Accuracy, precision and repeatability in preparing the intravitreal dose with a 1.0‐cc syringe

Editor, T he established dose of 0.5 mg ranibizumab (Lucentis, Novartis, Basel, Switzerland) is routinely injected into the vitreous cavity. The diluted drug has to be aspirated from the original glass vial into a disposable 1.0-cc plastic syringe and adjusted to the proposed dose. The actually expelled volume from the syringe may have a significant variance and may critically affect its biological efficacy [Meyer et al. 2010]. Thus, the presumed volume in the syringe and its preparation has to be accurate and precise, although the human error remains unknown (Figs 1 and 2). Raju & Weinberg (2002) filled 1.0-cc syringes with 0.1 versus 0.05 ml distilled water and determined a better accuracy for larger volume compared to smaller volume. Over 71% of the delivered 0.1 ml and 44% of the delivered 0.05 ml injections were within 10% of the intended volume. While this study included only one participant examining two volumes, we decided to perform a study with 11 participants preparing a set of syringes. We replaced ranibizumab by distilled water and measured the actual mass of fluid that is expelled in intravitreal injections (IVT) from individually prepared syringes. We included four nurses (group A) and seven treating physicians (group B), who were routinely involved in the preparation of syringes for IVT. All 11 health care professionals were asked to fill each 40 individual syringes with 0.05 ml distilled water (aqua ad iniectabilia, Delta Pharm, Pfullingen, Germany) in a 1.0-cc disposable syringe (BD Plastipak; Becton Dickinson & Co., Franklin Lakes, NJ, USA) in the prospective blinded study. The fluid in each syringe was slowly injected onto the top loading tray of an AC-powered high-precision weighing balance (AE 160; Mettler Toledo Lab Balances, Greifensee, Switzerland). This procedure was repeated using a total of 440 syringes from 11 individual volunteers. The balance was properly calibrated before the measurements. The mean mass of distilled water for all 11 participants dispensed onto the plastic tray was 53.75 mg (range 24.6 mg to 65.5 mg) compared to the expected mass of 50 mg or 0.05 ml water (Figs 3 and 4). The mean conformity of dispensed water was 7.39% greater than expected. Over 78% were within the 10% of the intended mass, and the calculated accuracy was 3.75 mg with a precision of ±6.38 mg. The lowest mass contained 37.5% of the highest measured. Forty-four samples (29 in group A and 15 in group B) contained <47 mg, and 52 samples (32 in group A and 20 in group B) more than 60 mg water. The mean reproducibility among all 11 participants was 4.8 mg ± 3.1 water. There was no statistical difference in the reproducibility between the two professional health care groups. In 11.8% of all samples, the equivalent ranibizumab dose was 20% or greater than expected (p = 0.02). Fig. 1. A protocol for training of nurses and physicians to prepare IVT was established. Approximately, 0.15 ml distilled water was manually aspirated into a 1.0-cc syringe using an 18-gauge needle (BD Microlance 3; Becton Dickinson & Co.). The 18-gauge needle was then exchanged by a 30-gauge needle (BD Microlance 3; Becton Dickinson & Co.), and possible air bubbles were gently expelled from the wall by tapping the syringe. The surplus of fluid was expelled from the syringe until the position of the plunger tip was adjusted to the 0.05-ml graduation line on the syringe barrel according to the individual estimation of the preparing person. The left image demonstrates the theoretical proper placement of the plugger in the syringe on the 0.05-ml graduation line of the syringe. The lower right image shows the clinical picture of two adjusted syringes, both appearing equally filled. The upper right image demonstrates, under a macroscopic magnification, a reduced volume in the left syringe. The measured mass of water delivered onto the tray is in the right syringe 45 mg, whereas 51 mg in the right syringe. Fig. 2. The graph indicates the relationship of accuracy and precision of repeated measurements as to reference value. Accuracy is defined as the degree of closeness of repeated measurements (conformity) and refers to the agreement between a measured value and the reference value. It indicates how close a measurement is to this value and relates to the quality of a result. Precision refers to the exactness of repeated independent measurements (uniformity) and indicates how close repeated measurements are under unchanged conditions. Precision gives the degree of refinement in the performance and does not relate to the reference value. It is therefore an indication of the repeatability of a result, which describes the variation arising when all efforts are made to keep conditions constant by using the same instrument and operator. Reproducibility describes the variation using the same measurement process among different operators. Thus, precision, repeatability and reproducibility relate to the quality of the performance to obtain the measurement, while accuracy relates to the quality of the values. Acta Ophthalmologica 2012