International Journal for Quality in Health Care 2010; Volume 22, Number 3: pp. 170 – 178
`Advance Access Publication: 9 April 2010
`
`10.1093/intqhc/mzq015
`
`Risk and pharmacoeconomic analyses of
`the injectable medication process in the
`paediatric and neonatal intensive
`care units
`
`ISABELLA DE GIORGI 1,2, CAROLINE FONZO-CHRISTE 1, LAURENCE CINGRIA 1, BE´ATRICE CAREDDA 3,
`VALE´RIE MEYER 3, RICCARDO E. PFISTER 3 AND PASCAL BONNABRY 1,2
`
`1Department of Pharmacy, Geneva University Hospitals, Geneva, Switzerland, 2School of Pharmaceutical Sciences, Universities of Geneva
`and Lausanne, Geneva, Switzerland, and 3Neonatal and Paediatric Intensive Care Units, Geneva University Hospitals, Geneva, Switzerland
`
`Address reprint requests to: Prof Pascal Bonnabry, Department of Pharmacy, Geneva University Hospitals, 4, rue Gabrielle-Perret-Gentil, 1211
`Geneva 14, Switzerland. Tel: þ41-22-382-39-74; Fax: þ41-22-382-39-70; E-mail: pascal.bonnabry@hcuge.ch, http://pharmacie.hug-ge.ch
`
`Accepted for publication 11 March 2010
`
`Abstract
`
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`Objective. To analyse safety risks in injectable medications. To assess the potential impact and pharmacoeconomic aspects of
`safety tools.
`
`Design. The injectable drug process was prospectively assessed using a failure modes, effects and criticality analysis. Criticality
`indexes were estimated based on their likelihood of occurrence, detection probability and potential severity. The impact of 10
`safety tools on the criticality index was calculated and extrapolated to all drugs injected daily. Yearly costs for a reduction in
`criticality by 1 point (¼1 quali) per day were estimated.
`
`Setting. Paediatric and neonatal intensive care units in a University Hospital.
`
`Participants. Two paediatric nurses, a neonatologist, three hospital pharmacists.
`
`Interventions. Qualitative and quantitative risk assessment.
`
`Main Outcome Measures. Failure modes, criticality indexes, cost-efficacy ratios.
`
`Results. Thirty-one failure modes identified, with the mean of their entire criticality indexes totalling 4540. The most critical
`failure mode was microbial contamination. The following gains were predicted: 1292 quali (46 500 per day by extrapolation)
`from ready-to-use syringes, 1201 (72 060) by employing a clinical pharmacist, 996 (59 780) from double check by nurses and
`984 (59 040) with computerized physician order entry. The best cost-efficacy ratios were obtained for a clinical pharmacist
`(1 quali ¼ 0.54 euros), double check (1 quali ¼ 0.71 euros) and ready-to-use syringes (1 quali ¼ 0.72 euros). Computerized
`physician order entry showed the worst cost-efficacy ratio due to a very high investment costs (1 quali ¼ 22.47 euros).
`
`Conclusion. Based on our risk and pharmacoeconomic analyses, clinical pharmacy and ready-to-use syringes appear as the
`most promising safety tools.
`
`Keywords: paediatrics, risk assessment, FMECA, hospital pharmacy services, cost-efficacy analysis, intensive care
`
`Introduction
`
`Medication errors are causing significant harm to hospitalized
`patients with high economic implications; the risk is particu-
`larly high in intensive care units [1]. Although medication
`errors and adverse drug events (ADEs) have received substan-
`tial attention in adults, relatively few published reports have
`addressed this issue in children. Information on paediatric
`medication use, particularly in neonates, is often lacking [2].
`
`Paediatric patients need weight-based dosing, which necessi-
`tates more calculations than for adults [3]. In addition, the
`range of licensed medications in appropriate dosage forms is
`limited, thus often requiring complex dose and dilution calcu-
`lations before administration. Previous studies have identified
`an error rate of 13 – 84% in hospitals when preparing and
`administering intravenous drugs to infants and children [4 – 6].
`Dose calculations are a common contributor to medication
`errors, with a factor 10 error being among the most common
`
`International Journal for Quality in Health Care vol. 22 no. 3
`# The Author 2010. Published by Oxford University Press in association with the International Society for Quality in Health Care;
`all rights reserved
`
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`[7]. In a 6-week prospective study in two university paediatric
`institutions, Kaushal et al. [8] found that medication errors
`occurred for 5.7% of prescriptions. Although the preventable
`ADEs rate was similar to that found in adult inpatients, errors
`with the potential to cause harm were three times more likely
`to occur in paediatric inpatients.
`risk analysis
`Awareness
`is
`growing
`that prospective
`approaches as used in a number of high hazard industries need
`to be applied to health care [9, 10]. Among other methods, the
`‘failure modes, effects and criticality analysis’ (FMECA) is a
`well-described tool to systematically assess a process. It ident-
`ifies possible or likely errors (‘failure modes’), and gauges what
`their effect may be even before they take place [11]. FMECA
`includes a quantitative evaluation of the criticality of each failure
`mode, and compares the top critical events in different process
`organizations, allowing a simple estimation of the impact of
`new tools on patient safety even before their implementation.
`The objectives of the current study were to perform a
`prospective risk analysis to quantitatively evaluate the safety
`of the current injectable medication process in the paediatric
`and neonatal intensive care units (PICU and NICU) of our
`University Hospital, with a special focus on the preparation
`and administration steps. We compared the potential impact
`of 10 safety tools on risk of ADEs and also classified these
`tools using pharmacoeconomic criteria.
`
`Method
`
`Setting
`
`The study was based on the activity of the PICU (10 beds)
`and the NICU (15 beds) of the Geneva University Hospitals
`(2000 beds).
`
`Current injectable medication process in the PICU and NICU. At
`the time of analysis, prescriptions were handwritten by the
`medical staff. Drug dispensing was performed by nurses
`from a ward stock, the stock being refilled by global orders
`to the central pharmacy. Nursing staff transcribed the orders
`to the nurse care plan and selected the drug from the ward
`stock for preparation and administration. No horizontal
`laminar flow hood (HFLA) was used for the preparation, but
`parenteral nutrition and some other drugs were compounded
`at the pharmacy. The name of the drug, the flow rate and
`the concentration of the solution were written on a sticky
`label for the prepared injectable. No systematic double check
`of the preparation (calculation, drugs used, dilution) was
`performed by a second nurse. Injectables were administered
`using syringe or volumetric pumps. No in-line filters were
`used with infusion lines. There was no clinical pharmacist
`integrated in any units but regular visits were organized by a
`pharmacist
`to discuss problems of preparation and
`administration of drugs with nurses.
`In the meantime, a computerized physician order entry
`(CPOE) named Clinisoftw and including clinical decision-
`support systems like monitoring of vital functions,
`infor-
`mation on drugs, patient history,
`laboratory and radiology
`results has been implemented.
`
`Risk and pharmacoeconomic analyses
`
`Design
`
`A FMECA was performed by a multidisciplinary team (two
`specialized nurses, a neonatologist and three hospital phar-
`macists) [12]. The analysis focused on the entire medication
`process of injectables, from prescription to administration,
`with a special attention to preparation and administration
`steps.
`
`FMECA risk analysis. A brainstorming strategy was used to
`determine all possible ways the injectable medication process
`might fail. Each team member had to write down all risks
`and possible failures they could envisage. These suggestions
`were then assembled and organized during a common
`discussion to become the failure modes. An Ishikawa’s
`diagram was built to organize them step by step (Fig. 1).
`Three frequently used drugs with different characteristics
`were chosen as models for injectables: gentamicin for anti-
`biotics and other common injectables; morphine for analge-
`sics and narcotics; dopamine for vasoactive and monitored
`drugs. The likelihood of occurrence of each failure mode for
`each model drug was classified from 1 to 10, the severity of
`the potential effect for the patient from 1 to 9 and the prob-
`ability to detect the failure from 1 to 9. The evaluation was
`carried out according to standardized tables, taking care to
`remain coherent in ranking similar events [12]. Scores were
`obtained by consensual quotation in the team. In particular,
`occurrence was supported by data from the systematic critical
`incident reporting of the two ICUs. The criticality index of
`each failure mode was calculated by multiplying the fre-
`quency, severity and detection scores, yielding a minimum of
`1 and a maximum of 810. The top 10 critical failure modes
`were determined by ranking the mean criticality indexes of
`the three model drugs.
`Ten tools to improve safety were chosen empirically
`(Table 1). Their potential benefit on the criticality indexes of
`the three model drugs was again assessed by the FMECA
`method.
`The term ‘quali’ ( plural: quali) was created to allow a con-
`venient transposition from the notion of criticality to the
`quality gain in the medication process. One quali was defined
`as a reduction of the criticality index by one point. Quali for
`the top 10 critical failure modes were compared between the
`different safety tools analysed.
`
`Generalization for economic estimate. As required in economic
`analyses, an extrapolation to the use of all daily injectable
`drugs was performed for each safety improvement tool (see
`Table 1), using data compiled during a large survey performed
`during the year 2003 in the same units [13]. On average, 7
`patients with 8 drugs per day were hospitalized in the PICU
`and 14 patients with 3 drugs in the NICU (overall a total of
`98 drugs per day). About 60 drugs were used as injectables.
`
`Cost analysis. Cost analysis was performed from a hospital
`perspective. The required investment in euros per year was
`calculated for each tool (at the time of publication: 1 euro ¼
`1.50 CHF ¼ 1.43 USD ¼ 130.90 JPY). Only direct costs
`were considered. Only medical supplies such as syringes,
`needles, in-line filters, face masks, etc. were taken into account
`
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`Figure 1 The Ishikawa’s diagram illustrating the five steps of the medication process with their associated failure modes.
`
`intermediate
`simple additional measures of asepsis,
`for
`dilution, in-line filters and vials of dilution. Additional human
`resources were necessary for double check by nurses and
`clinical pharmacist. The nurse’s double-checking time at each
`potential failure point was estimated at 20 s [14]. The total
`time for all injectable drug checks was converted into euros
`using the local wages scale (100% salary for nurse with
`intermediate level of experience ¼ 45 000 euros per year).
`The daily time requirements for a clinical pharmacist for both
`units were estimated to 50% (half-salary for pharmacist with
`intermediate level of experience ¼ 40 000 euros per year).
`The tasks considered for the clinical pharmacist were (i) to
`check the correct use of drugs by nurses through specific
`though not systematic interventions concerning preparation
`(respect of concentration; of solvent; etc.) and administration
`(detection of physicochemical
`incompatibilities; check the
`flow rate according to concentration of the solution, etc.) and
`(ii) audits of the drugs stock (organization; fridge, etc.). For
`the CPOE,
`initial
`investment costs and maintenance costs
`during 1 year were estimated at 1 million euro and 300 000
`euros, respectively. The estimations of initial investment and
`maintenance costs have been provided by the head of medical
`informatics’ team of the hospital. These costs are specific for
`a system to be used in the intensive care environment (adults
`
`and children), but cover the whole cost of the electronic
`patient record (not only the CPOE). For HFLA, the estimated
`costs included an initial investment plus the cost of aseptic
`preparations in the units. We estimated that 15 drugs could be
`provided in ready-to-use syringes (CIVAS), and we calculated
`the costs of development (3620 euros by drug), as well as
`their production cost (1.21 euros per syringe), based on our
`previous experience. The drug planner induced no costs [15].
`Cost-efficacy analysis. The cost
`in euros required for an
`improvement of one quali per day was calculated for each
`safety improvement tool by dividing the investment per year
`by all yearly quali (extrapolation from all daily injected drugs).
`
`Sensitivity analysis. A sensitivity analysis was performed to
`evaluate the influence of variations in estimated parameters
`on total costs (Table 1).
`
`Results
`
`The medication process of injectables was split up into
`five major steps, prescription,
`transcription, preparation,
`administration and storage. A total of 31 failure modes were
`determined during the brainstorming sessions (Fig. 1).
`
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`Risk and pharmacoeconomic analyses
`
`Table 1 The 10 safety tools, their associated costs, the percentage of injectable drugs injected daily affected by each safety
`tool, the extrapolated number used to multiply mean criticality index, and the parameters for sensitivity analysis, together
`with their estimated variation
`
`Safety tool
`
`Associated costs
`
`Percentage of affected
`injectable drugs
`(normalized per day)
`
`Extrapolated number
`to multiply mean
`criticality index
`(max ¼ 60)
`
`Sensitivity analysis:
`parameters with
`estimated variations
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`Free
`2964 800 euros on
`mean cost per
`year ¼ initial
`investments written off
`after 5 years
`+5 s spent for a check
`
`+10 years of
`experience
`+0.31 euros on price
`of a syringe (R & D)
`+0.42 euros on price
`of a vial
`
`No variation
`
`+2 in-line filters used
`by day (filters blocked;
`number of patients or
`central line)
`No variation
`
`27236 euros on mean
`cost per year ¼ initial
`investments written off
`after 5 years
`free
`
`Current situation
`Computerized
`physician order entry
`
`No costs
`Initial investment and
`maintenance
`
`100%
`100%
`
`Double check by
`nurses
`Clinical pharmacist
`
`Human resources
`
`100%
`
`Human resources
`
`100%
`
`Ready-to-use syringes
`
`Vial of dilution
`
`Development &
`production costs
`Medical supplies
`
`Intermediate dilutions Medical supplies
`
`In-line filters
`
`Medical supplies
`
`60% could be prepared
`as ready-to-use syringes
`45% concerned by a
`withdrawal of a small
`volume (,0.5 ml)
`45% concerned by a
`withdrawal of a small
`volume (,0.5 ml)
`70% administered via a
`central line
`
`Simple additional
`measures of asepsis
`Horizontal laminar
`airflow hood in the
`unit
`
`Medical supplies
`
`72% not ready-to-use
`
`Initial investment and
`medical supplies
`
`72% not ready-to-use
`
`Drug planner
`
`No costs
`
`16% administered at
`unusual dosing interval
`(e.g. every 18 h)
`
`60
`60
`
`60
`
`60
`
`36
`
`27
`
`27
`
`42
`
`42
`
`42
`
`10
`
`FMECA risk analysis
`
`The criticality indexes calculated from the frequency, severity
`and detection scores estimated by the team for each failure
`mode are summarized in Table 2. The average sum of all criti-
`cality indexes was 4540. Among the model drugs, gentamicin
`totalized the greatest sum of criticality index, followed by mor-
`phine and dopamine. The most critical failure mode (mean cri-
`ticality index ¼ 432) was microbial contamination during the
`preparation of medicines. The top 10 critical failure modes
`concerned mainly preparation (5 failure modes), followed by
`administration (4) and transcription (1). Top failure modes for
`preparation were microbial contamination (432), dosage errors
`(343), dilution errors (312), labelling errors (224) and selection
`errors (171). Top failure modes for administration were phys-
`icochemical
`incompatibilities (330), wrong flow rate (317),
`
`selection error (208) and drug given twice (194). The failure
`mode during transcription was poor writing and reading (235).
`
`Generalization for economic estimate
`
`In a total of 4540 criticality points averaged between the
`model drugs (272 400 criticality indexes per day by extrapol-
`ation), we expected to gain 1292 quali (46 500) with CIVAS,
`1201 (72 060) with a clinical pharmacist, 996 (59 780) with
`double check by nurses, 984 (59 040) with CPOE, 555
`(23 296) with in-line filters, 457 (12 348) with vial of dilution,
`408 (17 122) with HFLA, 170 (4590) with intermediate
`dilution, 144 (6192) with simple additional measures of
`asepsis and 98 (951) with the drug planner.
`The differences in quali of each safety tool for the top 10
`critical failure modes are shown in Fig. 2. For the most
`
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`Table 2 Failure modes and criticality indexes for the model drugs (top 10 of failure modes in grey)
`
`Failure modes
`
`During the study
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Gentamicin Morphine Dopamine Mean
`criticality
`index
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`245
`126
`105
`224
`60
`126
`160
`
`252
`162
`432
`245
`343
`336
`168
`192
`72
`108
`45
`56
`343
`336
`392
`378
`96
`
`336
`28
`56
`196
`48
`24
`48
`
`105
`54
`12
`224
`40
`126
`7
`
`252
`81
`432
`24
`294
`216
`120
`224
`35
`105
`60
`48
`294
`360
`126
`72
`56
`
`280
`28
`28
`196
`64
`32
`30
`
`48
`18
`9
`256
`16
`144
`48
`
`8
`96
`432
`18
`392
`384
`120
`256
`35
`56
`108
`72
`315
`294
`64
`56
`32
`
`8
`70
`98
`80
`192
`96
`36
`
`133
`66
`42
`235
`39
`132
`72
`
`171
`113
`432
`96
`343
`312
`136
`224
`47
`90
`71
`59
`317
`330
`194
`169
`61
`
`208
`42
`61
`157
`101
`51
`38
`
`Prescription
`
`Transcription
`
`Dosage error
`Prescription omitted
`Prescription omitted to be transcribed
`Poor writing and reading
`Stop order omitted
`Error of writing on the preparation card stuck on the pumps
`Wrong selection between two different drugs (sound-alike,
`look-alike, etc.)
`Wrong selection between several dosages or salts of a drug
`Wrong selection of the solvent of reconstitution or dilution
`Microbial contamination
`Preparation of a drug forgotten
`Dosage error
`Dilution error
`Error of calculation of the patient’s parameters
`Error in labelling of a prepared drug
`Precipitation (high concentration)
`Chemical degradation of drugs in a mixed preparation
`Inaccuracy of small volumes withdrawal
`Administration Pump doesn’t work
`Wrong flow rate
`Physicochemical incompatibilities
`Drug given twice
`Wrong administration time
`Wrong selection between two different drugs (sound-alike,
`look-alike, etc.)
`Wrong selection between several dosages or salts of a drug
`Wrong route of administration
`Wrong injection site
`Wrong patient
`Air introduced in central intravenous tubing
`Air introduced in peripheral intravenous tubing
`Storage (protection for light, temperature control of drugs,
`expiry date)
`
`Preparation
`
`Storage
`
`Total
`
`5738
`
`4025
`
`3857
`
`4540
`
`critical failure mode, i.e. microbial contamination, five safety
`tools allowed a gain in quali. The greatest improvement of
`384 quali was obtained with CIVAS whereas intermediate
`dilution was associated with a loss of quali (272). Six safety
`tools gained quali for the second most critical failure mode,
`dosage errors during preparation. For the third most critical
`failure mode, the wrong flow rate, almost none of the pro-
`posed tools allowed a significant safety improvement.
`
`quadrants, according to yearly costs gained per quali and total
`quali gained. Intervals were calculated with the sensitivity
`analysis. The best cost-efficacy ratio were obtained for a clini-
`cal pharmacist (1 quali ¼ 0.54 euros), for double check by
`nurses (1 quali ¼ 0.71 euros) and for CIVAS (1 quali ¼ 0.72
`euros). The CPOE showed the worst cost-efficacy ratio due to
`the very high investment costs (1 quali ¼ 22.47 euros).
`
`Cost-efficacy ratio
`
`Discussion
`
`Cost in euros per year and associated gain in quali for each
`tool are represented in Fig. 3. The 10 tools are laid out in four
`
`Our work confirms that FMECA is a feasible tool for a
`proactive assessment of the injectable medication process in
`
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`Figure 2 Top 10 of failures modes and comparative gain or loss of quali for each safety tool (mean CI ¼ mean criticality index).
`
`Figure 3 The 10 safety tools are laid out in four quadrants, according to yearly costs to gain 1 quali per day and total quali
`gained per day. Intervals were calculated with a sensitivity analysis.
`
`the PICU and NICU, even before the occurrence of
`adverse events. As most medication errors are multi-
`factorial, an FMECA was particularly useful
`in that
`it
`
`the global medication process.
`allowed consideration of
`Such errors are difficult to study and FMECA is a novel
`approach to predict
`the most cost-effective interventions.
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`simple tool can be used for all drugs with uneven injected
`times. Although the impact of this tool is limited, its cost is
`virtually zero.
`CPOE improved a considerable number of failure modes,
`but at high relative costs. A number of publications advocate
`the positive impact of a CPOE on drug prescription and
`administration safety
`in paediatric
`inpatients
`[28, 29].
`However, CPOE for paediatric drug management may also
`introduce new errors unseen with the previous paper pre-
`scription [30]. Han et al. [31] even reported an increase in
`mortality from 2.8 to 6.6% in a paediatric referral centre
`after implementation of a commercially available CPOE
`system. This unexpected result was only partially attributable
`to the new prescription tool itself, and was associated with
`major changes in the organization processes. Such contradic-
`tory results highlight the difficulty of a successful implemen-
`tation of a CPOE, no doubt influenced by the quality and
`the exhaustiveness of the program itself, but also by numer-
`ous technical, organizational, cultural and human factors.
`CPOEs are often included in more complete electronic
`patient record systems, and their high costs may be justifiable
`as their advantages extend well beyond the specific safety
`issues of injectable drugs.
`Overall, the two major interests of an FMECA are its
`simple application and the quantitative character of the evalu-
`ation made possible by combining three complementary
`factors. The evaluation is easy to perform and not too time-
`consuming. A FMECA is therefore very helpful to decide
`and prioritize actions to be taken. Moreover the active brain-
`storming and discussion necessary to find consensual bench-
`marks contribute to the development of a very clear and
`shared vision of the process organization, accounting for all
`the different perspectives. The structured analysis allows con-
`structive,
`objective
`and
`respectful
`discussions. Team
`members noticed that they gained extensive comprehension
`on each other’s constraints.
`The major limitation of FMECA is an unavoidable subjec-
`tivity component. As the team becomes larger and multidis-
`ciplinary this bias is minimized. In the current study, we
`obtained consensual benchmarks between all members of
`the team, thus guaranteeing the highest possible objectivity.
`To further limit variability, the scores were based on explicit
`criteria published earlier [12]. It should be noted that the
`specific mark found for a failure mode is not an essential
`result, as the main goal is to rank risks and compare orders
`of magnitude. A further limitation is that it is impossible to
`assess the impact of a combination of multiple failures on a
`specific outcome. However,
`the separate analysis of each
`failure mode is also an advantage as it leads to a deeper
`understanding of the risk associated to each step, thus allow-
`ing targeted improvements. The FMECA method has not
`been fully validated but is recommended by the Institute for
`Healthcare Improvement [32].
`Our
`results on criticality of
`injectable medication are
`specific to our local situation. Conclusions may not be
`directly applicable to the injectable medication process in
`every PICU. However, the impact of some safety tools on
`the criticality can easily be generalized. Most of the reported
`
`De Giorgi et al.
`
`These would then need to be tested and measured in
`PICUs and NICUs.
`Unlike other reports, we voluntarily did not focus exclu-
`sively on prescriptions by examining also the preparation and
`administration steps, which are seldom investigated in the lit-
`erature [16]. Prot et al. [17] for instance analysed and classi-
`fied drug administration errors but did not include errors
`occurring during the preparation step. However, such specifi-
`cation appears to make sense, since errors at the adminis-
`tration stage have been found to be the most common ones
`in paediatric patients [18].
`In our current work, microbiological contamination during
`preparation was the most critical failure mode. A similar
`result was found in a recently published large multi-centre
`audit of six European hospital departments [19]. Aseptic
`procedures required for the safe preparation of intravenous
`drugs were frequently violated by staff, often unaware of the
`potential harm. CIVAS offer a safe alternative to reduce
`microbiological contamination and dilution errors and avoid
`drug wastage. An earlier development of ready-to-use vanco-
`mycin syringes for our NICU was very satisfying [20]. HFLA
`alone was unable to significantly reduce risks of microbiolo-
`gical contamination as it requires qualified operators, standar-
`dized protocols and a quality control procedure to be
`efficient.
`The difficulties encountered when preparing infusions
`from concentrated stock solutions in intensive care units are
`highlighted in the literature [21, 22]. To further improve
`preparation in paediatrics,
`the most critical step in this
`FMECA, we have begun studying the safest procedure with
`the best accuracy for solutions prepared by three different
`techniques:
`(i) small volumes withdrawn as currently,
`(ii)
`intermediate dilutions and (iii) standardized vials of dilution.
`The most cost-effective way of reducing the criticality of
`injectable drugs was expected for a clinical pharmacist in the
`NICU and PICU. Physicochemical
`incompatibilities during
`administration were one of the most critical failure modes,
`and its improvement was worthy of note. Our results agree
`with numerous publications demonstrating the benefit of a
`paediatric clinical pharmacist, particularly in the prescription
`step [23, 24]. One study reported savings of $9135 per year
`in a 10-bed PICU of a university-affiliated children’s hospital
`[25].
`The use of in-line filters was proposed in order to reduce
`microbiological contamination of injectable medications, but
`there is no convincing evidence so far of their efficiency in
`preventing catheter-related infections [26]. The advantages of
`such devices are a reported reduction of phlebitis, and the
`elimination of air, filtration of particulate contaminants and
`drugs precipitates. The fact that in-line filters cannot be used
`with colloids and blood and may complicate drug adminis-
`tration by adsorption and are expensive has to be considered
`in the cost-efficacy analysis [27].
`Some drugs with uneven administration times, such as
`gentamicin, are particularly prone to wrong administration
`times. To avoid errors in the calculation of the correct
`administration time, a drug planner giving the time of next
`injection based on the last injection may be used [15]. This
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`Amneal Pharmaceuticals LLC – Exhibit 1015 – Page 176
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`failure modes also concern other institutions and our data
`appear as a good starting point to locally repeat a similar
`evaluation of the medication process.
`
`Conclusion
`
`The use of a prospective risk analysis such as FMECA has
`allowed a quantitative evaluation of the safety of paediatric
`patients in connection with the injectable medication process.
`The FMECA allowed generating tools for continuous safety
`improvement by modelling the relative safety gain for specific
`tools or new developments. Based on a pharmacoeconomic
`analysis in our local setting, the involvement of a clinical phar-
`macist and the introduction of ready-to-use syringes for selected
`drugs have been shown to be the most cost-effective tool.
`
`Acknowledgements
`
`The authors wish to acknowledge Prof. Bernard Testa for
`the careful reading of the article.
`
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