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Risk of Patient Harm Related to Unnecessary Dilution of Ready-to-Administer Prefilled Syringes

A Literature Review

Degnan, Daniel D. PharmD, MS, CPPS, FASHP; Bullard, Tacia N. MSN, RN, CNL; Davis, Mary Beth Hovda MSN, RN, VA-BC

Author Information
doi: 10.1097/NAN.0000000000000366
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Abstract

Medication errors, particularly those involving intravenous (IV) push practices, are a serious issue. IV medication errors occur more frequently than other types of medication errors, with reported rates of 48% to 81%.1–3 Manipulation of parenteral products and the complexity of IV push medication preparation and administration can lead to higher rates of medication errors related to dilution, which could result in wrong dose and/or wrong concentration errors, wrong drug due to mislabeling, as well as the risk of product contamination. IV medication errors also more often result in patient harm or death.4,5 This increased risk of harm may be due to the immediate bioavailability of the drug, a narrow therapeutic window, and the challenge of reversing systemic effects.6,7 Preparation of IV medications by conventional methods (using a vial and syringe) involves multiple, complex steps and presents numerous opportunities for error. For example, 1 prospective observational study of 107 nurses preparing and administering 568 IV medications by conventional methods found that 69.7% of IV administrations observed had at least 1 clinical error, and 25.5% of the errors were reported as serious (where serious is defined as likely to lead to permanent reduction or loss of function or death).8 A systematic review of studies reporting error rates in IV therapy identified the reconstitution step of IV medication preparation as the most error-prone.9 Thus, opportunities to reduce the number of steps in preparation, particularly dilution, may be the most impactful in reducing errors.

In 2014, the Institute for Safe Medication Practices (ISMP) conducted a survey intended to gauge the extent and variability of dilution practices related to IV push medications in adult patients. Data were collected from 1773 nursing professionals in the United States and found that >80% of respondents reported further diluting medications for adults before IV push administration.10 This practice was not limited to patient-specific doses prepared and dispensed by the pharmacy but included commercially available ready-to-administer (RTA) syringes. RTA syringes, by definition, do not require any type of manipulation, including dilution. Less than half of respondents reported “never” diluting a manufacturer's RTA syringe. In addition, >50% of respondents reported having drawn medication into a manufacturer's RTA syringe of diluent.10 To address these safety issues, ISMP conducted an IV Push Medication Safety Summit of expert stakeholders in 2014. As a result of this summit, ISMP developed and published Safe Practice Guidelines for Adult IV Push Medications in 2015.11 Moreover, in 2016, the Infusion Nurses Society (INS) published the Infusion Therapy Standards of Practice, highlighting administration of IV push medication in a safe manner.12 A follow-up ISMP survey conducted in 2018 revealed that these unsafe practices were ongoing.13 The unsafe practice of diluting medications incorrectly or when dilution is not indicated may compromise the sterility of the medication, potentially affecting the potency or stability of the drug, and adding unnecessary complexity and error to the preparation and administration process. The focus of this article is to review the literature and examine the incidence and nature of errors related to dilution of RTA syringes in the hospital setting. The reasons behind the unsafe practice of unnecessary dilution of RTA syringes in the inpatient clinical setting are also discussed.

BACKGROUND

RTA syringes are defined by ISMP as injectable products containing the active drug in solution at the required concentration and volume, presented in the final container and ready to be administered to the patient.11 Similarly, the World Health Organization defines an injectable medicine as being RTA when it requires no additional dilution or reconstitution and is presented in the final container or device, ready for administration or connection to a needle or administration set.14

RTA syringes have been shown to reduce the risk of errors relative to preparation and administration of medications by conventional means using a vial and syringe.15 The reduction in medication errors with RTA IV medications may be attributed to the reduced cognitive complexity associated with their preparation, where cognitive complexity refers to high mental workload and attentional demands. Tasks that require reduced mental resources improve work performance and quality by providing fewer opportunities for error, stress, and fatigue.16 A work system analysis of anesthesia providers at a US hospital identified system vulnerabilities associated with the use of syringes of IV medication prepared by the anesthesia providers by conventional methods using a vial and syringe compared with commercially available RTA syringes.17 The majority of system vulnerabilities that rated as high risk with the syringes prepared by anesthesia providers were related to cognitive complexity.17 In contrast, cognitive complexity was not identified as a vulnerability in the RTA syringe system.17 Another prospective observational study found one or more errors in the preparation or administration of IV drugs in 49% of 430 IV drug doses prepared in a hospital setting. Using a 10-point scale of severity (where zero was no harm and 10 was death), 1% of errors were potentially severe (score of >7), 29% potentially moderate (score of 3-7), and 19% potentially minor (score of <3).2 Multiple step preparation of IV medications by conventional methods using a vial and syringe was associated with a 14% error rate, whereas no errors were associated with RTA IV medications in this study.2

GUIDELINES AND RECOMMENDATIONS

To address these important patient safety issues, multiple professional societies and expert panels have issued guidelines and consensus statements recommending the use of RTA syringes whenever possible (Table 1).

TABLE 1
TABLE 1:
Guideline Recommendations for Intravenous Push Medications in Ready-to-Administer Formsa

The assessment of risks to patients from IV push administration practices was also the subject of a multidisciplinary expert panel convened in 2015.23 The panel reviewed published guidelines, identified characteristics of ideal RTA devices or systems, and evaluated currently available IV push delivery devices and methods.23 The panel found that virtually all guidelines recommend using single-use syringes; not pooling leftover syringe contents; not administering medicines from a single-use vial to multiple patients; labeling preparations with the name, dose, and concentration of the drug; avoiding provider-prepared drugs for administration; and using manufacturer-prepared unit doses that were produced under current Good Manufacturing Practices (cGMPs).11,18,19,24–30

The 7 characteristics of an ideal RTA device or system identified by the panel included:

  • Prefilled standard single dose
  • Manufacturer-prepared under cGMPs
  • Single-patient-use only
  • No assembly required (ie, no needles, plunger, or labeling needed at the point of care)
  • No drug manipulation required (eg, no need for further dilution)
  • Labeling information consistent with ISMP labeling requirements (including clear, easily understood, readable, and unobscured labels and easy-to-read gradations showing best contrast [vertical gradations preferred])
  • Label and barcode on the outside of tamper-evident package.23

An assessment of current delivery systems found that some manufacturer-prepared RTA devices met all 7 characteristics. Similarly, a scoring matrix developed to evaluate 6 domains (procurement, dispensing, safety, usability, efficiency and compliance, and regulatory standards and best practices) found that manufacturer-prepared RTA delivery systems scored highest.23 The findings of this panel were consistent with those of the second Consensus Development Conference on the Safety of Intravenous Drug Delivery Systems held in 2008.31

Despite these recommendations and guidelines, several surveys of health care professionals conducted in recent years have shed light on practices that may lead to errors related to dilution, labeling, or microbial contamination when manipulating RTA syringes. In particular, the practice of unnecessary dilution of RTA syringes (defined as additional dilution of the contents of an RTA syringe, when it is not indicated) has emerged as an ongoing issue.

Moreover, US Pharmacopeia (USP) Chapter <797> (USP 797) provides guidance on compounding sterile products for hospitals on conditions and practices to prevent errors that can potentially result in patient harm because of microbial contamination. It can become challenging for clinicians to comply with these safe practice methods when compounding of IV push medications is performed in a nonsterile environment away from the patient's bedside. Risk of contamination increases when preparing sterile medications under conditions that might not meet standards in USP <797>.27

However, little is known about the incidence and types of risks associated with manipulation of RTA syringes in the hospital setting. In this article, recent literature regarding risks associated with unnecessary dilution of RTA syringes in the inpatient clinical setting is reviewed.

Search Strategy and Study Selection

The PubMed database was searched to identify studies of errors related to the use of RTA syringes for IV push medications within the last 10 years. An additional search was conducted using other search engines to identify relevant articles in the grey literature. The references of reviews and included studies were also screened for eligible studies. Duplicates were removed and records were excluded based on topic relevance (eg, drug or disease focused, product contamination, not related to IV administration). Following a review of abstracts, full texts were retrieved for a subset of citations of interest. Articles that were unrelated to the primary focus (eg, drug/disease focus) and technical review articles were excluded. Additionally, review articles were selected to be included in other sections of the manuscript (ie, Introduction, Background, and Discussion). The flowchart of the literature search is outlined in Figure 1. A summary of the articles identified for inclusion in the review is found in Table 2.

Figure 1
Figure 1:
Literature search flowchart.
TABLE 2
TABLE 2:
Summary of Literature Reviewed

RESULTS

Review of literature demonstrates dilution and labeling errors through both surveys and observational studies. In addition, microbial contamination errors will be discussed.

Dilution and Labeling Errors

Surveys of RTA Clinical Practice

A series of surveys were conducted by ISMP to assess practices associated with the administration of IV push medications. A 2010 ISMP survey found an increase in the incidence of nurses preparing or manipulating IV medications on the clinical unit, and a 2012 ISMP survey identified the unsafe practice of using prefilled cartridges as a vial to withdraw the medication into another syringe before administration.37,38 Another ISMP survey of 1773 nursing professionals in the United States in 2014 found that 83% of respondents reported further diluting medications for adults before IV push administration.10 Only 42% reported “never” diluting a manufacturer's RTA syringe, indicating that more than half of the nurses did engage in this practice. Additionally, 54% reported having drawn medication into a manufacturer's RTA syringe of diluent, a practice potentially leading to labeling and drug/dose concentration errors.10

A follow-up ISMP survey was conducted in 2018.13 Participants included 997 nurses, advance practice nurses, nurse anesthetists, anesthesiologists, and physicians in the United States. Three quarters of respondents indicated that they receive 50% or fewer IV push medications in RTA syringes. Two thirds of respondents reported withdrawing medication from an RTA syringe or cartridge and transferring to another syringe for administration, with the most common reason given being the desire to dilute the medication. A similar percentage to the 2014 survey, 84% (compared to 83% in 2014), reported further diluting medications for adults before IV push administration. However, when evaluating frequency of dilution of adult IV push medications by container type, 70% reported “never” diluting a manufacturer's RTA syringe (compared to 42% in 2014), indicating an improvement in practice in this area. Fifty-six percent of respondents reported having drawn medication into a manufacturer's prefilled syringe of diluent, a similar percentage to the 2014 survey (54%). With respect to syringe labeling practices, only half of respondents reported “always” labeling IV push medication syringes prepared away from the patient's bedside, whereas 28% indicated that they “never” or “rarely” labeled IV push medication syringes that were prepared away from the patient's bedside.13 These unsafe dilution and labeling practices could contribute to errors and possible patient harm.

A survey by Heindel and Stivers32 published in 2017, regarding IV push practices of 78 nurses at a US hospital, reported that 57.7% indicated that they frequently draw medications out of a Carpuject (Hospira Inc, a Pfizer company, New York, NY) prefilled cartridge-based system into another syringe. In addition, 69.1% of nurses indicated that they regularly used prefilled flush syringes for reconstitution or dilution, creating a risk for mislabeled or unlabeled syringes containing medication.32

In a survey study by Prentiss et al,33 pre- and post-surveys were conducted before and after staff education related to the knowledge of and practices with use of a Carpuject prefilled cartridge system, as well as narcotic administration and dilution practices, in a US hospital. In total, 125 nurses were surveyed before the intervention and 153 nurses after the intervention. The pre-survey found that 28% of respondents indicated that they wanted to dilute the prefilled syringe before administration compared with 16.9% post-survey. Therefore, despite staff education, practices that could potentially introduce errors persisted.33

Observational Studies

A prospective, multisite observational study was conducted across 3 health systems within the United States, wherein researchers observed IV push medication preparation and administration by nursing and recorded errors against a list of predefined steps.34 Two groups were observed: preparation and administration of a commercially available RTA product (102 observations) and preparation and administration of conventional vial and syringe IV push practice (227 observations). The RTA products were associated with a statistically significant lower error rate overall (22% vs 79% for conventional IV push practice). Commercially available RTA products demonstrated fewer medication errors compared with conventional IV push preparation. RTA products were associated with zero disinfection errors, 3 labeling errors, and 21 dilution errors (where a dilution error was defined as a dilution that occurred when none was indicated). In contrast, the errors reported with IV push conventional practice were 153 disinfection errors, 18 labeling errors, and 64 dilution errors.34 This study confirms that the opinions with respect to dilution and labeling captured in the surveys of nurses and other health care professionals10,13,32,33 translate into actual errors in practice.34

Microbial Contamination Errors

According to the Association for Professionals in Infection Control and Epidemiology, proper technique is critical in the prevention of contamination during the preparation and administration of sterile medications.24 In particular, preparation of sterile injectables outside of International Organization of Standardization (ISO) Class 5 settings creates opportunities for microbial contamination via contact with hands and surfaces.24 A prospective risk analysis (failure modes, effects, and criticality analysis) was conducted to quantitate the safety of the preparation and administration steps of the current injectable medication process at newborn and pediatric intensive care units.35 The risk analysis identified 31 possible failure modes, with the most critical failure mode for preparation being microbial contamination. In this study, the use of commercially available RTA syringes provided the greatest opportunity for system safety improvement with respect to microbial contamination.35

A study by Stucki et al36 was conducted to estimate the probability of microbial contamination of prefilled syringes by simulating syringe-filling operations in 3 different hospital environments: an ISO class 5 clean room with an ISO class 5 horizontal laminar-airflow hood, an ISO class 7 drug preparation area of an operating room, and an uncontrolled decentralized pharmacy on a ward. Four high-risk manipulations were carried out with the filling of the syringes: simple filling, 3-second contact with ungloved fingers on the hub of the syringe, 3-second contact between a nonsterile object and the hub of the syringe, and exposure of the filled syringe to ambient air for 10 minutes. A total of 1500 syringes were prepared (100 for each of the 4 manipulations, for each of the 3 environments). The results showed that none of the syringes from the clean room were contaminated with microorganisms, whereas 6% of those prepared in the operating room and 16% of those prepared on the ward were contaminated. Furthermore, a significant increase in contamination was noted among syringes in contact with nonsterile objects or fingers, or with ambient air, as compared with those syringes that were simply filled.36 This study suggests that syringes prepared or manipulated in a nonsterile environment (eg, an operating room outside of sterile field or ward area) would have a higher risk of contamination compared with those prepared in a sterile environment.

DISCUSSION

Our review found that the use of RTA syringes reduces the opportunities for error relative to conventional vial and syringe methods of IV push medication preparation, which is consistent with current guidelines and recommendations by various societies. It was also observed that the unnecessary manipulation of RTA syringes may result in errors and subsequent patient harm. The types of errors associated with unnecessary manipulation of RTA syringes were predominantly related to dilution, resulting in incorrect concentrations of medications, microbial contamination, and the potential for incorrect labeling. An ISMP Medication Safety Alert! reported a 15-year-old boy who received the wrong drug (epinephrine instead of bupivacaine) due to an unlabeled syringe. As a result, the patient's blood pressure increased, and he was thought to have malignant hyperthermia. The error was later identified when he developed ventricular tachycardia and pulmonary edema. He was immediately sent to an intensive care unit and fortunately did not experience any permanent patient harm.39 Another article published in 2019 by ISMP reported 2 cases of wrong-route (intraspinal) administration of tranexamic acid and bupivacaine or ropivacaine when selecting products for regional anesthesia.40 Similarly, in 2015, a patient case was reported for a 68-year-old woman scheduled for total knee replacement who was administered intrathecal tranexamic acid by the anesthesiologist who intended to administer bupivacaine and morphine. The tranexamic acid was ordered by the surgeon for wound irrigation to minimize blood loss. These syringes were prepared by the staff in the surgical suite. The vials were similar in size (10 mL), and the wrong drug was picked by the anesthesiologist during preparation. The surgical procedure was stopped because the patient experienced myoclonus of lower extremities and seizures. She also developed ventricular tachycardia and required ventilator support.41 The operating room is a high-stress environment, more prone to human errors. Additionally, a higher risk of compromising product sterility exists when syringes are manipulated in a nonsterile environment (eg, outside of the sterile room of an operating room or ward area) compared with those prepared in a sterile environment. Although published guidelines, consensus statements, and expert panels endorse the use of commercially available RTA syringes and detail safe practices, surveys of health care professionals indicate that best practices are not always implemented.

The reasons behind the continuation of the unsafe practice of unnecessary dilution of IV push medications were explored in the 2018 ISMP survey.42 The primary reasons cited by most survey respondents for further diluting adult IV push medications were to facilitate administering the drug slowly, to avoid patient discomfort, and to reduce the risk of extravasation.42 These may not be clinically necessary reasons for prefilled ready-to-use syringes that do not require further manipulation. Furthermore, close monitoring by nurses during administration process and following the institution and clinical society guidelines are recommended. The factors influencing these decisions related to the training practitioners received (through professional education, orientation, or on-the-job training), in some cases supported by facility policies or recommendations in drug references. Where additional dilution is necessary and indicated, ISMP recommends the pharmacy dilute the medication and provide clearly labeled syringes for administration.42 Furthermore, ISMP recommends establishing specific facility policy regarding dilution practices to clearly indicate which medications require dilution and if dilution by a nurse is even necessary prior to administration of the medication.11,12 Another reason cited for the perpetuation of the practice of unnecessary dilution of adult IV push medications is related to drug shortages, which have resulted in reduced availability of RTA syringes in the desired volume and concentrations, as well as the desire to conserve drugs by administration of partial doses from RTA syringes (saving the remainder for future use). The unsafe practice of using an RTA syringe as a multiple-dose vial increases the risk of errors and contamination and should be avoided.42 A third reason for the persistence of unnecessary dilution practices relates to the prevalent misunderstanding that a 10-mL syringe must be used to administer IV push medications through a central catheter.42 However, INS recommends that a syringe appropriately sized for the medication should be used once patency of the line has been confirmed using a 10-mL syringe to flush the line.12(pS58)

ISMP recommends establishing a facility-specific policy with respect to which IV push medications may be diluted, where the dilution should take place, and guidelines around how the medication should be diluted and administered.42 A gap analysis to assess unsafe IV push medication practices and identify opportunities for improvement may be warranted. Another means to aid clinicians in identifying barriers to safe injection practices in the hospital environment is the tracer tool developed by the Joint Commission Resources.43 The use of this tool can help to focus performance improvement efforts and reach the goal of dispensing medications in the most RTA form possible.43

LIMITATIONS

Limited evidence is available on risks associated with unnecessary dilution of RTA syringes. Additionally, there is variability in types of available evidence (observational studies, risk analysis, and surveys).

There were 3 surveys included in this review: ISMP,37,42 Heindel and Stivers,32 and Prentiss et al.33 General limitations of these types of surveys include: self-reporting, which may not represent actual practice; that people may not be able to communicate their thoughts effectively; and that cross-organizational applicability can be limited due to low response rates. In observational studies such as Hertig et al,34 the Hawthorne effect (HE) must be considered, because when clinicians are being observed they may tend to improve performance and, therefore, impact the results. However, HE is difficult to quantify due to heterogeneity in definition and the tasks performed.44 Other limitations reported by the authors include variability of cultures, policies, and procedures between different sites. Furthermore, observed rates can be affected due to sequential observations in this study. In Stucki et al,36 the study assessed microbial contamination in syringes during preparation in the laboratory, which limits the applicability to nurse administration steps. According to the authors, the risk analysis by De Giorgi et al35 contains an unavoidable subjectivity component, and, with a larger and multidisciplinary team, the bias may be minimized. Also, the failure mode effects and critical analysis tool is not a fully validated method and it does not have the ability to assess the impact of a combination of multiple failures on a specific outcome. Additionally, the analysis evaluated the pediatric intensive care unit and neonatal intensive care unit of one university hospital, and the results may not apply across the health care continuum.

CONCLUSION

This review found that the use of commercially available RTA syringes is associated with reduced risk of error, relative to conventional vial and syringe methods of IV push medication preparation and administration. Reductions in errors may lead to reduced patient harm. Greater awareness of the risks associated with unnecessary dilution of RTA syringes is still needed to eliminate this unsafe practice and thereby further improve outcomes. Furthermore, facilities can utilize resources such as the tracer tool developed by the Joint Commission Resources to identify gaps and develop a facility-specific action plan.43

ACKNOWLEDGMENT

The authors thank Marjorie Zettler for medical writing and editorial assistance.

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      Keywords:

      dilution; intravenous push medication; medication safety; prefilled syringe; ready-to-administer syringe; ready-to-use syringe

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