Acta Ophthalmologica 2012
Correspondence:
Domagoj Ivastinovic, MD
Department of Ophthalmology,
Medical University of Graz
Auenbruggerplatz 4,
8036 Graz,
Austria
Tel: + 43 316 385 3817
Fax: + 43 316 385 3261
Email: [email protected]
Accuracy, precision and
repeatability in preparing
the intravitreal dose with a
1.0-cc syringe
Carsten H. Meyer, Zingpeng Liu,
Christian Brinkmann, Eduardo B.
Rodrigues and Hans-Martin Helb
Department of Ophthalmology, University of Bonn, Bonn, Germany
doi: 10.1111/j.1755-3768.2010.02072.x
Editor,
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 individu-
T
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.
ally 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. 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.
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Acta Ophthalmologica 2012
References
Fig. 3. The repeatability among all 11 participants had a mean accuracy of 4.8 mg ±3.1.
There was no statistical difference in the
reproducibility between both groups.
The International Standards Organization (ISO) permits a defined range
of error in the accuracy of loading
according to their nominal capacity or
the size of the syringe. The conventional capacity tolerance of any
syringe is defined by the sum of its
nominal maximal capacity V1 and the
actually expelled volume V2. For
example, if a 1.0-cc syringe is filled up
to the 0.05-ml graduation line for an
IVT, the tolerance for nominal capacity V1 is 1.5% and the tolerance for
the expelled volume V2 is 2% [Erstad
et al. 2006]. IVT in ophthalmology
are mainly performed using 1.0-cc
syringes, which are frequently filled by
0.05 ml. The calculated tolerance
for an intravitreal injection of 0.05 ml
applied in a 1.0-cc syringe is (1.0 ml ·
0.015) + (0.05 ml · 0.02) = 0.016 ml.
Thus, the calculated standard variance
of the actual volume of 0.05 ml of
ranibizumab follows the equation
0.05 ± 0.016 or an applied volume
between 0.034 and 0.066 ml. Our
experimental results highly agree with
these calculations. Following this
assumption and a known specific
weight of 1.04 mg ⁄ ml for ranibizumab
would imply an actual delivered mean
dose of (0.5375 ml · 1.04 mg ⁄ ml) =
0.58 mg ± 0.17 (range 0.41 ) 0.75 mg)
ranibizumab per injection.
Gerding & Timmermann (2010)
analyzed the accuracy and precision of
0.5 mg dose ranibizumab injections.
The application was performed in 3
different modes: 1) after preadjustment
of the desired dose in the syringes with
normal (PA) and 2) with forced injection (PAF), and 3) by differential
volume reduction from an overdose
filled syringe (DI). The mean injection
e166
Fig. 4. In reference to an expected mass of
50 mg or 0.05 ml distilled water our measurements determined a mean of 53.75 mg distilled water (range 24.6–65.5 mg) with a
normal distribution of measured values for
all 11 participants (440 syringes). Forty four
samples contained less than 47 mg, 52 samples more than 60 mg.
of DI mode was 0.5059 mg (95% confidence interval [CI]: 0.4903 ) 0.5214).
PA resulted in a lower dose (mean:
0.4542, CI: 0.4339 ) 0.4744) and the
PAF mode in a higher dose (0.5335,
CI: 0.5130 ) 0.5540). They concluded
that the routinely used Lucentis injection sets results in a relatively uncontrolled application of ranibizumab
doses and recommended to use smaller
syringes, thus confirming the established ISO standard range of error for
the loading, which primarily depends
on size of a syringe. For example, if a
0.5-ml syringe is filled by 0.05 ml, the
calculated tolerance is (0.5 ml ·
0.0075)+(0.05 ml · 0.01)=0.00875 ml.
Thus, the calculated standard variance
of the actual volume of 0.05 ml in
a 0.5-cc syringe follows the equation
0.05 ± 0.0087 ml or an applied volume between 0.0413 and 0.0587 ml. All
these examples demonstrate that the
accuracy and precision of the current
manual approach to prepare the correct dose in a syringe remain limited.
In conclusion, treating physicians
need confidence that the intended dosage of the drug is actually delivered
[Wolf et al. 2010]. However, we determined a significant variance in the
accuracy, precision and repeatability
to prepare a proposed dose for IVT.
Our findings may have potentially
important clinical implications as our
data indicate a considerable variation
of the applied mass using the standard
equipment for IVT.
Erstad AJ, Erstad BL & Nix DE (2006):
Accuracy and reproducibility of small-volume injections from various-sized syringes.
Am J Health Syst Pharm 63: 748–750.
Gerding H & Timmermann M (2010): Accuracy and precision of intravitreally injected
ranibizumab doses: an experimental study.
Klin Monbl Augenheilkd 227: 269–272.
Meyer CH, Krohne TU & Holz FG (2010):
Concentrations of unbound bevacizumab
in the aqueous of untreated fellow eyes
after a single intravitreal injection in
humans. Acta Ophthalmol. [Epub ahead of
print].
Raju JR & Weinberg DV (2002): Accuracy
and precision of intraocular injection volume. Am J Ophthalmol 133: 564–566.
Wolf A, Gandorfer A, Haritoglou C, Koller
C, Thalmeier A & Kampik A (2010):
Volumenberechnungen zur aktuellen intravitrealen Injektion von Lucentis. Ophthalmologe 107: 435–438.
Correspondence:
Carsten H. Meyer
Department of Ophthalmology
University of Bonn
Ernst-Abbe-Street 2
53127 Bonn
Germany
Email: [email protected]
Prevalence of
undercorrection of
refractive error in rural
Central India
The Central India eye and
medical study
Vinay Nangia,1 Jost B. Jonas,1,2 Ajit
Sinha,1 Rajesh Gupta1 and Krishna
Bhojwani1
1
Suraj Eye Institute, Nagpur, Maharashtra, India
2
Department of Ophthalmology, Medical Faculty Mannheim of the RuprechtKarls-University Heidelberg, Mannheim,
Germany
doi: 10.1111/j.1755-3768.2010.02073.x
Vinay Nangia and Jost B. Jonas contributed
equally to this work.