediatrics 2009 Apr;123(4):e609–13.10.1542/peds.2008-3080Search in Google Scholar PubMed
59. Hill SE, Heldman LS, Goo ED, Whippo PE, Perkinson JC. Fatal microvascular pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN J Parenter Enteral Nutr 1996 Feb;20(1):81–7.10.1177/014860719602000181Search in Google Scholar PubMed
60. Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion solutions to reduce the risk of incompatibility. Am J Health-Syst Pharm AJHP Off J Am Soc Health-Syst Pharm 2008 Sep 1;65(17):1648–54.10.2146/ajhp070471Search in Google Scholar PubMed
61. Vogel Kahmann I, Bürki R, Denzler U, Höfler A, Schmid B, Splisgardt H. [Incompatibility reactions in the intensive care unit. Five years after the implementation of a simple “colour code system”]. Anaesthesist 2003 May;52(5):409–12.10.1007/s00101-003-0481-3Search in Google Scholar PubMed
63. Kanji S, Lam J, Johanson C, Singh A, Goddard R, Fairbairn J, et al. Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units. Crit Care Med 2010 Sep;38(9):1890–8.10.1097/CCM.0b013e3181e8adccSearch in Google Scholar PubMed
64. De Giorgi I, Guignard B, Fonzo-Christe C, Bonnabry P. Evaluation of tools to prevent drug incompatibilities in paediatric and neonatal intensive care units. Pharm World Sci PWS 2010 Aug;32(4):520–9.10.1007/s11096-010-9403-zSearch in Google Scholar PubMed
65. Trissel LA. Handbook on injectable drugs, 18th ed. Bethesda: American Society of Health-System Pharmacy, 2015:1280 p.Search in Google Scholar
66. Jack T, Brent BE, Boehne M, Müller M, Sewald K, Braun A, et al. Analysis of particulate contaminations of infusion solutions in a pediatric intensive care unit. Intensive Care Med 2010 Apr;36(4):707–11.10.1007/s00134-010-1775-ySearch in Google Scholar PubMed PubMed Central
67. Sasse M, Dziuba F, Jack T, Köditz H, Kaussen T, Bertram H, et al. In-line Filtration Decreases Systemic Inflammatory Response Syndrome, Renal and Hematologic Dysfunction in Pediatric Cardiac Intensive Care Patients. Pediatr Cardiol 2015 Aug;36(6):1270–8.10.1007/s00246-015-1157-xSearch in Google Scholar PubMed PubMed Central
68. Boehne M, Jack T, Köditz H, Seidemann K, Schmidt F, Abura M, et al. In-line filtration minimizes organ dysfunction: new aspects from a prospective, randomized, controlled trial. BMC Pediatr 2013;13:21.10.1186/1471-2431-13-21Search in Google Scholar PubMed PubMed Central
69. Foster J, Richards R, Showell M. Intravenous in-line filters for preventing morbidity and mortality in neonates. Cochrane Database Syst Rev 2006;(2):CD005248.10.1002/14651858.CD005248.pub2Search in Google Scholar PubMed
70. Gasch J, Leopold CS, Knoth H. Drug retention by inline filters--effect of positively charged polyethersulfone filter membranes on drug solutions with low concentration. Eur J Pharm Sci Off J Eur Fed Pharm Sci 2011 Sep 18;44(1–2):49–56.10.1016/j.ejps.2011.06.004Search in Google Scholar PubMed
71. Ennis CE, Merritt RJ, Neff DN. In vitro study of in line filtration of medications commonly administered to pediatric cancer patients. JPEN J Parenter Enteral Nutr 1983 Apr;7(2):156–8.10.1177/0148607183007002156Search in Google Scholar PubMed
72. Werner BP, Winter G. Particle contamination of parenteralia and in-line filtration of proteinaceous drugs. Int J Pharm 2015 Dec 30;496(2):250–67.10.1016/j.ijpharm.2015.10.082Search in Google Scholar PubMed
73. Heyman S. Toxicity and safety factors associated with lung perfusion studies with radiolabeled particles. J Nucl Med Off Publ Soc Nucl Med 1979 Oct;20(10):1098–9.Search in Google Scholar
75. Takenaka S, Karg E, Roth C, Schulz H, Ziesenis A, Heinzmann U, et al. Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. Environ Health Perspect 2001 Aug;109(Suppl 4):547–51.10.1289/ehp.01109s4547Search in Google Scholar PubMed PubMed Central
76. Khandoga A, Stampfl A, Takenaka S, Schulz H, Radykewicz R, Kreyling W, et al. Ultrafine particles exert prothrombotic but not inflammatory effects on the hepatic microcirculation in healthy mice in vivo. Circulation 2004 Mar 16;109(10):1320–5.10.1161/01.CIR.0000118524.62298.E8Search in Google Scholar PubMed
77. Nemmar A, Vanbilloen H, Hoylaerts MF, Hoet PH, Verbruggen A, Nemery B. Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster. Am J Respir Crit Care Med 2001 Nov 1;164(9):1665–8.10.1164/ajrccm.164.9.2101036Search in Google Scholar PubMed
78. Barber T. Chapter 1. Introduction and overview. In control of particulate matter: contamination in healthcare manufacturing. Buffalo Grove, IL: Interpharm Press, 2000:1–26.Search in Google Scholar
79. Di Paolo ER, Hirschi B, Pannatier A. Quantitative determination of particulate contamination in intravenous administration sets. Pharm Weekbl Sci 1990 Oct 19;12(5):190–5.10.1007/BF01980045Search in Google Scholar PubMed
80. Backhouse CM, Ball PR, Booth S, Kelshaw MA, Potter SR, McCollum CN. Particulate contaminants of intravenous medications and infusions. J Pharm Pharmacol 1987 Apr;39(4):241–5.10.1111/j.2042-7158.1987.tb06260.xSearch in Google Scholar PubMed
81. van Lingen RA, Baerts W, Marquering ACM, Ruijs GJHM. The use of in-line intravenous filters in sick newborn infants. Acta Paediatr Oslo Nor 1992 2004 May;93(5):658–62.10.1111/j.1651-2227.2004.tb02993.xSearch in Google Scholar
82. Staven V, Waaseth M, Wang S, Grønlie I, Tho I. Utilization of the tyndall effect for enhanced visual detection of particles in compatibility testing of intravenous fluids: validity and reliability. PDA J Pharm Sci Technol PDA 2015 Apr;69(2):270–83.10.5731/pdajpst.2015.01020Search in Google Scholar
83. Saller V, Matilainen J, Grauschopf U, Bechtold-Peters K, Mahler H-C, Friess W. Particle shedding from peristaltic pump tubing in biopharmaceutical drug product manufacturing. J Pharm Sci 2015 Apr;104(4):1440–50.10.1002/jps.24357Search in Google Scholar
84. Dewan PA, Ehall H, Edwards GA, Middleton DJ, Terlet J. Plastic particle migration during intravenous infusion assisted by a peristaltic finger pump in an animal model. Pediatr Surg Int 2002 Sep;18(5–6):310–14.10.1007/s00383-002-0810-7Search in Google Scholar
85. Bowen JH, Woodard BH, Barton TK, Ingram P, Shelburne JD. Infantile pulmonary hypertension associated with foreign body vasculitis. Am J Clin Pathol 1981 Apr;75(4):609–14.10.1093/ajcp/75.4.609Search in Google Scholar
86. Popińska K, Kierkuś J, Lyszkowska M, Socha J, Pietraszek E, Kmiotek W, et al. Aluminum contamination of parenteral nutrition additives, amino acid solutions, and lipid emulsions. Nutr Burbank Los Angel Cty Calif 1999 Sep;15(9):683–6.10.1016/S0899-9007(99)00124-0Search in Google Scholar
87. Sedman AB, Klein GL, Merritt RJ, Miller NL, Weber KO, Gill WL, et al. Evidence of aluminum loading in infants receiving intravenous therapy. N Engl J Med 1985 May 23;312(21):1337–43.10.1056/NEJM198505233122101Search in Google Scholar
88. Stellmack M, Rhodes K. Metal contamination in bio-pharmaceutical drugs: solving a puzzle without all the pieces. October 2010. Available at: www.contractpharma.com.Search in Google Scholar
89. Stellmack M, Rhodes K. Contamination control – metal particles. Meddling metals can contaminate biopharmaceuticals. December 2010. Available at: www.pharmquality.com.Search in Google Scholar
90. Wilkins DJ, Myers PA. Studies on the relationship between the electrophoretic properties of colloids and their blood clearance and organ distribution in the rat. Br J Exp Pathol 1966 Dec;47(6):568–76.Search in Google Scholar
91. Kanke M, Simmons GH, Weiss DL, Bivins BA, DeLuca PP. Clearance of 141C3-labeled microspheres from blood and distribution in specific organs following intravenous and intraarterial administration in beagle dogs. J Pharm Sci 1980 Jul;69(7):755–62.10.1002/jps.2600690703Search in Google Scholar
92. Ilium L, Davis SS, Wilson CG, Thomas NW, Frier M, Hardy JG. Blood clearance and organ deposition of intravenously administered colloidal particles. The effects of particle size, nature and shape. Int J Pharm 1982 Oct 1;12(2):135–46.10.1016/0378-5173(82)90113-2Search in Google Scholar
93. DeLuca PP, Rapp RP, Bivins B, McKean HE, Griffen WO. Filtration and infusion phlebitis: a double-blind prospective clinical study. Am J Hosp Pharm 1975 Oct;32(10):1001–7.10.1093/ajhp/32.10.1001Search in Google Scholar
94. Maddox RR, John JF, Brown LL, Smith CE. Effect of inline filtration on postinfusion phlebitis. Clin Pharm 1983 Feb;2(1):58–61.Search in Google Scholar
95. Allcutt DA, Lort D, McCollum CN. Final inline filtration for intravenous infusions: a prospective hospital study. Br J Surg 1983 Feb;70(2):111–13.10.1002/bjs.1800700219Search in Google Scholar PubMed
96. Falchuk KH, Peterson L, McNeil BJ. Microparticulate-induced phlebitis. Its prevention by in-line filtration. N Engl J Med 1985 Jan 10;312(2):78–82.10.1056/NEJM198501103120203Search in Google Scholar PubMed
97. Campbell L. I.v.-related phlebitis, complications and length of hospital stay: 2. Br J Nurs Mark Allen Publ 1998 Jan 10;7(22):1364–6, 1368–70, 1372–3.10.12968/bjon.1918.104.22.16833Search in Google Scholar PubMed
98. Douglas FG, Kafilmout KJ, Patt NL. Foreign particle embolism in drug addicts: respiratory pathophysiology. Ann Intern Med 1971 Dec;75(6):865–80.10.7326/0003-4819-75-6-865Search in Google Scholar PubMed
99. Tomashefski JF, Hirsch CS, Jolly PN. Microcrystalline cellulose pulmonary embolism and granulomatosis. A complication of illicit intravenous injections of pentazocine tablets. Arch Pathol Lab Med 1981 Feb;105(2):89–93.Search in Google Scholar
100. Doessegger L, Mahler H-C, Szczesny P, Rockstroh H, Kallmeyer G, Langenkamp A, et al. The potential clinical relevance of visible particles in parenteral drugs. J Pharm Sci 2012 Aug;101(8):2635–44.10.1002/jps.23217Search in Google Scholar PubMed
101. Puntis JW, Wilkins KM, Ball PA, Rushton DI, Booth IW. Hazards of parenteral treatment: do particles count? Arch Dis Child 1992 Dec;67(12):1475–7.10.1136/adc.67.12.1475Search in Google Scholar PubMed PubMed Central
102. Von Glahn WC, Hall JW. The reaction produced in the pulmonary arteries by emboli of cotton fibers. Am J Pathol 1949 Jul;25(4):575–95.Search in Google Scholar
103. Wartman WB, Hudson B, Jennings RB. Experimental arterial disease. II. The reaction of the pulmonary artery to emboli of filter paper fibers. Circulation 1951 Nov;4(5):756–63.10.1161/01.CIR.4.5.756Search in Google Scholar
104. Stehbens WE, Florey HW. The behavior of intravenously injected particles observed in chambers in rabbits’ ears. Q J Exp Physiol Cogn Med Sci 1960 Jul;45:252–64.10.1113/expphysiol.1960.sp001470Search in Google Scholar PubMed
105. Lehr H-A, Brunner J, Rangoonwala R, 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 Feb 15;165(4):514–20.10.1164/ajrccm.165.4.2108033Search in Google Scholar PubMed
106. Dorris GG, Bivins BA, Rapp RP, Weiss DL, DeLuca PP, Ravin MB. Inflammatory potential of foreign particulates in parenteral drugs. Anesth Analg 1977 Jun;56(3):422–8.10.1213/00000539-197705000-00022Search in Google Scholar PubMed
107. Breaux CW, Duke D, Georgeson KE, Mestre JR. Calcium phosphate crystal occlusion of central venous catheters used for total parenteral nutrition in infants and children: prevention and treatment. J Pediatr Surg 1987 Sep;22(9):829–32.10.1016/S0022-3468(87)80648-6Search in Google Scholar
108. Monte SV, Prescott WA, Johnson KK, Kuhman L, Paladino JA. Safety of ceftriaxone sodium at extremes of age. Expert Opin Drug Saf 2008 Sep;7(5):515–23.10.1517/14740322.214.171.1245Search in Google Scholar PubMed
109. Goldstein B, Giroir B, Randolph A. International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 2005 Jan;6(1):2–8.10.1097/01.PCC.0000149131.72248.E6Search in Google Scholar PubMed
110. Gradwohl-Matis I, Brunauer A, Dankl D, Wirthel E, Meburger I, Bayer A, et al. Influence of in-line microfilters on systemic inflammation in adult critically ill patients: a prospective, randomized, controlled open-label trial. Ann Intensive Care 2015 Dec;5(1):36.10.1186/s13613-015-0080-xSearch in Google Scholar PubMed PubMed Central
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