An observational study to evaluate the efficiency and safety of ioversol pre-filled syringes compared with ioversol bottles in contrast-enhanced examinations

Abstract

Background

The use of pre-filled syringes for contrast media (CM) administration allows efficient and optimized workflow during radiologic diagnostic procedures, and reduces the risk of contamination, providing benefits for both patients and healthcare workers.

Purpose

To compare the efficiency and safety of ioversol (Optiray^TM) bottles and pre-filled syringes in clinical practice.

Material and Methods

This was an observational, non-interventional, prospective, multicenter study conducted at 72 centers in Germany. Patients undergoing contrast-enhanced computed tomography (CT) examinations with ioversol were enrolled. The use of ioversol bottles and pre-filled syringes in the diagnostic procedure was recorded in terms of efficiency (residual volume, re-use of CM) and safety (adverse events [AEs]).

Results

A total of 10,836 patients were enrolled and included in this study. Ioversol bottles and syringes were used in 72% and 28% of cases, respectively. Analysis of the volume of CM in bottles before and after examinations, together with the volume used during the examination, suggested that in 22.5% of cases a new bottle was connected during the procedure. Further analysis revealed that in 80.2% of cases, the remaining volume of CM in the bottles could potentially be used for subsequent investigations, compared with <1% of cases for pre-filled syringes. For the total study population, AEs and serious AEs were reported in 30 (0.28%) and four (0.037%) patients, respectively, with no significant difference observed between ioversol bottles and syringes.

Conclusion

Administration of ioversol for contrast-enhanced CT examinations is associated with a low incidence of AEs and is generally safe and well tolerated. Ioversol pre-filled syringes were associated with lower residual volumes and less potential re-use compared with bottles.

Keywords

Computed tomography adults contrast agents – intravenous safety

Time and economic pressures from examining increasing numbers of patients has led to increases in the overall efficiency of radiology departments (1), and ways of optimizing workflow are constantly being sought to meet demand. Multiple use of syringes in automatic injectors has been identified as a potential way of improving efficiency, owing to the reduction in time needed to assemble and refill syringes (2, 3). However, the multiple use of autoinjector syringes and direct filling of autoinjectors from multiple-dose bottles have been identified as a source of microbiologic contamination (2, 4–8). Several reports have described the contamination of contrast media (CM), syringes and tubes, as well as cross-infections between patients, related to the use of multiple-use bottles in different patients (9–13). The re-use of CM left in multiple-dose bottles by autoinjector syringe filling after a radiological procedure has also been associated with an increased risk of contamination and patient infection (2, 4–8, 14, 15). It is common for equipment to be connected to a patient by the intravenous route through an extension tube fitted with a non-return valve − this extension tube is then changed for each patient, thus reducing the risk of cross-contamination between patients; however, transmission of blood-borne diseases between patients has been known to occur despite such precautions during contrast-enhanced computed tomography (CT) (15, 16). Although risk of contamination can, therefore, be reduced through the implementation of hygienic barriers (7) and good aseptic techniques during equipment/injection set-up, a risk of contamination remains with multiple-use products, even with optimized hygienic environments (4, 7). Thus, the re-use of CM and frequent handling of the bottles, syringes, tubes, and connectors during injector assembly and refilling may have implications for patient safety by increasing the risk of contamination and patient infection.

Disposable, pre-filled contrast syringes minimize the risk of contamination and patient infection during diagnostic procedures when used correctly and on a single-use basis, and have been associated with efficiency improvements owing to the lower potential for misadministration and reduced manipulation of equipment during injector assembly (1–3, 6).

An observational, non-interventional, prospective, multicenter study was conducted to examine the use of ioversol (Optiray^TM) bottles and pre-filled syringes in clinical practice. Specifically, ioversol use was evaluated in terms of residual volume of CM and re-use of CM, as well as the monitoring of adverse events (AEs), to compare the efficiency and safety of ioversol pre-filled syringes and bottles in patients undergoing contrast-enhanced CT examinations.

Material and Methods

Study design

This was an observational, non-interventional, prospective, multicenter study. Patients undergoing ioversol-enhanced CT examinations were enrolled between August 2006 and April 2007 at 72 centers in Germany. The study was conducted in accordance with the International Conference on Harmonization – Good Clinical Practice guidelines, and with the local rules and regulations in Germany, submitted to the local BfArM (Bundesamt fuer Arzneimittel und Medizinprodukte; Federal Institute for Drugs and Medical Devices) and BKK (participating physician registration). All patients provided informed consent. The study was sponsored by Covidien.

Patients

Men and women undergoing contrast-enhanced CT examinations according to daily clinical practice conditions, who were eligible for administration of ioversol bottles or pre-filled syringes for diagnostic purposes according to the approved summary of product characteristics (SPC) (17), were enrolled in the study. Owing to the non-interventional design of the study, decisions on patient recruitment were entirely at the discretion of the participating investigators, as guided by the indications and contraindications listed in the SPC.

Contrast administration and variables

Ioversol bottles were compared with ioversol pre-filled syringes in terms of residual volume and safety. Each patient was administered ioversol supplied either as a bottle (200 mL or 500 mL) or as a pre-filled syringe (50, 75, 100, and 125 mL), based on the decision/preference of the participating investigators. The volume of ioversol administered depended on the patient, the concentration of ioversol, the type of investigation and the imaging technique used. It can vary between 1 mL and 150 mL, with a maximum total volume of 250 mL or less. The applied dose of ioversol was adapted to the patient's body weight, protocols approved/established in each center, as well as the appropriate indications, according to the approved SPC for ioversol (17). The same methods of volume calculation were used regardless of whether ioversol was supplied by bottle or as a pre-filled syringe. There were no restrictions with regard to whether the ioversol was administered by power injector or manual injection.

For each patient, indication, medical history, concomitant disease, medication use, risk factors (including allergic predisposition), and demographic data were documented before CT examination. Criteria evaluated during and after the CT examination included: ioversol concentration, flow rates, and injection method used. Safety monitoring included documentation of any AEs or serious AEs both during and up to 1 h after CT examination. Serious AEs were assessed on a patient basis and were defined using typical pharmacovigilance criteria, e.g. fatal outcome, life-threatening, hospitalization or prolonged patient's stay in hospital, significant or permanent incapacity, clinically relevant according to the reporting HCP. Following the examination, any remaining volumes of ioversol in bottles and pre-filled syringes were recorded. Furthermore, radiologists were asked directly whether any remaining volumes would potentially be used for subsequent procedures. The responses of investigators were analyzed according to the volume of ioversol remaining in the bottle (<25, 25–75, 75–175, 175–275, 275–375, and >375 mL) or pre-filled syringe (<25, 25–75, and 75–175 mL; ranges were kept the same as for bottles despite 125 mL being the maximum syringe volume). All data were reported by participating physicians on an individual case report form per patient.

Statistical methods

In a large postmarketing study by Covidien (formerly Mallinckrodt), summarized in the ioversol approved SPC (17), AEs were reported with an incidence of 0.4%, for the most frequent AE, to less than 0.1% (Covidien, data on file). Based on these data, sample size was calculated to be sufficient to detect rare AEs until an incidence of approximately 0.04%. According to the binomial distribution, it was calculated that the sample size needed to ensure a 99% certainty of observing at least one AE with an estimated incidence of 0.04% was 11,000. Even for evaluable observations lower than 15%, sample size would still be sufficient to ensure with a 99% certainty the observation of a rare AE with an incidence of about 0.04% (10,000 patients needed for an incidence of 0.00046). Double-sided parametric and non-parametric statistical testing was performed as appropriate using the 0.05 significance level. All data were analyzed using SAS^® version 8.02.

Results

A total of 10,836 patients were enrolled (48.1% men/boys, 50.8% women/girls) with an average age of 60.9 years (range, 11–100 years) (Table 1). A total of 5033 patients (46.4%) had between one and seven concomitant diseases and/or risk factors that could potentially influence tolerability of ioversol-enhanced imaging. The most common individual risk factor was an adverse reaction to a previously administered CM in 4168 (38.5%) patients. Other specific risk factors reported included: diabetes with micro- and macroangiopathy (6.9%); coronary heart disease (5.6%); allergic predisposition (4.1%); cardiac insufficiency (2.3%); peripheral occlusive arterial disease (1.5%); and renal insufficiency (0.9%).
Table 1
Patient baseline characteristics

Ioversol device unknown Ioversol pre-filled syringe Ioversol bottle Difference* (P value) Total (n = 10,836)

Patients, n (%) 37 (0.3) 3015 (27.8) 7784 (71.8) 10,836 (100)

Sex, n (%)

Male 20 (0.4) 1401 (26.9) 3796 (72.8) – 5217 (48.1)

Female 16 (0.3) 1597 (29.0) 3890 (70.7) – 5503 (50.8)

Unknown 1 (0.9) 17 (14.7) 98 (84.5) – 116 (1.1)

Age (years)

Mean (SD) 59.4 (14.0) 61.0 (15.3) 60.8 (14.9) 0.2 (P = 0.61) 60.8 (15.1)

Range 31–79 14–98 11–100 11–100

Weight (kg)

Mean (SD) 77.4 (16.1) 77.5 (15.3) 76.8 (15.1) 0.7 (P = 0.03) 77.0 (15.1)

Range 45–120 35–185 28–181 28–185

Height (cm)

Mean (SD) 169.7 (11.1) 170.7 (9.3) 170.5 (9.0) 0.3 (P = 0.19) 170.5 (9.1)

Range 140–190 143–200 101–204) 101–204

BMI (kg/m²)

Mean (SD) 26.8 (4.6) 26.5 (4.5) 26.4 (4.6) 0.1 (P = 0.13) 26.4 (4.6)

Range 17.8–38.7 14.5–57.1 14.2–93.1 14.2–93.1

Difference between pre-filled syringe and bottle groups

BMI, body mass index; SD, standard deviation

Overall use of ioversol bottles and pre-filled syringes

In total, 7784 (71.8%) patients were examined using ioversol bottles, compared with 3015 (27.82%) for ioversol pre-filled syringes. The types of injection system used in the investigations with ioversol pre-filled syringes or ioversol bottles are listed in Table 2. In 92.3% of the investigations, ioversol was used at a concentration of 300 mg/mL (Table 3). The majority of investigations were of the abdomen (n = 5263, 48.8%), followed by lungs/thorax (n = 2967, 27.4%), then head/neck (n = 2142, 19.8%). The remaining body regions were brain/spinal cord (n = 333, 3.1%), vascular system (n = 306, 2.8%), liver (n = 257, 2.4%), suspected metastases (n = 180, 1.7%), heart (n = 28, 0.3%), and other (n = 58, 0.5%). No clear pattern was observed when assessing which ioversol concentration was used as per body system, except that there was more variation, particularly of higher ioversol concentrations used, when larger volumes of CM were required (for imaging the vascular system, heart, liver, or suspected metastases.
Table 2
Types of injection system used for administration of ioversol from pre-filled syringes or bottles

Ioversol pre-filled syringe, n (%) Ioversol bottle, n (%) Total, n (%)

Manual injection 296 (2.74) 229 (2.12) 525 (4.86)

Medrad injection system 479 (4.44) 2683 (24.84) 3162 (29.28)

Metron injection system 381 (3.53) 1831 (16.96) 2212 (20.48)

Ulrich injection system 2 (0.02) 1287 (11.92) 1289 (11.94)

Covidie injection system 1492 (13.82) 281 (2.60) 1773 (16.42)

Covidie* Optivantage DH injection system 273 (2.53) 503 (4.66) 776 (7.19)

Other 92 (0.85) 970 (8.98) 1062 (9.83)

Total 3015 (27.92) 7784 (72.08) 10,799 (100.00)

Formerly Tyco Mallinckrodt

Table 3
Concentration of ioversol used

Ioversol concentration (mg/mL)

n (%) 160 240 300 320 350 Unknown Total

Ioversol pre-filled syringe 0 84 (2.79) 2830 (93.86) 61 (2.02) 3 (0.86) 37 (1.23) 3015 (27.82)

Ioversol bottle 1 (0.01) 11 (0.14) 7167 (92.07) 227 (2.92) 344 (4.42) 34 (0.44) 7784 (71.83)

Unknown 0 0 0 0 0 37 37

Total 1 (0.01) 95 (0.88) 9997 (92.26) 288 (2.66) 347 (3.20) 108 (1.00) 10,836 (100.00)

The volume of ioversol in bottles prior to the procedures and the remaining volume of ioversol in bottles and pre-filled syringes after completion of investigations was recorded and analyzed (Table 4). The total volume of ioversol used, in the majority of cases, was 100 mL or less (79.2% and 70.2% for ioversol bottle and pre-filled syringe examinations, respectively). By comparing volumes reported to be present in ioversol bottles at the start of and after the procedures, as well as the volume indicated to have been used, it was determined that in at least 1754 (22.53%) investigations a new bottle was required and connected during the examination. By comparison, a new pre-filled syringe was connected in 57 (1.89%) examinations.
Table 4
Volume of contrast media remaining after completion of investigations with ioversol bottles and pre-filled syringes (n = 10,796)

Proportion prior to start, n (%) Proportion remaining after completion, n (%)

Volume in ioversol bottle (mL)

<25 348 (4.47) 1792 (23.02)

25–75 377 (4.84) 1513 (19.44)

75–175 2552 (32.79) 1901 (24.42)

175–275 1924 (24.72) 421 (5.41)

275–375 424 (5.45) 421 (5.41)

>375 1084 (13.93) 698 (8.97)

Unknown 1075 (13.81) 1038 (13.34)

Total 7784 (100.00) 7784 (100.00)

Volume in ioversol pre-filled syringe ^† (mL)

<25 – 1887 (62.65)

25–75 – 199 (6.61)

75–175 – 8 (0.27)

Unknown – 918 (30.48)

Total – 3012 (100.00)

Data regarding use of pre-filled syringe or bottle not provided for 37 patients. Data for three patients receiving ioversol as pre-filled syringes werealso excluded from analyses, because the information was not compatible with marketed pre-filled syringes presentations

^†Ioversol pre-filled syringes are approved for single use only, therefore, volume prior to the start of the procedure was assumed to be 100%

Potential re-use of ioversol bottles and pre-filled syringes

The extent of use of CM from the same bottles or pre-filled syringes for more than one procedure was examined (Table 5). Radiologists were asked directly whether any remaining volumes would potentially be used for subsequent procedures. From the subset of investigators from whom this information was available (n = 9856), 5989 (60.77%) indicated that the remaining CM could be used for a subsequent procedure or procedures. When analyzed according to bottle use or pre-filled syringe use, 5969 (99.67%) cases of re-use were with ioversol bottles vs.* 20 (0.33%) for the pre-filled syringes. Overall, an increased relative risk of continued use of 96.9 (95% confidence interval [CI]: 62.6–149.9) for ioversol bottles (80.22%) vs. prefilled syringes (0.83%) remains.
Table 5
Continued potential use of remaining contrast medium with ioversol bottles and pre-filled syringes*

Re-use of remaining volume, n/N (%) Proportion of total re-use, %

Ioversol bottle^† 5969/7441 (80.22) 99.67

Ioversol pre-filled syringe^‡ 20/2415 (0.83) 0.33

Total 5989/9856 (60.77) 100.00

Data regarding use of pre-filled syringe or bottle not provided for 37 patients

^†Information on re-use of volume remaining in ioversol bottles not known for 343 patients

^‡Information on re-use of volume remaining in ioversol pre-filled syringes not known for 600 patients

A more detailed analysis of the re-use of CM according to the volume of remaining contrast media was carried out. The responses of investigators were analyzed according to the volume of ioversol remaining in the bottle (<25, 25–75, 75–175, 175–275, 275–375, and >375 mL) or pre-filled syringe (<25, 25–75, and 75–175 mL). For volumes <25 mL, investigators reported that the remaining CM would potentially be used for subsequent procedures in patients in 20.46% and 0.27% of cases for ioversol bottles and pre-filled syringes, respectively.

Safety

A total of 30 patients (0.28%) reported a total of 54 AEs (Table 6). Occurrence of AEs did not vary significantly between ioversol pre-filled syringes (0.33%) and ioversol bottles (0.26%; relative risk of AE in pre-filled syringe versus bottle: 1.29 [95% CI: 0.61–2.75]). Overall, urticaria was the most often reported AE, followed by nausea and erythema. Of the 30 patients experiencing an AE, 20 patients had an anaphylactoid adverse reaction. Serious AEs were reported for four patients (0.037%), three of which were anaphylactoid adverse reactions, and required hospitalization. The most common concomitant disease or risk factor among those patients who reported an AE was ‘allergic predisposition’ (n = 11).
Table 6
Adverse events with ioversol bottles and pre-filled syringes

Ioversol bottle (n = 7784), n (%) Ioversol pre-filled syringe (n = 3015), n (%)

Patients with ≥1 AE 20 (0.26) 10 (0.33)

AE

Urticaria 9 (0.12) 4 (0.13)

Nausea 8 (0.10) 3 (0.10)

Erythema 4 (0.05) 2 (0.07)

Vomiting 2 (0.03) 1 (0.03)

Pruritis 2 (0.03) 2 (0.07)

Cough – 2 (0.07)

Edema 1 (0.01) 2 (0.07)

Dizziness 1 (0.01) –

Throat irritation 1 (0.01) –

Sensation of foreign body 1 (0.01) –

Feeling hot 1 (0.01) –

Eczema 1 (0.01) –

Rash 1 (0.01) –

Chills 1 (0.01) –

Muscle spasm 1 (0.01) –

Involuntary muscle contraction 1 (0.01) –

Hypertension 1 (0.01) –

Bradycardia 1 (0.01) –

Angioedema 1 (0.01) –

AE, adverse event

Discussion

This large, observational, non-interventional study provided insight into the actual use of ioversol bottles and pre-filled syringes in clinical practice. The study comprised a large patient population (>10,000 patients enrolled), selected from a variety of diagnostic centers in Germany using ioversol CM from either bottles or pre-filled syringes. Overall, the study supports previous findings that ioversol is generally safe and well tolerated (18). As expected, no difference was found between bottles and syringes in terms of the reporting rate of AEs (0.26 and 0.33%, respectively), indicating that both forms of ioversol delivery are well tolerated.

The overall volume of ioversol used in examinations was 100 mL or less in the majority of cases (79.2% and 70.2% for bottle and pre-filled syringes, respectively). The volume of ioversol in pre-filled syringes was sufficient to accommodate most CT examinations without the need to connect new syringes during the procedure (1.89% of examinations connected a new syringe). The availability of different volumes of ioversol pre-filled syringes (50, 75, 100, and 125 mL) allows the physician to adapt the pre-filled syringe volume according to the individual patient, thereby minimizing the need to connect a new syringe and reducing the volume of unused CM. For ioversol bottles, with volumes up to 500 mL, the use of <100 mL in examinations could imply the re-use of an individual container in up to five different patients. By specifically analyzing the volume of CM used/remaining, it was estimated that a new bottle was connected in approximately 22.53% of cases. These data suggest that the volume available in the bottle prior to the start of the examination was not sufficient to complete the investigation. Furthermore, it is likely that the bottle selected to initiate the investigation contained unused agent from a previous investigation, owing to the insufficient volume available. These data are supported by the high potential for re-use in this study, where the likelihood of continued multiple use of CM from bottles was almost 100-fold greater compared with pre-filled syringes (80.22% vs.* 0.83%, respectively). Moreover, for residual volumes >25 mL, the remaining CM would potentially be used for subsequent procedures in 20.46 and 0.27% of cases for ioversol bottles and pre-filled syringes, respectively. This suggests that there was a bias in behaviour that discourages re-use of pre-filled syringes. Indeed, this was not unexpected considering that ioversol pre-filled syringes are indicated for single use only. Furthermore, evidence from studies shows that single-use syringes are less likely be involved with microbial contamination (2, 4–8, 14, 15), and, therefore, are potentially safer for patients.

Use of the remaining volume in at least one subsequent procedure, together with the reduced expense of using disposable devices for contrast injections, may appear to have obvious economic and time efficiency benefits; however, studies have demonstrated that pre-filled syringes for CM administration can enhance efficiency in radiology units by providing benefits in terms of time-efficient assembly of injection systems and prevention of contamination (1–3). For example, one study has shown that despite the increased number of system changes, there was no significant difference in time taken for assembly of an automatic injector system for single-use pre-filled syringes versus a multiple-use protocol (2). Moreover, the advantages of pre-filled syringes for CM administration have also been acknowledged during discussions among leading figures in hospital and clinical pharmacy. In addition to improved patient safety through reductions in administration and labelling errors, reductions in microbial contamination and embolisms, significant benefits for healthcare workers and clinics (for example, reducing needlestick injuries, cleaning times, and time required for each procedure), and cost-effectiveness were also acknowledged (1, 6–8).

Although cost and efficiency were not assessed in the current study, evidence from a radiology department in the UK has suggested that pre-filled CM syringes are easier to use, faster, cleaner, and more cost-effective compared with manually filling syringes with CM (7). Furthermore, pre-filled syringes were thought to be technically less demanding to prepare and make inventory control much easier. In one department, pre-filled syringes took 15 s to set up compared with 120 s to fill and set up an empty syringe. Assuming a list of 50 patients and three scanners, this resulted in a real-time saving of 87.5 min each day; therefore, for the same fixed costs, the use of pre-filled syringes allowed an extra three patients to be seen each day (7). Furthermore, as pre-filled syringes are already labelled with product name, concentration, batch number and expiry date, the possibility of using the wrong preparation is reduced, allowing more generalist radiographer technicians and nurses to administer the CM while more qualified staff can carry out other procedures (7). Such observations are likely to be applicable to all radiology departments. Further study is required to determine whether any cost difference between pre-filled syringes and bottles would be negated by efficiency savings elsewhere.

Concerns have previously been raised relating to the practice of switching bottles during a procedure, using the same bottle for multiple patients and the overall hygiene aspects related to CM administration (2, 4–6, 9, 10, 14, 15, 19, 20). One systematic review showed that multi-vial drugs were the most common route for patient-to-patient transmission of hepatitis B virus (20). Contamination of multi-use bottles is much more likely when basic hygiene guidelines are not followed (19). Although some studies suggest that re-use from large containers may be acceptable provided that stringent hygiene procedures are followed (21–23), the majority of reports highlight concerns over these practices (2, 4–6, 9, 10, 14, 15). Indeed, even within an experimental setting where intensive hygienic preventative measures were followed, syringes used to administer CM and saline solutions for multidetector CT showed contamination with skin and oral flora on surfaces of devices, such as CT syringes (2). The authors conclude that optimization of environments does not prevent contamination of syringes and, therefore, multiple-use syringes for more than one patient should be prohibited owing to the risk of septic complications (2, 4). These results are supported by studies showing that transmission of infections with CM through the filling of multiple-use syringes is associated with an increased risk of contamination and patient infection (2, 10, 13, 15, 21, 24), as well as cases of cross-infections with the use of multiple-use vials or bottles without use of contrast media (11, 12). Use of pre-filled syringes may, therefore, help reduce the risk of contamination. The appropriate use of single-use products, such as syringes, disposable tubes, and connectors of automatic injectors, is further supported by national restrictions from regulatory authorities (2, 25, 26). It should be noted that re-use of single-use devices will not only put patients at risk of cross-contamination, but can affect their safety, performance, and effectiveness (26). Despite the important implications of contamination via CM, there are no official practice guidelines issued by the BfArM regarding the use/re-use of either single- or multi-use CM bottles with regard to prevention of contamination in Germany.

This study did not investigate the actual re-use of ioversol in subsequent procedures. As such, the data on ioversol re-use are based on the response of radiologists, while the actual re-use may be significantly lower than is suggested by the data provided here. However, the response of radiologists showed that there was almost a 100-fold difference between the potential re-use of the remaining volume of ioversol in pre-filled syringes and in bottles. This, together with the observation that pre-filled syringes were associated with lower remaining volumes after the procedure, suggests that syringes are less likely to be used for subsequent examinations compared with bottles. Ioversol pre-filled syringes are approved for single use only and are available across a range of volumes to ensure that the appropriate volume can be administered without substantial excess of unused CM. The results from this study highlight the hypothetical potential re-use of pre-filled syringes in clinical practice and show that they are generally used in accordance with the label, and that any remaining volume would not be sufficient to carry out a second exploration. This latter point could be clarified in additional studies that monitor the total volume of CM used according to volume of pre-filled syringe selected. Microbiologic contamination of the remaining CM in the bottles and syringes was not measured in this study and, therefore, direct comparisons of contamination risk cannot be made using the data from this study alone. Further investigation is required to determine whether there is a difference in contamination risk between ioversol pre-filled syringes and ioversol bottles. Prospective analysis would also be useful for assessing the risk of administration error, embolisms, microbial contamination during preparation and administration, mislabelling errors and sharps injuries, as well as reducing time required for procedures for ioversol pre-filled syringes vs. ioversol bottles.

Lastly, this was an observational, non-interventional study, and as such more patients received ioversol bottles compared with pre-filled syringes (72% vs. 28%). The study enrolled over 10,000 patients, however, and provides useful insight into the use of ioversol in daily clinical practice. Further studies that directly compare the re-use and risk of contamination with ioversol bottles and pre-filled syringes would provide evidence to confirm the results of this study.

In conclusion, administration of ioversol for contrast-enhanced CT examination is generally safe with a low incidence of AEs. Ioversol pre-filled syringes are associated with lower remaining volumes and a lower potential risk of re-use in subsequent procedures compared with ioversol bottles. The results of this large observational study suggest that single-use ioversol pre-filled syringes may be associated with potentially lower risk of contamination compared with ioversol bottles used for multiple patient CT examinations.

Conflict of interest: None.

	Ioversol device unknown	Ioversol pre-filled syringe	Ioversol bottle	Difference* (P value)	Total (n = 10,836)
Patients, n (%)	37 (0.3)	3015 (27.8)	7784 (71.8)		10,836 (100)
Sex, n (%)
Male	20 (0.4)	1401 (26.9)	3796 (72.8)	–	5217 (48.1)
Female	16 (0.3)	1597 (29.0)	3890 (70.7)	–	5503 (50.8)
Unknown	1 (0.9)	17 (14.7)	98 (84.5)	–	116 (1.1)
Age (years)
Mean (SD)	59.4 (14.0)	61.0 (15.3)	60.8 (14.9)	0.2 (P = 0.61)	60.8 (15.1)
Range	31–79	14–98	11–100		11–100
Weight (kg)
Mean (SD)	77.4 (16.1)	77.5 (15.3)	76.8 (15.1)	0.7 (P = 0.03)	77.0 (15.1)
Range	45–120	35–185	28–181		28–185
Height (cm)
Mean (SD)	169.7 (11.1)	170.7 (9.3)	170.5 (9.0)	0.3 (P = 0.19)	170.5 (9.1)
Range	140–190	143–200	101–204)		101–204
BMI (kg/m²)
Mean (SD)	26.8 (4.6)	26.5 (4.5)	26.4 (4.6)	0.1 (P = 0.13)	26.4 (4.6)
Range	17.8–38.7	14.5–57.1	14.2–93.1		14.2–93.1

	Ioversol pre-filled syringe, n (%)	Ioversol bottle, n (%)	Total, n (%)
Manual injection	296 (2.74)	229 (2.12)	525 (4.86)
Medrad injection system	479 (4.44)	2683 (24.84)	3162 (29.28)
Metron injection system	381 (3.53)	1831 (16.96)	2212 (20.48)
Ulrich injection system	2 (0.02)	1287 (11.92)	1289 (11.94)
Covidie* injection system	1492 (13.82)	281 (2.60)	1773 (16.42)
Covidie* Optivantage DH injection system	273 (2.53)	503 (4.66)	776 (7.19)
Other	92 (0.85)	970 (8.98)	1062 (9.83)
Total	3015 (27.92)	7784 (72.08)	10,799 (100.00)

	Ioversol concentration (mg/mL)
Ioversol pre-filled syringe	0	84 (2.79)	2830 (93.86)	61 (2.02)	3 (0.86)	37 (1.23)	3015 (27.82)
Ioversol bottle	1 (0.01)	11 (0.14)	7167 (92.07)	227 (2.92)	344 (4.42)	34 (0.44)	7784 (71.83)
Unknown	0	0	0	0	0	37	37
Total	1 (0.01)	95 (0.88)	9997 (92.26)	288 (2.66)	347 (3.20)	108 (1.00)	10,836 (100.00)

	Proportion prior to start, n (%)	Proportion remaining after completion, n (%)
Volume in ioversol bottle (mL)
<25	348 (4.47)	1792 (23.02)
25–75	377 (4.84)	1513 (19.44)
75–175	2552 (32.79)	1901 (24.42)
175–275	1924 (24.72)	421 (5.41)
275–375	424 (5.45)	421 (5.41)
>375	1084 (13.93)	698 (8.97)
Unknown	1075 (13.81)	1038 (13.34)
Total	7784 (100.00)	7784 (100.00)
Volume in ioversol pre-filled syringe ^† (mL)
<25	–	1887 (62.65)
25–75	–	199 (6.61)
75–175	–	8 (0.27)
Unknown	–	918 (30.48)
Total	–	3012 (100.00)

	Re-use of remaining volume, n/N (%)	Proportion of total re-use, %
Ioversol bottle^†	5969/7441 (80.22)	99.67
Ioversol pre-filled syringe^‡	20/2415 (0.83)	0.33
Total	5989/9856 (60.77)	100.00

	Ioversol bottle (n = 7784), n (%)	Ioversol pre-filled syringe (n = 3015), n (%)
Patients with ≥1 AE	20 (0.26)	10 (0.33)
AE
Urticaria	9 (0.12)	4 (0.13)
Nausea	8 (0.10)	3 (0.10)
Erythema	4 (0.05)	2 (0.07)
Vomiting	2 (0.03)	1 (0.03)
Pruritis	2 (0.03)	2 (0.07)
Cough	–	2 (0.07)
Edema	1 (0.01)	2 (0.07)
Dizziness	1 (0.01)	–
Throat irritation	1 (0.01)	–
Sensation of foreign body	1 (0.01)	–
Feeling hot	1 (0.01)	–
Eczema	1 (0.01)	–
Rash	1 (0.01)	–
Chills	1 (0.01)	–
Muscle spasm	1 (0.01)	–
Involuntary muscle contraction	1 (0.01)	–
Hypertension	1 (0.01)	–
Bradycardia	1 (0.01)	–
Angioedema	1 (0.01)	–

Footnotes

ACKNOWLEDGEMENTS

The authors acknowledge the editorial support provided by Medicus International, which was funded by Covidien. This study was funded by Covidien.

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	Ioversol concentration (mg/mL)
n (%)	160	240	300	320	350	Unknown	Total
Ioversol pre-filled syringe	0	84 (2.79)	2830 (93.86)	61 (2.02)	3 (0.86)	37 (1.23)	3015 (27.82)
Ioversol bottle	1 (0.01)	11 (0.14)	7167 (92.07)	227 (2.92)	344 (4.42)	34 (0.44)	7784 (71.83)
Unknown	0	0	0	0	0	37	37
Total	1 (0.01)	95 (0.88)	9997 (92.26)	288 (2.66)	347 (3.20)	108 (1.00)	10,836 (100.00)