You are here

Article Text

Article menu

Download PDFPDF

Review
Accuracy of intravenous and enteral preparations involving small volumes for paediatric use: a review
Free
  1. L P Ainscough1,
  2. J L Ford1,
  3. C W Morecroft1,
  4. M Peak2,
  5. M A Turner3,
  6. A J Nunn1,2,
  7. M Roberts1
  1. 1School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
  2. 2Paediatric Medicines Research Unit, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
  3. 3Liverpool Women's Hospital NHS Foundation Trust, Liverpool, UK
  1. Correspondence to Dr M Roberts, School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK; m.roberts1{at}ljmu.ac.uk

Abstract

Background Children often need to be administered very small volumes of medicines that are authorised for use in adults. Neonatal drug delivery is particularly challenging, and doses are often immeasurable with the equipment currently available.

Aim To summarise research to date on the accuracy of intravenous and enteral medicine preparation requiring small volumes (<0.1 mL), with a focus on paediatric use and to identify areas for further work.

Method Twenty-three publications were identified for the narrative review via: Web of Science (1950–2016), Cumulative Index to Nursing and Allied Health Literature (1976–2016), Excerpta Medica Database (1974–2016) and International Pharmaceutical Abstracts (1970–2016) searches. Nine additional papers were identified through backward citation tracking and a further 17 were included from the personal knowledge of the review team.

Results Measurement of volumes (<0.1 mL), for enteral and intravenous dosing, accounts for 25% of medicine manipulations within paediatric hospitals. Inaccuracies are described throughout the literature with dose administration errors attributed to technique, calculation, dilution and problems associated with equipment. While standardised concentrations for intravenous infusion and drug concentrations that avoid measurement of small volumes would ameliorate problems, further work is needed to establish accurate methods for handling small volumes during the administration of medicines to children and risk minimisation strategies to support staff involved are also necessary.

Conclusions This review has revealed a paucity of information on the clinical outcomes from problems in measuring small volumes for children and highlighted the need for further work to eliminate this source of inaccurate dosing and potential for medication error.

  • PAEDIATRICS
  • MEDICAL ERRORS

https://doi.org/10.1136/ejhpharm-2016-001117

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    EAHP Statement 6: Education and Research

    Introduction and background to paediatric medicine

    Children have historically been referred to as ‘therapeutic orphans’,1 suggesting that they were traditionally overlooked within research into disease and pharmacological treatment. This has considerably limited the numbers of licensed or authorised medicines available for children.2 In healthcare, the term ‘children’ is often used as an umbrella term for all subgroups of paediatric patients and can cover preterm babies weighing 500 g to adolescents weighing 100 kg. The physiological and pharmacological disparity between them is profound, creating further challenges in developing suitable drug therapy in this area.3

    Newer legislation, such as the European Union's Paediatric Regulation, has been put in place as the growing need for the development and authorisation of children's medicines has been recognised.4 A report by the European Commission stated that as a result of the regulation, paediatric medicine has become an integral part of medicine development with >600 paediatric investigation plans (PIPs) being agreed from 2007 to 2012.4 The effect on drug development remains to be seen due to the lengthy nature of trials and legalities surrounding marketing authorisation. Neonates are the most neglected group in this population as only 30% of current PIPs include them.4

    The lack of commercially available age-appropriate formulations makes it difficult to administer medicines to children accurately.5 Doses required for children can vary 100-fold throughout childhood. Consequently, proportions of the marketed dosage forms are required to allow an appropriate paediatric dose to be given by manipulation, often with a medicine being used off-label.6 ,7 Examples of manipulation include additional dilution of an injection to allow the required volume to be measured accurately or to provide an accurate rate of infusion. Manipulation occurs frequently in specialist and high dependency care, and research has shown that this often leads to errors.8

    Previously, 12.3% of prescribed doses of liquid medicines (for oral and intravenous use) on neonatal intensive care units (NICUs) and other children's wards were reported as being immeasurable with the available dosage forms.9 Additionally, only 35% of prescriptions issued on NICU use formulations in a licensed way; a figure far less than in other areas of paediatric medicine10–12 despite advances made towards innovative drug formulations for paediatric patients.4 An important consequence of this is that healthcare professionals are often required to give children very small volumes of medicines that are licensed for use in adults.13–15 Intravenous delivery is the most widely used method of medicine administration in very ill preterm and term neonates and children.16

    Children are exposed to potential adverse drug events up to three times more frequently than adult inpatients, and it is estimated that up to 54% of these errors involve intravenous medicines.17 In high dependency units, such as NICU, 91% of admissions were associated with a medication error compared with 50% of neonatal admissions to other wards.17 Medication error rates vary widely between studies, depending on settings and methods involved. In a review of 11 studies, Chedoe et al18 identified that the highest rate at which medication errors occur in NICU was 5.5 errors per 100 prescriptions. Prescribing and administration errors, across five different hospitals in London, were reported on average as 13.2% and 19.1%, respectively, and administration errors most commonly originated from medicine preparation errors.19 Patients in this setting are at a greater risk due to the small volumes often required; an error that may only seem slight to the naked eye but could represent a 10-fold error or more, a scenario unlikely to occur in the adult setting.20

    Where children and medication errors are concerned, higher risk is associated with increased vulnerability to adverse effects. This risk is due to a number of factors: inability to communicate effectively; a higher prevalence of rare diseases in childhood, thus creating a lack of clinical experience in treatment; constant physical and psychological changes over time, including intraindividual and interindividual variation in drug metabolism during growth and development; small medicine doses often involving decimal points, thus giving opportunity for significant degrees of error; and errors in prescription writing due to the lack of appropriate formulations.21–23 The need to reduce medication errors and improve patient safety in this area is clear.

    Methods

    Search strategy

    Searches were undertaken using four databases: Web of Science (1950–2016), Cumulative Index to Nursing and Allied Health Literature (1976–2016), International Pharmaceutical Abstracts (1970–2016) and Excerpta Medica Database (1974–2016). Limits were applied to the Web of Science search (see online supplementary appendix A). An adaptive search strategy, based on one developed for a previous review, was used.24 The search strategy is presented in online supplementary appendix B. Following the selection of publications for inclusion, backward citation tracking was undertaken for each paper if it was indexed in SCOPUS. Additional relevant publications were highlighted for inclusion by members of the review team.

    Selection of papers for inclusion

    Titles and abstracts were screened by one reviewer (LPA). Three experts in the field of paediatric and neonatal formulation research (AJN, MAT and JLF) reviewed the titles selected to confirm that they were suitable for inclusion and to recommend the inclusion of any additional literature known to them. Publications were included in this review if they related to the accuracy of intravenous and enteral medicine preparation for children and/or involved small volumes (<0.1 mL).

    Results

    Search results

    Database searches identified 5948 unique references, of which 2313 ,15 ,19 ,25–44 were selected. A further nine references were identified through backward citation tracking14 ,45–52 and 17 were highlighted by the review team5–9 ,53–64 (see online supplementary appendix C).

    Narrative review

    Manipulation of medicines for intravenous and enteral use: small volumes

    Recent studies have investigated the practice of manipulating medicines in order to provide accurate doses for children, in particular the requirement to dilute very small volumes (<0.5 mL).13–15 One study identified that the measurement of volumes of <0.1 mL, for both enteral and intravenous dosing, accounts for a quarter of medicine manipulations within paediatric and neonatal hospital settings. Frequently, these volumes are required for intravenous administration.15 Isaac et al35 found that 25% of patients on paediatric intensive care units were prescribed a medicine that required a small volume measurement of ≤0.2 mL, with the intravenous route accounting for 80% of the drug delivery methods. Uppal et al14 provide further support, stating that 7.4% of intravenous doses require preparation with <0.1 mL of stock solution. It was concluded that this is necessary for the paediatric use of a wide range of narcotics and immunosuppressants in Canada14 with captopril, morphine, furosemide and ranitidine the most commonly found in the UK.35

    Small volume measurement and preparation for administration often involves the administrator using relevant calculations, along with dilution and subsequent mixing with compatible diluents, thereby introducing a potential for errors to occur. A number of publications suggest that a high incidence of imprecision and dilution errors occur in the preparation of intravenous medicines and the preparation of small volumes of medicines is inaccurate.13 ,26 ,41 ,56

    What is our current understanding about the accuracy of prepared intravenous medicines?

    Morphine infusions prepared for a NICU in a UK hospital showed concentration deviations outside of the British Pharmacopoeia limit set for morphine sulfate injection (a maximum of ±7.5% from the labelled concentration).26 19.2% of infusions were outside of the limit when prepared by nurses on the ward and 7.8% were outside this limit when made within a pharmacy-run intravenous preparation service. Ninety-three per cent of these ‘out of specification’ results occurred when volumes of ≤1 mL of morphine injection were required to prepare the infusions.26

    Furthermore, this problem was echoed in a direct observational study of a non-clinical environment in Canada, in which healthcare professionals prepared morphine sulfate infusions. Errors were detected at each and every stage of the preparation, and a significantly higher number was found when preparation required smaller dose volumes and the use of more concentrated solutions, that is, where more dilution was required. For example, the use of 10 mg/mL solution to produce a required concentration of 0.6 mg/50 mL required volume measurement of 0.06 mL.13

    Studies in anaesthesiology, where the use of intravenous medicines is essential, indicated similar findings. Analyses of the content of unused syringes containing drugs regularly used in anaesthesiology (fentanyl, thiopental, lidocaine, atracurium) revealed that 29% showed drug concentrations outside the specified acceptability range and 4% contained more than twice the targeted drug concentration. Errors closely correlated with multiple dilutions of high-strength formulations, and hence measurements of small volumes of initial drug solution, and these were seen particularly in preparations involving fentanyl.41 The complexity of preparation, often involving multiple calculations, was implicated in dilution error. High rates of imprecision were observed where serial dilution was required.41

    Campino et al29 concluded that errors in precision were more common than calculation errors with regard to concentrations of tobramycin and vancomycin solutions administered on a regional NICU. Precision errors were defined as deviation between target concentration of solution and actual concentration determined in the laboratory by >±10%. Calculation errors were defined as the deviations between prescribed dose and calculated dose by nurses that would theoretically be given by >±10%. Occurrence rates were 37.9% and 4.6%, respectively.29

    A high incidence of errors, which were defined as any deviation from the prescription or manufacturer's instructions during preparation or administration, was observed during intravenous medicine preparation and administration in German and UK teaching and non-teaching hospitals (48% and 49%, respectively). Most of these errors were associated with multiple step preparations;42 ,61 very small volumes and the use of unfamiliar preparations were later identified as contributing reasons for errors within multiple step preparations.43

    Discrepancies were found between ordered and delivered concentrations of opiates in neonatal and paediatric critical care in Canada.39 Two-thirds of infusions were outside of the accepted limits of variation for the study (defined as ≤10% from the ordered concentration in line with US and Canadian pharmaceutical preparations), with 6% of infusions having a twofold higher concentration than ordered. The inconsistencies ranged from –78% to +210% from the desired concentration. Specifics regarding volume measurement were not stated.39

    A wide variation was ascribed, in part, between ordered and actual concentrations of preparations of dobutamine, dopamine and epinephrine in a paediatric intensive care unit, to a failure to account for salt components within some formulations. Such drugs are used in critically ill patients, and variability in dosing could well contribute to haemodynamic instability.45 Differences between prescribed and actual concentrations (ranging from 75.8% to 102.4% of the prescribed concentration) of vancomycin infusions were also documented after investigation on a paediatric and neonatal intensive care unit, although possible reasons for discrepancies were not given.59

    The requirement for dilution of ‘adult’ vials in order to give paediatric doses has yielded errors in the region of 10–100-fold from the point of prescribing to administration.36 ,53 Thirty-one per cent of prescriptions on a neonatal unit required one-tenth of a ready-made vial, and 4.8% required less than one-hundredth.30 Thus, there is evidence that small volume measurements are often inconsistent. Our interpretation of this evidence is that healthcare faces a very real problem. Significant opportunities for catastrophic medicine administration errors exist; such errors would cause avoidable morbidity and mortality.

    The preparation and administration stages involved in intravenous therapy involve the most error.55 ,62 The ability of nurses to use calculations successfully in this process has been praised, with a call for further investigation into other phases involved in preparation and administration.62 Failure modes analysis supported this, and 5 out of the top 10 ‘critical failure modes’ occurred within the preparation stage.55 A systematic review of where errors occur identified that reconstitution of drug and diluent was a significant area and the need for further work to establish the most efficient and accurate technique to produce correct preparations was identified.38

    Problems arising from equipment

    Inaccuracies can also arise from the equipment used to prepare paediatric doses of intravenous medicines. The dead space within a syringe can contribute to overdosing. Dead space volume is the volume that remains in the syringe, within the hub and needle space, after the plunger is fully compressed and could be inadvertently administered. For this reason, it is vital that preparation technique is correct as it has been reported that doses as high as 4.5 times of those recommended can inadvertently be given. In the case of a drug with a narrow therapeutic index such as digoxin, this can result in potentially toxic levels.28 ,44 Berman et al54 noted variably high serum levels of digoxin in low birthweight infants given similar doses and that flushing the syringe after its contents were expelled resulted in more than twice the intended dose being administered to the infant as the dead space volume was administered.

    Furthermore, an incident occurred that involved the administration of a bolus dose of metoclopramide that had been prepared using an incorrect technique. Metoclopramide was measured in the same syringe as subsequent sodium chloride volume measurement; consequently, the dead space volume of metoclopramide was also administered to a neonate, resulting in a two to three times overdose.42

    Casella et al46 reported unacceptably large errors when small volumes, for example, 0.01 mL, were measured using 0.3 mL insulin syringes. Coefficient of variations tended to decrease as larger volumes were measured and mean errors as large as ±2% have been found in accuracy and reproducibility investigations, in some cases resulting in inaccuracies of at least one syringe division. With this said, this size of error can still be within standards set for syringes by the International Organization for Standardization and, depending on the medicament, be considered as clinically irrelevant.48

    Dosing accuracy varies depending on the brand, size of syringe and the liquid measured. Investigating the accuracy and reproducibility of different types of syringe used to measure small volumes (0.05  and 0.1 mL) for intravitreal injection, variability was apparent with Nipro TB syringes yielding the best accuracy.40 As a result, there has been a call for manufacturers to consider dosing volumes in relation to potential patient sizes and to also provide guidance on optimum administration devices to use with reference to the pharmaceutical agent.34 The cumulative error of stages involved in the preparation of intravenous medicines is multiplicative and therefore could be as high as 38%, depending on what is considered acceptable. These data take into account vial concentration, calculation errors, forced rounding errors, volumetric errors of syringe and inaccuracies in dead space.39

    Impact of dosing inaccuracies

    Investigation into the clinical impact of inaccuracies to date is limited. As an example, Parshuram et al49 studied the impact of unanticipated variation in intravenous methotrexate dosing but failed to demonstrate a significant link between measured total methotrexate dose given and serum concentration or clinical toxicities.

    Does place of preparation or healthcare professional performing the preparation have an effect on accuracy?

    Errors are commonly found when infusions are prepared at the point of care13 ,26 ,41 ,52 and improvements are made when a centralised system for preparation is used.26 ,47 However, both methods yield worrying deviations from the required stated concentrations.

    The use of prefilled syringes for infusions provides more efficient treatment in an emergency situation than preparation of the infusions at the bed side; a significant reduction in deviation from the expected concentration was also shown in one comparison.25 The same investigation confirmed that precision and accuracy vary depending on the healthcare professional preparing the prefilled syringes; pharmacists are more accurate than physicians. Furthermore, a calmer environment for preparation yields increasing precision as demonstrated by those prepared in pharmacy and those sourced from the pharmaceutical industry.25 Previous studies indicated that nurses were less prone to error introduction in preparation tasks than anaesthetists, but more errors were introduced at the calculation stage by nurses than anaesthetists.32 Recently, no differences in the accuracy and precision of intravitreal dose preparation of 0.05 mL using 1.0 mL disposable syringes57 were noted between nurses and physicians.

    What practices are in place to reduce inaccuracies?

    The UK National Patient Safety Agency65 issued an alert acknowledging the risk associated with injectable medicines and recommended risk assessment for all injectables, although it has been argued that the developed tool did not specifically consider the issues faced when preparing intravenous medicines for children and neonates.66

    No specific guidance on how to manage issues of inaccuracies is available, so nursing staff have adopted crude methods such as carrying out dilution in a large syringe after initial measurement of medicine volume (leaving the dead space volume within the initial syringe),67 using insulin syringes with no dead space and including the dead space volume in the dose calculation.28

    Dead space volume must be considered if drawing up multiple medicines into the same syringe. If three medicines are drawn up sequentially, a larger amount of the first two will be administered. When the second is drawn up, the dead space volume of the first will be released from the hub and needle space into the graduated portion, to make way for the second, and the same with the volume of the second as the third is drawn up.63

    An investigation into the measurement of insulin using pen injectors (NovoPen and BD Pen) and syringes has shown that both device types are inaccurate at measuring 1 unit of insulin (100 units/mL), with devices improving in accuracy with progressively larger volumes. This research did not use half unit pens that are now available. Syringes overdosed and pen injectors consistently underdosed. Pen injectors were significantly more accurate than syringes but variability in dosing was similar for both.33 Subsequently, improved accuracy of prefilled insulin pens as opposed to vial and syringe methods has been demonstrated.58 Therefore, pen injectors may be favourable; however, education is required if patients are transferred between different devices.33 Casella et al46 concluded that the error introduced when measuring ≤2 units (100 units/mL) is so large that dilution of insulin before measurement should be carried out where possible in an inpatient setting. Furthermore, the smallest syringe possible is often chosen to measure the required volume; this has been adapted as a technique and is supported by evidence.31 ,48 ,50 ,51 In addition, Isaac et al56 explored different methods of small volumes measurement of insulin and concluded that all showed inaccuracies; this included dilution and direct withdrawal with and without priming. For volumes of ≥0.05 mL, direct withdrawal may be more accurate, but dilution methods show better reproducibility.

    The implementation of standardised concentrations of intravenous infusions for paediatrics may reduce common inaccuracies and errors.13 ,14 ,26 ,64 Implementation of standardised concentrations in conjunction with other interventions, such as use of ‘smart’ syringe pumps and relabelling of infusions (formatting label information to match pump programming), resulted in a significant reduction in error.37 Improved dosing precision was confirmed with a paediatric vial containing an age-appropriate concentration of amikacin in comparison to an adult vial, with a fivefold higher concentration.27 The concern over increased cost and confusion between different vial concentrations likely stands as a barrier to implementation for different products and hospitals worldwide.

    The results of a survey demonstrating acceptability of proposed standard concentrations of 17 medicines, commonly given by infusion, among 164 critical care units (63% of UK NHS trusts) have been provided to the Intensive Care Society in the UK.68 Similar work was carried out in USA by the Institute for Safe Medicine Practices69 as a result of numerous safety alerts70 ,71 and many institutions employ standardised concentrations. Seventeen standardised weight categories and corresponding doses for 74 primarily (86.5%) intravenous medicines were established for the neonatal population with an aim of reducing the problems associated with dose delivery in this area.60

    Summary

    The requirement to measure small volumes, for both oral and intravenous use, occurs frequently in paediatric settings. There is a substantial source of error involved in all stages of preparation of doses involving the use of such volumes. The errors introduced translate into discrepancies between the concentrations of drugs that are prescribed and the concentrations that are administered. Much literature describes deviations in the concentration of opiates for infusion. This occurs whether medicine is prepared at ward or pharmacy level. Published research has concluded the requirement of paediatric standardised infusion concentrations, but it is questionable how realistic this is for all settings. Although pharmacy and industry-sourced prefilled syringes are used in some settings, it is not realistic for all scenarios. Further, it is highly unlikely that these devices would appear with appropriate dosing for paediatrics and thus manipulation prior to use would still be required. Further work is needed to establish the most accurate methods for handling small volumes during the administration of medicines to children. Risk minimisation strategies, such as specific training and additional information at the point of use to support staff involved, are also necessary.

    Conclusions

    This review identifies the need to quantify the sources of error in preparation of intravenous and enteral medicines, namely techniques and equipment used, the effects that this may have on therapy, with an estimation of cost implications. Work should lead to recommendations that will inform industrial and clinical aspects of medicine preparation in order to improve current practice and reduce these inaccuracies. It is hoped that this review of the extant data will pave the way for the future development of standardised concentrations of commonly used medicines in all settings including paediatrics. However, there will undoubtedly forever be a requirement for preparation and use of small volumes for drug delivery due to the wide range of dose and medicine requirements in paediatrics.

    References

    1. ↵
      1. Shirkey H
      . Therapeutic orphans. J Pediatr 1968;72:119–20. doi:10.1016/S0022-3476(68)80414-7
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Schirm E,
      2. Tobi H,
      3. de Vries TW, et al
      . Lack of appropriate formulations of medicines for children in the community. Acta Pædiatrica 2003;92:1486–9. doi:10.1111/j.1651-2227.2003.tb00837.x
      OpenUrl
    3. ↵
      1. Ernest TB,
      2. Elder DP,
      3. Martini LG, et al
      . Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol 2007;59:1043–55. doi:10.1211/jpp.59.8.0001
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      European Medicines Agency with its Paediatric Committee: 5-year Report to the European Commission. General report on the experience acquired as a result of the application of the Paediatric Regulation.: European Medicines Agency; 2012. http://ec.europa.eu/health/files/paediatrics/2012-09_pediatric_report-annex1-2_en.pdf (accessed 10 Sep 2016).
    5. ↵
      1. Nunn AJ
      . Making medicines that children can take. Arch Dis Child 2003;88:369–71. doi:10.1136/adc.88.5.369
      OpenUrlFREE Full Text
    6. ↵
      1. Rocchi F,
      2. Tomasi P
      . The development of medicines for children. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni Pharmacol Res 2011;64:169–75. doi:10.1016/j.phrs.2011.01.016
      OpenUrlCrossRefPubMed
    7. ↵
      1. Standing JF,
      2. Tuleu C
      . Paediatric formulations—getting to the heart of the problem. Int J Pharm 2005;300:56–66. doi:10.1016/j.ijpharm.2005.05.006
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Richey RH,
      2. Shah UU,
      3. Peak M, et al
      . Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. BMC Pediatr 2013;13:81. doi:10.1186/1471-2431-13-81
      OpenUrlCrossRefPubMed
    9. ↵
      1. Morecroft CW,
      2. Gill A,
      3. Caldwell NA, et al
      . Are prescribed doses of medicine for children measurable? Arch Dis Child 2012;97:e18-e. doi:10.1136/archdischild-2012-301728.37
      OpenUrl
    10. ↵
      1. Conroy S,
      2. McIntyre J,
      3. Choonara I
      . Unlicensed and off label drug use in neonates. Arch Dis Child 1999;80:F142–5. doi:10.1136/fn.80.2.F142
      OpenUrl
    11. ↵
      1. Oguz SS,
      2. Kanmaz HG,
      3. Dilmen U
      . Off-label and unlicensed drug use in neonatal intensive care units in Turkey: the old-inn study. Int J Clin Pharm 2012;34:136–41. doi:10.1007/s11096-011-9604-0
      OpenUrlPubMed
    12. ↵
      1. Laforgia N,
      2. Nuccio MM,
      3. Schettini F, et al
      . Off-label and unlicensed drug use among neonatal intensive care units in Southern Italy. Pediatr Int 2014;56:57–9. doi:10.1111/ped.12190
      OpenUrl
    13. ↵
      1. Parshuram CS,
      2. To T,
      3. Seto W, et al
      . Systematic evaluation of errors occurring during the preparation of intravenous medication. CMAJ 2008;178:42–8. doi:10.1503/cmaj.061743
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Uppal N,
      2. Yasseen B,
      3. Seto W, et al
      . Drug formulations that require less than 0.1 mL of stock solution to prepare doses for infants and children. CMAJ 2011;183:E246–8. doi:10.1503/cmaj.100467
      OpenUrlAbstract/FREE Full Text
    15. ↵
      1. Nunn A,
      2. Richey R,
      3. Shah U, et al
      . Estimating the requirement for manipulation of medicines to provide accurate doses for children. Eur J Hosp Pharm Sci Pract 2013;20:3–7. doi:10.1136/ejhpharm-2012-000133
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Shah UU,
      2. Roberts M
      . Parenteral liquids for intravenous and transdermal use. In: Bar-Shalom D, Rose K, eds. Pediatric formulations: a roadmap. New York, NY: Springer-Verlag, 2014;239–52.
    17. ↵
      1. Kaushal R,
      2. Bates DW,
      3. Landrigan C, et al
      . Medication errors and adverse drug events in pediatric inpatients. J Am Med Assoc 2001;285:2114–20. doi:10.1001/jama.285.16.2114
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Chedoe I,
      2. Molendijk HA,
      3. Dittrich STAM, et al
      . Incidence and nature of medication errors in neonatal intensive care with strategies to improve safety—a review of the current literature. Drug Saf 2007;30:503–13. doi:10.2165/00002018-200730060-00004
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Ghaleb MA,
      2. Barber N,
      3. Frnklin BD, et al
      . The incidence and nature of prescribing and medication administration errors in paediatric inpatients. Arch Dis Child 2010;95:113–18. doi:10.1136/adc.2009.158485
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. Koren G,
      2. Haslam RH
      . Pediatric medication errors—predicting and preventing tenfold disasters. J Clin Pharm 1994;34:1043–5. doi:10.1002/j.1552-4604.1994.tb01978.x
      OpenUrl
    21. ↵
      1. Fernandez CV,
      2. Gillis-Ring J
      . Medical progress. Strategies for the prevention of medical error in pediatrics. J Pediatr 2003;143:155–62.8p.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Blair K
      . Transforming nursing practice in medicines management in children's nursing. Exeter: Learning Matter Ltd, 2011.
    23. ↵
      1. Conroy S,
      2. Davar Z,
      3. Jones S
      . Use of checking systems in medicines administration with children and young people. Nurs Child Young People 2012;24:20–4. doi:10.7748/ncyp2012.04.24.3.20.c9024
      OpenUrlPubMed
    24. ↵
      1. Richey RH,
      2. Craig JV,
      3. Shah UU, et al
      . The manipulation of drugs to obtain the required dose: systematic review. J Adv Nurs 2012;68:2103–12. doi:10.1111/j.1365-2648.2011.05916.x
      OpenUrlPubMed
    25. ↵
      1. Adapa RM,
      2. Mani V,
      3. Murray LJ, et al
      . Errors during the preparation of drug infusions: a randomized controlled trial. Br J Anaesth 2012;109:729–34. doi:10.1093/bja/aes257
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Aguado-Lorenzo V,
      2. Weeks K,
      3. Tunstell P, et al
      . Accuracy of the concentration of morphine infusions prepared for patients in a neonatal intensive care unit. Arch Dis Child 2013;98:975–9. doi:10.1136/archdischild-2013-304522
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Allegaert K,
      2. Anderson BJ,
      3. Vrancken M, et al
      . Impact of a paediatric vial on the magnitude of systematic medication errors in neonates. Paediatr Perinat Drug Ther 2006;7:59–63. doi:10.1185/146300906X105096
      OpenUrlCrossRef
    28. ↵
      1. Bhambhani V,
      2. Beri RS,
      3. Puliyel JM
      . Inadvertent overdosing of neonates as a result of the dead space of the syringe hub and needle. Arch Dis Child 2005;90:F444–5. doi:10.1136/adc.2004.070045
      OpenUrl
    29. ↵
      1. Campino A,
      2. Santesteban E,
      3. Garcia M, et al
      . Intravenous drug preparation errors in a Neonatal Intensive Care Unit. A potential source of adverse events. An Pediatr (Barc) 2013;79:21–5. doi:10.1016/j.anpedi.2012.09.005
      OpenUrl
    30. ↵
      1. Chappell K,
      2. Newman C
      . Potential tenfold drug overdoses on a neonatal unit. Arch Dis Child 2004;89:F483–4. doi:10.1136/adc.2003.041608
      OpenUrl
    31. ↵
      1. Erstad AJ,
      2. Erstad BL,
      3. Nix DE
      . Accuracy and reproducibility of small-volume injections from various-sized syringes. Am J Health Syst Pharm 2006;63:748–50. doi:10.2146/ajhp050438
      OpenUrlFREE Full Text
    32. ↵
      1. Garnerin P,
      2. Pellet-Meier B,
      3. Chopard P, et al
      . Measuring human-error probabilities in drug preparation: a pilot simulation study. Eur J Clin Pharmacol 2007;63: 769–76. doi:10.1007/s00228-007-0319-z
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      1. Gnanalingham MG,
      2. Newland P,
      3. Smith CP
      . Accuracy and reproducibility of low dose insulin administration using pen-injectors and syringes. Arch Dis Child 1998;79:59–62. doi:10.1136/adc.79.1.59
      OpenUrlAbstract/FREE Full Text
    34. ↵
      1. Gurung K,
      2. Arenas-Lopez S,
      3. Wei L, et al
      . Accuracy of enteral syringes for liquid medicines prescribed in children. Arch Dis Child 2014;99:e3. doi:10.1136/archdischild-2014-306798.7
      OpenUrlAbstract/FREE Full Text
    35. ↵
      1. Isaac RE,
      2. Duncan H,
      3. Burridge A, et al
      . Which medicines commonly require small dose volumes on paediatric intensive care units and which are of concern? Arch Dis Child 2012;97:e8. doi:10.1136/adc.2010.184234
      OpenUrlAbstract/FREE Full Text
    36. ↵
      1. Koren G,
      2. Barzilay Z,
      3. Greenwald M
      . Tenfold errors in administration of drug doses: a neglected latrogenic disease in pediatrics. Pediatrics 1986;77: 848–9.
      OpenUrlAbstract/FREE Full Text
    37. ↵
      1. Larsen GY,
      2. Parker HB,
      3. Cash J, et al
      . Standard drug concentrations and smart-pump technology reduce continuous-medication-infusion errors in pediatric patients. Pediatrics 2005;116:E21–5. doi:10.1542/peds.2004-2452
      OpenUrl
    38. ↵
      1. McDowell SE,
      2. Mt-Isa S,
      3. Ashby D, et al
      . Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis. Qual Saf Health Care 2010;19:341–5. doi:10.1136/qshc.2008.029785
      OpenUrlAbstract/FREE Full Text
    39. ↵
      1. Parshuram CS,
      2. Ng GYT,
      3. Ho TKL, et al
      . Discrepancies between ordered and delivered concentrations of opiate infusions in critical care. Crit Care Med 2003;31: 2483–7. doi:10.1097/01.CCM.0000089638.83803.B2
      OpenUrlCrossRefPubMedWeb of Science
    40. ↵
      1. Sampat KM,
      2. Wolfe JD,
      3. Shah MK, et al
      . Accuracy and reproducibility of seven brands of small-volume syringes used for intraocular drug delivery. Ophthalmic Surg Lasers Imaging Retina 2013;44:385–9. doi:10.3928/23258160-20130601-02
      OpenUrl
    41. ↵
      1. Stucki C,
      2. Sautter AM,
      3. Wolff A, et al
      . Accuracy of preparation of i.v. medication syringes for anesthesiology. Am J Health Syst Pharm 2013;70:137–42. doi:10.2146/ajhp110654
      OpenUrlAbstract/FREE Full Text
    42. ↵
      1. Taxis K,
      2. Barber N
      . Ethnographic study of incidence and severity of intravenous drug errors. Br Med J 2003;326:684–7. doi:10.1136/bmj.326.7391.684
      OpenUrlAbstract/FREE Full Text
    43. ↵
      1. Taxis K,
      2. Barber N
      . Causes of intravenous medication errors: an ethnographic study. Qual Saf Health Care 2003;12:343–7. doi:10.1136/qhc.12.5.343
      OpenUrlAbstract/FREE Full Text
    44. ↵
      1. Watanachai A,
      2. Suprasongsin C
      . Deadspace: a potential error in concentration of medication during dilutional process in neonates. J Med Assoc Thai 2003;86:1128–32.
      OpenUrlPubMed
    45. ↵
      1. Allen EM,
      2. Van Boerum DH,
      3. Olsen AF, et al
      . Difference between the measured and ordered dose of catecholamine infusions. Ann Pharmacother 1995;29:1095–100.
      OpenUrlCrossRefPubMed
    46. ↵
      1. Casella SJ,
      2. Mongilio MK,
      3. Plotnick LP, et al
      . Accuracy and precision of low-dose insulin administration. Pediatrics 1993;91:1155–7.
      OpenUrlAbstract/FREE Full Text
    47. ↵
      1. Dehmel C,
      2. Braune SA,
      3. Kreymann G, et al
      . Do centrally pre-prepared solutions achieve more reliable drug concentrations than solutions prepared on the ward? Intensive Care Med 2011;37:1311–16. doi:10.1007/s00134-011-2230-4
      OpenUrlCrossRefPubMedWeb of Science
    48. ↵
      1. Lee SN,
      2. Wong AH,
      3. Mayer A, et al
      . Accuracy and reproducibility of syringe measurements. Am J Health Syst Pharm 1996;53:1166–9.
      OpenUrlPubMed
    49. ↵
      1. Parshuram CS,
      2. Dupuis LL,
      3. To T, et al
      . Occurrence and impact of unanticipated variation in intravenous methotrexate dosing. Ann Pharmacother 2006;40: 805–11. doi:10.1345/aph.1G334
      OpenUrlCrossRefPubMed
    50. ↵
      1. Raju JR,
      2. Weinberg DV
      . Accuracy and precision of intraocular injection volume. Am J Ophthalmol 2002;133:564–6. doi:10.1016/S0002-9394(01)01408-8
      OpenUrlCrossRefPubMed
    51. ↵
      1. Thobani SU,
      2. Steward DJ
      . The accuracy and variability of bolus injections with different sized syringes. Can J Anaesth 1992;39:198–201. doi:10.1007/BF03008656
      OpenUrlPubMedWeb of Science
    52. ↵
      1. Wheeler DW,
      2. Degnan BA,
      3. Sehmi JS, et al
      . Variability in the concentrations of intravenous drug infusions prepared in a critical care unit. Intensive Care Med 2008;34:1441–7. doi:10.1007/s00134-008-1113-9
      OpenUrlCrossRefPubMed
    53. ↵
      Anon. Zeroing in on medication errors. Lancet 1997;349:369. doi:10.1016/S0140-6736(97)80001-3
      OpenUrlCrossRefPubMedWeb of Science
    54. ↵
      1. Berman W,
      2. Whitman V,
      3. Marks KH, et al
      . Inadvertent overadministration of digoxin to low-birth-weight infants. J Pediatr 1978;92:1024–5. doi:10.1016/S0022-3476(78)80395-3
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      1. De Giorgi I,
      2. Fonzo-Christe C,
      3. Cingria L, et al
      . Risk and pharmacoeconomic analyses of the injectable medication process in the paediatric and neonatal intensive care units. Int J Qual Health Care 2010;22:170–8. doi:10.1093/intqhc/mzq015
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      1. Isaac RE,
      2. Duncan H,
      3. Marriott JF, et al
      . The effect of different manipulation techniques on the accuracy and reproducibility of small dose volume intravenous measurements. Arch Dis Child 2010;95:e1. doi:10.1136/adc.2010.190322.6
      OpenUrlAbstract/FREE Full Text
    57. ↵
      1. Meyer CH,
      2. Liu Z,
      3. Brinkmann C, et al
      . Accuracy, precision and repeatability in preparing the intravitreal dose with a 1.0-cc syringe. Acta Ophthalmol 2012;90:e165–6. doi:10.1111/j.1755-3768.2010.02072.x
      OpenUrlPubMed
    58. ↵
      1. Pfutzner A,
      2. Bailey T,
      3. Campos C, et al
      . Accuracy and preference assessment of prefilled insulin pen versus vial and syringe with diabetes patients, caregivers, and healthcare professionals. Curr Med Res Opin 2013;29:475–81. doi:10.1185/03007995.2013.775112
      OpenUrlCrossRefPubMed
    59. ↵
      1. Popescu M,
      2. Vialet R,
      3. Loundou A, et al
      . Imprecision of vancomycin prepared for intravenous administration at the bedside in a neonatal intensive care unit. Ann Fr Anesth Reanim 2011;30:726–9. doi:10.1016/j.annfar.2011.04.013
      OpenUrlCrossRefPubMed
    60. ↵
      1. Robinson CA,
      2. Siu A,
      3. Meyers R, et al
      . Standard dose development for medications commonly used in the neonatal intensive care unit. J Pediatr Pharmacol Ther 2014;19:118–26. doi:10.5863/1551-6776-19.2.118
      OpenUrl
    61. ↵
      1. Taxis K,
      2. Barber N
      . Incidence and severity of intravenous drug errors in a German hospital. Eur J Clin Pharmacol 2004;59:815–17. doi:10.1007/s00228-003-0689-9
      OpenUrlCrossRefPubMedWeb of Science
    62. ↵
      1. Wright K
      . Do calculation errors by nurses cause medication errors in clinical practice? A literature review. Nurse Educ Today 2010;30:85–97. doi:10.1016/j.nedt.2009.06.009
      OpenUrlCrossRefPubMedWeb of Science
    63. ↵
      1. Zenk K,
      2. Anderson S
      . Improving the accuracy of mini-volume injections. Infusion 1982;6:7–11.
      OpenUrl
    64. ↵
      1. Rashed AN,
      2. Whittlesea C,
      3. Forbes B, et al
      . The feasibility of using dose-banded syringes to improve the safety and availability of patient-controlled opioid analgesic infusions in children. Eur J Hosp Pharm 2014;21:306–8. doi:10.1136/ejhpharm-2014-000441
      OpenUrlFREE Full Text
    65. ↵
      National Patient Safety Agency. NPSA Alert 20: Promoting safer use of injectable drugs 2007. http://www.nrls.npsa.nhs.uk/resources/?entryid45=59812&q=0%c2%acinjectable%c2%ac (accessed 10 Sep 2016).
    66. ↵
      1. Isaac R,
      2. Correa J
      . Is The National Patient Safety Agency (NPSA) alert 20 risk assessment tool appropriate for use in a paediatric hospital? Arch Dis Child 2011;96:e1.
      OpenUrlAbstract/FREE Full Text
    67. ↵
    68. ↵
      1. Borthwick M,
      2. Keeling S,
      3. Keeling P, et al
      . Towards standardisation of drug infusion concentrations in UK critical care units. J Intensive Care Soc 2009;10:197–200. doi:10.1177/175114370901000309
      OpenUrlCrossRef
    69. ↵
      Institute for Safe Medicine Practices. Standard Concentrations of Neonatal Drug Infusions. 2011. http://www.ismp.org/tools/PediatricConcentrations.pdf (accessed 10 Sep 2016).
    70. ↵
      Institute for Safe Medicine Practices (1999). ISMP Action Agenda for October—December 1998. http://www.ismp.org/newsletters/acutecare/articles/A1Q99Action.asp (accessed 10 Sep 2016).
    71. ↵
      National Patient Safety Agency. Intravenous Morphine Administration on Neonatal Units—Signal. http://www.nrls.npsa.nhs.uk/resources/?entryid45=130181. Intravenous Morphine Administration on Neonatal Units—Signal (accessed 10 Sep 2016).

    Footnotes

    • Contributors LPA carried out the initial literature search. AJN, JLF and MAT reviewed papers for suitability and suggested additional literature for inclusion. MR and LPA drafted the manuscript. AJN, JLF, MAT CWM and MP reviewed the draft manuscript and suggested revisions. MR redrafted the manuscript prior to submission.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.