Annales Pharmaceutiques Fran~aises (201 1) 69, 30-37
`
`Disponible en ligne sur
`·;;;' S1 i o
`www.sciencedirect.com
`
`)iri..;r
`
`Elsevier Masson France
`EMlconsulte
`www.em-consulte.com
`
`ELSEVll::R
`MASSON
`
`ORIGINAL ARTICLE
`Centralized intravenous additive services (CIVAS):
`The state of the art in 2010
`
`UCRI, unite centralisee de reconstitution d'injectables: le point en 2010
`
`J.-D. Hecq
`
`Universite catholique de Louvain, cliniques universitaires UCL de Mont-Godinne,
`1, avenue Therasse, 5530 Yvoir, Belgium
`
`Received 10 June 2010; accepted 14 September 2010
`Available online 30 December 2010
`
`KEYWORDS
`CIVAS;
`Compounding;
`Errors;
`Patient care;
`Patient safety;
`Intravenous infusion
`
`In hospitals, the major part of the drugs is administered by intravenous way and
`Summary
`the majority of the reconstitution of injectable drugs are carried out right before the admin(cid:173)
`istration to the patient by the nursing staff. The risks and errors related to the preparation
`and the administration of the injectable drugs are numerous. The standardization then the
`centralization of the preparations and reconstitution by the hospital pharmacy make it possi(cid:173)
`ble to reduce these various risks and errors. In addition to the preparation of the mixtures of
`parenteral nutrition as well as doses of anticancer chemotherapy, many other treatments can
`be taken in charge, such as antibiotics, antiemetics and pain treatments. Consequent equip(cid:173)
`ment is necessary but the realization of these treatments proves non-overdrawn insofar as a
`certain quantity of production is reached. The reconstitution of the intravenous treatments by
`a centralized intravenous admixture service guarantees the chemical stability and the micro(cid:173)
`biological quality of the ready-to-use injectable drugs and contributes to the quality and the
`total management of the care of the patient.
`© 2010 Elsevier Masson SAS. All rights reserved.
`
`MOTS CLES
`Erreurs;
`Perfusion
`intraveineuse ;
`Preparation
`medicamenteuse ;
`
`Resume En milieu hospitalier, la majeure partie des medicaments est administree par voie
`intraveineuse et la plupart des reconstitutions des injectables sent realisees juste avant
`!'administration au patient par le personnel infirmier. Les risques et erreurs lies a la standardis(cid:173)
`ation puis la centralisation des preparations et reconstitutions dans le service de pharmacie
`hospitaliere permettent de reduire ces differents risques et erreurs. Outre la preparation
`des melanges de nutrition parenterale ainsi que des doses de chimiotherapie anticancereuse,
`
`E-mail address: Jean-Daniel.Hecq@uclouvain.be
`
`0003-4509/S - see front matter© 2010 Elsevier Masson SAS. All rights reserved.
`doi: 10.1016/j.pharma.2010.09.002
`
`Hospira, Exh. 2023, p. 1
`
`

`
`Ce ntralized intravenous additive services (CIVAS): The state of t he art in 2010
`
`31
`
`Securite des
`patients ;
`Soins des patients ;
`Unite centrale de
`reconstitution
`d'injectables
`
`de nombreux autres traitements peuvent etre pris en charge, a savoir les antibiotiques, les
`antiemetiques et les antidouleurs. Un equipement consequent est necessaire mais la realisation
`de ces traitements s'avere non deficitaire pour autant que l'on atteigne une certaine quantite
`de production. La reconstitution des traitements intraveineux par une unite centralisee de
`reconstitution d'injectables garantit la stabilite chimique et la qualite microbiologique des
`doses injectables pretes a l'emploi et contribue a la qualite et au management global des soins
`du patient.
`© 2010 Elsevier Masson SAS. Tous droits reserves.
`
`Place of injectable drugs in hospital
`treatments
`
`These qualities must be preserved in the administered
`perfusion to t he patient.
`
`In hospitals, the major part of the drugs is managed by intra(cid:173)
`venous way. The majority of the reconstitutions of injectable
`is carried out right before t he administration by the nursing
`team. Lastly, the operating room is gene rally the only asep(cid:173)
`tic zone except if the hospital instit ution has aseptic units
`for cancer patients.
`Several authors tried to quant ify t he quantity of
`injectable administrated to the patients.
`Turco [1] reports that 24% of the administered doses to
`hospitalized patients are injectable drugs, while 38% of the
`patients receive at least an injection per day.
`According to Simmons [2], 30 to 50% of the patients
`receive medications by intravenous way, percentage con(cid:173)
`firmed by Taxis and Barber (28%) [3].
`Kwan and Anderson [4) estimate that 40% of medications
`and solutions are managed by intravenous way while Rwabi·
`hama et al. [5] note that 49% of the pat ients are under
`perfusion.
`The risks related to the preparation and the administra(cid:173)
`t ion of t he injectable drugs are numerous:
`• incomplete and ambiguous regulations;
`• procedures of the complex pre parations;
`• missing of essential technical information;
`• multidisciplinary absence of process;
`• error of selection of the drug and/ or the diluent;
`• use of the drug, the diluent or the aqueous solution after
`expiry date;
`• miscalculation;
`• physicochemical incompatibility;
`• error of patient;
`• error of route of administration;
`• bad technique of preparation and/or asepsis;
`• protection of the operator and/ or the environment;
`• varied levels of knowledge, experiment and competence
`in the personnel of care [6].
`
`Factors affecting drug stability
`
`Many authors studied and detailed the physicochemical fac·
`tors influencing the stability of the molecules in solution
`[7- 19].
`A drug is considered stable in solution insofar as it
`preserves 90% of the initial concentration (United States
`Pharmacopeia [USP] standards).
`To determine this stability, the concentration of the
`active ingredient will be pe rformed by high-pressure liq(cid:173)
`uid chromatography or gas chromatography, microbiological
`test (for certain antibiotics) or by any other specific test
`making it possible to differentiate the active molecule from
`its breakdown products.
`Moreove r, t here cannot be a decomposition of the active
`ingredient in toxic product and the initial appearance of the
`solution cannot be modified.
`In short terms, when one wants to evaluate or know
`the stability of a drug in solution, it is necessary to
`know:
`• final concentration of the reconstituted product;
`• nature, pH and ionic force of the diluent;
`• pH and ionic force of final dilution;
`• nature of container (polyvinyl chloride, ethylvinyl
`acetate, polypropylene, etc.) to avoid the phenomenon
`of sorption and salting out;
`• conditions of storage (refrigerator, ambient temperature,
`body temperature, protection from light);
`• nature of the set of administrat ion (PVC, polyethylene,
`etc.);
`• protection from the light during the administrat ion.
`
`Methods of preparation and/or
`reconstitution
`
`Forms of the injectable drugs
`
`The pharmaceutical companies provide the injectable drugs
`in the form of ampuls, flasks of powder, concentrated solu·
`tions or mini·perfusions.
`Minimal qualities of t hese forms are physicochemical
`stability, sterility, t he absence of particles and pyrogenic
`substances as well as long-term validity.
`
`The principal methods are t he syringe, the set transfer, the
`sophisticated perfusions or the sophisticated flasks.
`The syringe is one of t he systems most used for the recon(cid:173)
`stitution of the injectable drugs.
`The set transfer is also strongly used, eit her in the shape
`of a double needle, or in the shape of a double needle itself
`surrounded by a plastic protection. Among the sophisticated
`perfusions, let us quote the minibag, which is equipped at
`the site of injection with a receptacle making it possible to
`
`Hospira, Exh. 2023, p. 2
`
`

`
`32
`
`J.-D. Hecq
`
`receive the vial insofar as this one reaches a diameter of
`22mm.
`The ADD-Vantage® system is on the other hand delivered
`like such. The vial is connected already beforehand to the
`perfusion.
`On the other hand, some flasks are already equipped
`with a needle of transfer and require at this time to use
`a perfusion definitely more traditional (Monovial®).
`Lastly,
`there exist now
`systems of assembly(cid:173)
`reconstitution using of the traditional perfusions and
`the traditional vials (Vial-Mate®).
`
`Microbiological quality of the injectable
`reconstituted medications
`
`infectious
`that
`(20,21] highlighted
`Several authors
`complications could occur among patients receiving of
`the intravenous solutions. The risk of contamination of
`injectable solutions administrated to the patients is all the
`more high as the products are prepared in a non-controlled
`environment.
`This risk increases with the number of handling carried
`out during the addition of additional medications to the
`solution of perfusion (22].
`In 1953, the first report/ratio of microbiological conta(cid:173)
`mination of a perfusion appeared.
`O'Hare et al. (23] describe a fatal case of anaphylactic
`shock following the perfusion of a solution of glucose of 10%
`contaminated "by inadvertency" with Aerobacter aero(cid:173)
`genes. The same year, Michaels and Ruebner [24] announce
`that two patients receiving an intravenous therapy devel(cid:173)
`oped a pyrexia allotted to a bacillus coliform present in the
`system of perfusion.
`Wilmore and Dudrick (25] postulate that the parenteral
`solution itself can cause infection and suggest t hat the
`contamination can be introduced into the system of per(cid:173)
`fusion by penetrating not filtered air in the container
`during the addition of the drugs to the perfusion or
`during t he intermittent administration of parenteral med(cid:173)
`ications.
`Holmes and Allwood (26] describe the five types of possi(cid:173)
`ble contamination: contamination by air, contamination by
`touching, administration of additives, site of injection, use
`of contaminated disinfectants.
`Several authors studied the percentage of contamination
`of solution of perfusion following the addition of various
`medications: 3% [27], 3.75% (28] , 3.8% (29], 4.9% (30], 10%
`(31], 25% (22].
`In 2001, Mansfield [32] observed the preparation of
`injectable in four hospitals. The results were surprising:
`• the surface of preparation was never cleaned;
`• in a hospital, 84% of the nurses wore gloves during han(cid:173)
`dling, which was absolutely not the case in the three
`others;
`• no nurse had washed her hands beforehand;
`• the bottles were not regularly disinfected (0 to 1.67%),
`the site of injection of the minibags neither (0 to 1.67%);
`• in two hospitals out of four, the window of the room where
`the constitutions were carried out were open in 58% of the
`observations.
`
`Errors: review of the literature
`
`A review of the literature makes it possible to quantify
`the errors of asepsis, the errors of duration of administra·
`tion, the errors of administration, the errors of labelling,
`the errors of preparations and the errors of compatibil·
`ity.
`Thus, the errors of asepsis were observed in 19% (33],
`58% [33], 71% [34] or 100% (33] of t he cases.
`The errors of duration of administration take place in
`0.2% [35], 1% (36], 6% [37,38], 26% (39] of the administra(cid:173)
`tions.
`Errors of administration occur in 3% (40], 6% [35], 10%
`(33], 23% (41], 24% (33], 36% (42] of the cases.
`The labelling is non-existent in 20% [33], 43% [33], 99%
`(33] of the observations.
`Errors of preparations reported in 1% [35], 2% [33], 4%
`(38], 7% (42], 8% [40], 10% [39], 19% (41], 24% (33], 40%
`(41], 79% (33].
`During mixtures of medications, it was raised, accord(cid:173)
`ing to the observations, 17% (43], 23% (44] and 86% of
`compatibility, 2% (45], 3.4% (46], 11% [43] and 18.6% of
`incompatibility. In addition, 10.3% (46] to 72% [44,46] of the
`mixtures carried out were not studied in the international
`literature.
`
`How to reduce these errors?
`
`Standardization of the methods of preparation
`
`The standardization of the methods of preparation and
`administration makes it possible to the medical staff
`to prepare the injectable medications according to vali(cid:173)
`dated methods. This standardization is based on various
`sources and certain authors carried out such standardiza(cid:173)
`tions (47- 49] .
`
`Centralization of the preparations and
`reconstitutions in pharmacy
`
`Parenteral nutrition
`It is at the end of the 1970s that become the prepa(cid:173)
`ration of the mixtures standardized under horizontal
`laminar airflow hood (or out of isolator) of binary mix(cid:173)
`tures (amino acid+ glucose) or of ternary mixtures (amino
`acid+ glucose+ lipids). The incentives to taking in charge
`these preparations are:
`• an increase in the microbiological quality of the end prod(cid:173)
`uct, possibilities of contamination being brought back
`from 18 to two;
`• an increase in the physicochemical quality of the end
`product, mixtures of parenteral nutrition containing up
`to 50 different molecules;
`• a lightening of the nursing team workload.
`
`The improvement of the microbiological quality of the
`end product was shown in particular by Miller et al. [50]
`in 1971 who noted that the contamination of the solutions
`of perfusion resulted from a weak aseptic technique rather
`than of an aseptic lack of environment.
`
`Hospira, Exh. 2023, p. 3
`
`

`
`Centralized intravenous additive services (CIVAS): The state of the art in 2010
`
`33
`
`Table 1 Cefepime during the year 2000.
`Cefepime durant l'annee 2000.
`
`Average I production
`Preparation time (minute)
`Cost (per minute)
`Team cost(€)
`Cost in material used (€)
`Total cost(€)
`
`Pharmacy
`
`33.72
`3.48
`0.408
`1.420
`0.502
`1.922
`
`Nursing
`
`5.51
`0.533
`2.937
`0.233
`3.170
`
`Difference
`
`1.248
`
`Allinson et al. [51) in 1979 showed that none of the 360
`bottles of perfusion in which one had added a drug under
`hood to flow of laminar air were contaminated.
`Brier et al. (52) in 1981 show that, when one adheres to an
`aseptic technique, the environment in which the additions
`are carried out is the most important variable affecting the
`degree of microbiological contamination of the solutions.
`The incidence of the contamination under laminar airflow
`hood is significantly less than the contamination of the solu·
`tions carried out on a clean table.
`
`Cytotoxics
`It was during the 1980s that hospital pharmacies started to
`deal with the reconstitution and the preparation of anti(cid:173)
`cancer doses of chemotherapy. These doses are carried out
`under vertical laminar airflow hoods or in isolators. The
`incentives are identical to the precedents. With these three
`elements, the protection of the manipulator towards the
`toxicity of the handled products is added.
`
`Centralized intravenous additive services (CIVAS)
`Beside the mixtures of parenteral nutrition and anticancer
`cures of chemotherapy, there remains an important quan(cid:173)
`tity of injectable medications, in particular antibiotics,
`antiemetics and pain treatment.
`The incentive of taking in charge these various medica(cid:173)
`tions are identical to the precedents.
`One-fifth element is added which is the economic aspect.
`Indeed, the preparation of series of standardized injectable
`doses is made more quickly, is less expensive in material
`used for the preparation and is less expensive in labour. Thus
`developed the CIVAS.
`Several works documented this subject (53- 55).
`Reference books provide data of stability (1,54,56-62).
`These books furnish a lot of information on physical sta-
`bilities (visual, pH, modification of colouring). Chemical
`stability is described for 12 hours at 7 days on average. The
`concentrations used, the containers can be different (flex(cid:173)
`ible PVC bags, polyolefin, reservoirs) and the solutions of
`perfusion can be different.
`
`Cost of reconstitution of injectable doses
`
`In order to estimate the time and the cost of preparation
`of injectable drugs, it is necessary to time the make ready
`time which must include the disinfection of the area of work
`of the laminar air flow hood, its loading, the preparation in
`itself, the labelling and the putting in bags, storage with
`
`the refrigerator and the cleaning of the work area of the
`hood.
`The most complete studies concerning all the opera(cid:173)
`tions relating to the reconstitution and the preparation of
`an injectable drug at the ward provide the times ranging
`between 4.71 and 6.51 minutes [63- 66), with an average of
`5.51 minutes.
`Table 1 details these data for the reconstitution at the
`pharmacy of an antibiotic, cefepime, and compares them
`with the time and the cost of preparation at the ward by
`the nursing team (67).
`During the year 2000, the average quantity of cefepime
`ready-to-use bags manufactured by batch is 33. 72. The aver(cid:173)
`age time of preparation, all operations included, rises to
`3.48 minutes.
`The cost per minute rises to 0.408 € at the pharmacy and
`0.533 € at the ward, the cost of the material used being
`respectively of 0.502 and 0.233€.
`The cost of preparation of a bag of cefepime rises to
`1.922 €
`in pharmacy and 3.170€ at the ward, with a dif(cid:173)
`ference of 1.248€ on account of the reconstitution in
`pharmacy.
`If storage in a freezer is used, it will be neces(cid:173)
`sary to add to this timing the time necessary to store
`the bags in the freezer just as the time necessary with
`placing these bags in the microwave oven. Various tim(cid:173)
`ings were carried out during time for certain molecules
`(67].
`Table 2 shows that the average quantity of bags manu(cid:173)
`factured at the same time is higher (55.83 minutes), since
`the guarantee of long-term stability is ensured by freezing
`(68].
`If the preparation time is a little higher (3.89 minutes
`instead of 3.48 minutes), the cost in material used is weaker
`(0.301 €
`instead of 0.502 €).
`The difference on account of the reconstitution in phar(cid:173)
`instead of 1.248€ (67].
`macy rises then with 1.282 €
`Various
`timings were carried out for four other
`molecules (69- 72], ceftazidime, cefuroxime, piperacilline
`+ tazobactam and vancomycine, without or with microwave
`freeze-thaw treatment.
`Table 3 allows the comparison of the unit time of produc(cid:173)
`tion for these molecules, between the years 2000 (wit hout
`freezing) and 2005 (with microwave freeze-thaw treat(cid:173)
`ment).
`During the first period, the average quantity produced
`by batch varies from 24.60 to 45.67 units, according to the
`molecules, with unit times of production varying 3.09 to
`3.60 minutes.
`
`Hospira, Exh. 2023, p. 4
`
`

`
`34
`
`Table 2 Cefepime during t he year 2005.
`Cefepime durant l'annee 2005.
`
`Pha rmacy
`
`Nursing
`
`Average I production
`Preparation time (minute)
`Cost (minute)
`Team cost(€)
`Cost in material used (€)
`
`Total cost (€)
`
`55,830
`3.89
`0.408
`1.587
`0.301
`
`1.888
`
`5.51
`0.533
`2.937
`0.233
`
`3.170
`
`J.-D. Hecq
`
`Difference I
`
`1.282
`
`Table 3 Comparison of t he unit time of production (minute) and quantities produced in 2000 and 2005.
`Comparaison du temps unitaire de production (minute) and /es quantites produites en 2000 et 2005.
`2000
`2005
`
`Mean time
`
`Produced quantity
`
`Mean time
`
`Produced quantity I
`
`Cefepime
`Ceftazidime
`Cefuroxime
`Piperacilline + tazobactam
`Vancomycine
`
`3.48
`3.28
`3.54
`3.60
`3.09
`
`33.72
`45.67
`33.72
`40.13
`24.60
`
`3.89
`3.83
`3.58
`3.99
`3.48
`
`55.83
`53.25
`55.83
`52.64
`52.75
`
`During the second period, the average quantities pro(cid:173)
`duced by batch are higher (52.64 to 5.83) and average times
`of production a little higher (3.48 to 3.99minutes).
`The difference on account of the reconstitution in phar(cid:173)
`macy varies from 1.224 to 1.432€ (Table 4) [67].
`On the basis of indirect load " pharmacy" provided by the
`financial management of the hospital institution, including
`
`the cost of material (Table 5) and the ratio of surfaces of the
`CIVAS within the service of pharmacy, it is easy, by a rule of
`three, to calculate the indirect loads per m2 • This value,
`multiplied by t he number of m2 occupied by the CIVAS, will
`be the n divide d by the numbe r of amounts annually pro(cid:173)
`duced in order to identify t he cost by produced amounts. At
`the Unive rsity Hospital of Mont-Godinne, these values rise
`
`Table 4 Comparison of t he team costs (€)between pharmacy and nursing.
`Comparaison des coQts en personnel (€) entre la pharmacie et le nursing en 2005.
`2000
`
`2005
`
`_ I
`
`Mean time (minute)
`
`Produced quantity
`
`Difference pharmacy/nursing(€)
`
`Cefepime
`Ceftazidime
`Cefuroxime
`Piperacilline + tazobactam
`Vancomycine
`
`3.89
`3.83
`3.58
`3.99
`3.48
`
`55.83
`53.25
`55.83
`52.64
`52.75
`
`-1 .282
`- 1.295
`-1 .408
`- 1.224
`-1 .432
`
`Nursing team cost/minute: 0.533€; pharmacy technician cost/minute: 0.408€
`
`.
`
`Table 5 Material(€).
`Materiel (€) .
`2 meters width vertical laminar air flow hood
`Additional extractor for vertical Laminar air flow hood
`520 liters freezer
`500 liters refrigerator
`Microwave oven
`Thermowelding machine HB 65
`Personal computer for printer
`Printer
`Peristaltic pump
`
`12,576.74
`1295.00
`1298.97
`793.26
`744.20
`5925.54
`1308.00
`1859.20
`5697.56
`
`2
`2
`3
`4
`4
`3
`1
`1
`3
`
`25, 153.48
`2590.00
`3896.91
`3173.04
`2976.80
`17,776.62
`1308.00
`1859.20
`17,092.68
`
`Hospira, Exh. 2023, p. 5
`
`

`
`Centralized intravenous additive services (CIVAS): The state of t he art in 2010
`
`35
`
`with 2.41 € per amount if t he annual production adds up
`20,000 doses, 1.60€ for a production of 30,000 doses, 1.20€
`for 40,000 produced doses and 1.02 per 47 ,000 amounts.
`In this last case, which represents the current annual pro·
`duction, a profit emerges from 0.22 to 0.41 € per produced
`amount.
`
`New developments
`
`In 2004, the USP inserted a new chapter relative to the
`''compounding'': chapter 797 (73] . This chapter describes in
`particular the compounding but the responsibilities for the
`personnel, the levels of risk and their determination, the
`t raining and the evaluation of the personnel, quality and
`control of environment, the limit of the periods of use.
`In addition, a " Guide to good practices for preparation
`off medicinal products in pharmacies" on the initiative of
`the PIC'S (www.picscheme.org). Lastly, in Belgium, a royal
`decree (R.D.) of June 29, 2007 published with the monitor
`of February 23, 2007 (p. 8840- 2) authorizes in particular the
`delegation of preparations to other hospital pharmacists lay·
`ing out of the installation and the equipment adequate or
`with a pharmaceutical company having an authorization of
`manufacture (R.D. of June 6, 1960) relating to the manufac·
`ture and the wholesale distribution of t he drugs.
`This R.D. authorizes thus collaboration between hospi·
`tal for certain packaging operations, reconditioning and
`production. These collaborations can be local, regional or
`national.
`Pharmacy department are now presented with an
`alternative to manually prepared intravenous medica·
`tion: robotic preparation of intravenous medication (74].
`The first modern
`IV
`robot,
`the
`lntellifill
`IV Robot
`(www.fhtinc.com), was int roduced in 2002, followed by
`competitors: RIVA Robot (www.intelligenthospitals.com),
`Cytocare Robot (www.health-robotics.com),
`IV station
`Robot (www.healt h-robotics.com) and Cytotoxic formulat·
`ing machine (http://www.medicaldispensing.nl).
`These robots have similar characteristics: hardware that
`performs the compouding, software to control the process,
`operating in an aseptic ISO class 5 area. Pharmacy staff must
`periodically stock the robot with the appropriate medica·
`tions. Robots can operate in a batch or patient-specific mode
`and must be cleaning between the operations of compound·
`ing.
`At this time, each robot has particular characteristics:
`lntellifill IV Robot produce only syringes, RIVA Robot produce
`syringes and bags, Cytocare Robot is exclusively built for the
`preparation of hazardous medications, IV Station is smaller
`t han t he three preceding robots and can be placed in the
`ward, Cytotoxic formulating machine must be placed in a
`vertical laminar air flow hood and connected with a chimio·
`software (www.computer·engineering.fr).
`
`Conclusion
`
`Already in 1990, Allwood, famous for numerous publica·
`tions about the stability of the injectable drugs affirmed
`t hat "the provision of CIVAS for individual patients is cer·
`tain to be the next leap forward for hospital pharmacy.
`
`Any action that minimises the margin of error or improves
`patient care, as well as reducing costs and litigation risks is
`of increasing significance to health care management. The
`supply of single-dose, patient-specific, ready-to-administer
`parenteral doses, particularly intravenous injections, will
`become an essential aspect of good pharmacy practice, just
`as TPN and cytotoxic preparation services are now firmly
`established" [75].
`Our data show even a very light profitability, which should
`be an additional argument at the time of the annual bud·
`getary decisions.
`The reconstitution of the intravenous treatments by a
`CIVAS contributes to the total management of the care of
`the patients [76].
`
`Conflict of interest statement
`
`None.
`
`References
`
`[1] Turco SJ.Parenteral admixtures and incompati bilities. Sterile
`dosage forms. Their preparation and clinical application. 4th
`ed. Baltimore, MD: Lippincott Williams ft Wilkins; 1994, 239.
`[2] Simmons BP. CDC guidelines for the prevention and control of
`nosocomial infections, guideline for prevention of intravascu·
`tar infections. Am J Infect Control 1983;11 :183-99.
`[3] Taxis K, Barber N. Ethnographic study of incidence and severity
`of intravenous drug errors. Br Med J 2003;326:684-90.
`[4] Kwan JW, Anderson W . Pharmacists's knowledge of infusion
`devices. Am J Hosp Pharm 1991;48:S52- 3.
`[5] Rwabihama JP, Aubourg R, Oliary J, et al. Usage et mesusage
`de la voie intraveineuse pour !'administration de medicaments
`en medecine interne. Presse Med 2006;35:1453-60.
`[6] Clarck C. Safety with injectable medicines. Clin Pharm Eur
`2007; 7: 13-6.
`[7] Allen LY. Parenteral admixture incompatibilities: an introduc·
`tion. Int J Pharm Compd 1997;1:165-7.
`[8] Barnes AR. Near·patient stabilities. J Clin Pharm Ther
`1996;21 :49- 55.
`[9] Connors KA, Amidon GL, Stella VA. Principles of chemical stabil·
`ity of pharmaceuticals. Chemicals stability of pharmaceuticals.
`2nd ed. New York: John Wiley ft Sons; 1986.
`[10] Delneuville I. Quelques aspects galeniques de la preparation
`injectable en milieu hospitalier. Journee de formation post·
`universitaire de !'Association f rancophone des pharmaciens
`hospitaliers de Belgique; 1994.
`[11] Gindre I. Creation d'une base de donnees sur CD·Rom,
`cons:ue dans un langage international a base de pictogrammes,
`concernant la stabilite et la compatibilite des medicaments
`injectables. Memoire du diplome d'etudes specialisees de
`pharmacie hospitaliere et des collectivites. Faculte de phar·
`macie, universite Poincare-Nancy I; 2000.
`[12] Hecq JD, Evrard JM, Matheise G. Stabilite de quelques medica·
`ments utilises en PCA. Douleur Analg 1993;3:85- 100.
`[13] Jaminet F. lnconvenients et incompatibilites des associations
`medicamenteuses dans les solutions pour perfusion. Phar·
`makon 1974;18:7-31.
`[14] Lima HA. Drug stability and compatibility. Specials considera·
`tions for home health care. Int J Pharm Compd 1997;1 :301-5.
`[15] Myhr K. Addition of drugs to infusion fluids. Pharmaceuticals
`considerations on preparation and use. Acta Anaesthesiol Scand
`1985;29:71- 5.
`
`Hospira, Exh. 2023, p. 6
`
`

`
`36
`
`J.-D. Hecq
`
`[16] Newton DW.Physicochemical determinants of incompatibility
`and instability in injectable drug solutions and admixtures.
`Handbook on injectable drugs. 2nd ed. Washington: ASHP;
`1980.
`[17] Newton DW.Physicochemical determinants of incompatibility
`and instability of drugs for injection and infusion. Handbook
`on injectable drugs. 3r<1 ed. Bethesda, MD: ASHP; 1983.
`[18] Stella VJ.Fondamentals of drug stability and compatibility.
`Handbook on injectable drugs. 4th ed. Bethesda, MD: ASHP;
`1986.
`[19] Trissel LA. Drug stability and compatibility issues in drug deliv(cid:173)
`ery. Handbook on injectable drugs. 7th ed. Bethesda, MD: ASHP;
`1992.
`[20] Dickerson RN, Brown RO, White KG.Parenteral nutrition solu(cid:173)
`tions. Clinical nutrition. Parenteral nutrition. 2nd ed. Editions
`Saunders Company; 1993 [edited by Rombeau Jl and Caldwell
`MD].
`[21 J Maki DG, Mermel LA. Infections due to infusion therapy. Hospital
`infections. 4th ed. Lippincott : Raven Publishers; 1998 [edited
`by Bennett JV and Brachman PS].
`[22] Gandy R, Beaumont l, Lee G, Cumming I. Risk management and
`the aseptic preparation of medicines. EHP 1998;4:114-9.
`[23] O'Hare JM, Shapiro MW, Creeden FY. Fatal reaction following
`intravenous 10% dextrose. Am J Surg 1953;85:658-63.
`[24] Michaels I, Ruebner B. Growth of bacteria in infusion fluids.
`Lancet 1953;261 :772-4.
`[25) Wilmore DW, Dudrick SJ. An in-line filter for intravenous solu(cid:173)
`tions. Arch Surg 1961 ;99:462-3.
`[26) Holmes CJ, Allwood MC. The microbiological contamination
`of intravenous infusions during clinical use. J Appl Bacteriol
`1979;46:247-67.
`[27) Ernerot L, Thoren S, Sandell E. Studies on microbial conta(cid:173)
`mination of infusion fluids arising from drug additives and
`administration. Acta Pharm Suec 1973;10:141-6.
`[28) Woodside W, Woodside ME, D'Arcy EM. Intravenous fluids as
`vehicle of infection. Pharm J 1975;215:606.
`[29] Deeb EN, Natsios GA. Contamination of intravenous fluids by
`bacteria and fungi during preparation and administration. Am
`J Hosp Pharm 1971 ;28:764-7.
`[30] Letcher Kl, Thrupp LD, Shapiro DJ. In use contamination of
`intravenous solutions in flexible plastic containers. Am J Hosp
`Phann 19n;29:673-6.
`[31) Dieu B. Etude de la contamination microbienne des melanges
`medicamenteux extemporanes administres par perfusion
`veineuse. Faculte de medecine et de pharrnacie de Rouen;
`1983.
`[32) Mansfield A. An observational study in four hospitals. Current
`issues in intravenous preparation and administration in Europe.
`Baxter satellite symposium. EAHP Amsterdam; 2001.
`[33] Cousins DH, Sabatier B, Segue D, et al. Medication errors in
`intravenous drug preparation and administration: a multicen(cid:173)
`tre audit in UK, Germany and France. Qual Saf Health Care
`2005;14:190- 5.
`[34] Guchelaar HJ, Colen HBB, Kalmeijer MD, et al. Med(cid:173)
`ication errors, hospital pharmacist perspective. Drugs
`2005;65:1735-46.
`[35) Greengold NL, Shane R, Schneider P, et al. The impact of ded(cid:173)
`icated medication nurses on the medication administration
`error rate. Arch Intern Med 2003;163:2359-67.
`[36) Calabrese AD, Erstad BL, Brand K, et al. Medication adminis(cid:173)
`tration errors in adult patients in the ICU. Intensive Care Med
`2001;27:1592- 8.
`[37) Hartwig SC, Denger SD, Schneider PJ. Severity-indexed incident
`report-based medication error-reporting program. Am J Hosp
`Pharm 1991;48:2611-6.
`[38) Tissot E, Cornette C, Capellier G, et al. Assessment of med(cid:173)
`ication errors: methodological details. Intensive Care Med
`1999;25:1478.
`
`[39] Wirtz V, Taxis K, Barber N. An observational study of intra(cid:173)
`venous medication errors in the United Kingdom and in
`Germany. Pharm World Sci 2003;25:104- 11 .
`[40) Taxis K, Barber N. Causes of intravenous medication errors:
`an ethnographic study. Qual Saf Health Care 2003;5:
`343-7.
`[41) Taxis K, Barber N. Incidence and severity of intravenous
`drug errors in a German hospital. Eur J Clin Pharmacol
`2004;59:815-7.
`[42] Taxis K, Barber N. Ethnographic study of incidence and
`severity of intravenous drug errors. Br Med J 2003; 326:
`684-7.
`[43) Dubois C, Dive A, Bourtembourg M, et al. Apport d'un pharma(cid:173)
`cien hospitalier dans une unite de soins intensifs. Experience
`aux cliniques universitaires UCL de Mont-Godinne. AG AFPHB;
`2002.
`[44) Serurier C, Chenot ED, Vigneron J, et al. Assessment of
`injectable drug's administration in two intensive care units and
`determination of potential physico-chemical incompatibilities.
`Eur J Hosp Pharm Sci 2006;5:96-9.
`[45) Tissot E, Cornette C, Demoly P, et al. Medication errors at the
`administration stage in an intensive care unit. Intensive Care
`Med 1999;25:353-9.
`[46] Gikic M, Di Paolo ER, Panatier A, et al. Evaluation of
`physicochemical incompatibilities during parenteral drug
`administration in a pediatric intensive care unit. Pharm World
`Sci 2000:88-91 .
`[47) Benjamin B. Proceedings of a summit on preventing patient
`harm and death from i. v. medication errors. Am J Health Syst
`Pharm 2008;65:2367-79.
`[48) Sanborn MO, Moody ML, Harder KA, Pepper GA, Scanlon M, Vaida
`AJ, Zuggic M. Second