Tonometer validation and intraocular pressure reference values in the normal chinchilla (Chinchilla lanigera)

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1 Veterinary Ophthalmology (2018) 21, 1, 4 9 DOI: /vop Tonometer validation and intraocular pressure reference values in the normal chinchilla (Chinchilla lanigera) Kevin C. Snyder,*, Andrew C. Lewin,*, Christoph Mans* and Gillian J. McLellan*,, *Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin Madison, Madison, WI 53792, USA; McPherson Eye Research Institute, University of Wisconsin Madison, Madison, WI 53792, USA; and Department of Ophthalmology & Visual Sciences, University of Wisconsin Madison, Madison, WI 53792, USA Address communications to: G. J. McLellan Tel.: (608) Fax: (608) gillian.mclellan@wisc.edu Abstract Objectives To determine accuracy and precision of three commonly used tonometers (TonoVet â and TonoLab â (ICare Oy, Finland) rebound tonometers, and Tono-Pen VET TM (Reichert, NY) applanation tonometer) in normal chinchillas, and to establish a normal intraocular pressure (IOP) reference range in this species. Methods The anterior chambers of three chinchilla eyes were cannulated ex vivo and readings obtained at manometric IOPs from 5 to 80 mmhg, using each of the three tonometers in random order. Data were analyzed by linear regression, ANOVA, and Bland Altman plots. Tonometry was performed in both eyes of 60 chinchillas (age 8 weeks 16.2 years) using the TonoVet â and relationship between age and IOP analyzed using linear regression. For all statistical tests, P < 0.05 was significant. Results Intraocular pressure values obtained using the Tono-Pen VET TM and TonoVet â (in dog calibration mode; d ) showed strong linear correlation with manometry within the physiologic and clinically relevant range of IOP (0 50 mmhg). The TonoVet â d setting displayed significantly greater precision over the full range of IOP evaluated than the Tono-Pen VET TM, and both TonoVet and Tono-Pen VET TM were significantly more accurate than the TonoLab â tonometer. Mean SD IOP (TonoVet â d ) in chinchillas was mmhg, and the 95% reference interval was mmhg. Conclusions Both the Tono-Pen VET TM and TonoVet â provided clinically acceptable estimates of IOP in chinchillas. The TonoVet â provides accurate and precise IOP values, while Tono-Pen VET TM derived measurements showed greater variability. Values obtained either with the TonoLab â or TonoVet â used in the unspecified calibration setting were inaccurate in this species. Key Words: chinchilla, intraocular pressure, manometry, TonoLab, Tono-Pen Vet, TonoVet INTRODUCTION The chinchilla originated from the high altitude environment of the Andes Mountains in western South America with two reported wild species, Chinchilla chinchilla and Chinchilla lanigera. 1,2 It is thought the domestic chinchilla originated from the Chinchilla lanigera. 3 The chinchilla is used as a model for laboratory research 4 7 and is an increasingly popular companion animal. While ocular parameters for the Chinchilla lanigera have been documented previously, reported intraocular pressure (IOP) values have varied widely from a mean of 2.9 mmhg to a mean of mmhg, measured with the TonoVet â and Tono-Pen VET TM, respectively Previous studies did not validate the tonometer reading accuracy relative to manometric IOP. As pet chinchillas increase in popularity, their presentation for evaluation of ophthalmic disease can be expected to rise, and it is important to establish reference IOP values using a tonometer validated for this species, as a standard for comparison. Commercially available handheld tonometers commonly used in veterinary medicine use the concept of either applanation tonometry or rebound tonometry The 2017 American College of Veterinary Ophthalmologists

2 tonometry and iop in the normal chinchilla 5 Tono-Pen VET TM is an applanation tonometer which estimates the force required to flatten a predetermined area of the cornea and which has been validated and is used in a range of species, including cats, dogs, horses, and humans. 12,14 19 The TonoLab â and TonoVet â tonometers, are both handheld rebound tonometers that calculate IOP by using a solenoid to propel a lightweight magnetized probe toward the cornea. As the probe contacts the corneal surface and rebounds, the movement of the probe creates an electrical voltage change detected by the solenoid that in turn, is converted to an IOP measurement using a predetermined algorithm. 11 Rebound tonometry is commonly used in veterinary medicine and has been validated in dogs, 15,16,20 cats, 21 horses, 20 rabbits, 22 avian species, 23,24 mice, 25 monkeys, 26,27 reptiles and frogs, and humans. 31,32 Neither applanation nor rebound tonometers measure IOP directly; IOP is estimated using equations and prior calibration settings established by the manufacturer. No tonometer has been calibrated specifically for use on chinchilla eyes, which likely contributes to the wide range of mean IOP values previously reported for this species. The purpose of this study was to validate the Tono-Pen VET TM, TonoLab â, and TonoVet â for measurement of IOP in chinchilla eyes as compared to direct manometric pressure measurements and to determine the most clinically applicable instrument for use by veterinarians and researchers. The overall goal of this study was to use the most clinically applicable, validated instrument to establish a reference range for IOP in the normal chinchilla. MATERIALS AND METHODS All procedures involving live animals were conducted in accordance with the ARVO Statement on the Use of Animals in Research, under a protocol approved by the UW- Madison Institutional Animal Care and Use Committee. Manometry: animals Three adult chinchillas (estimated 5 years of age) were humanely euthanized for medical reasons unrelated to the research study and refrigerated within 30 min postmortem. Manometry studies were completed on eyes in situ, one eye from each chinchilla, within 10 h postmortem. The chinchillas had no previous medical history of ocular disease. Before cannulation, each eye was examined with slit-lamp biomicroscopy to ensure the absence of signs of corneal disease, uveitis, and other ocular abnormalities. Manometry setup A 25-gauge needle was connected to a pressure transducer (DTXPlus, Argon Medical Devices, Singapore) and continuous physiologic recorder (Dash 4000 Pro, GE Healthcare, Chicago, IL). The transducer line was filled with isotonic saline, and the physiologic recorder was calibrated to zero with a mercury manometer connected to the transducer via polyethylene tubing. The pressure transducer was placed horizontally at the level of the chinchilla s eye. After calibration of the pressure transducer and physiologic recorder, the mercury manometer was disconnected. A lateral canthotomy was performed to enhance visualization of the limbus and facilitate placement of needles into the anterior chamber. The anterior chamber was cannulated using two 25-gauge needles introduced at the limbus at the 2 o clock and 9 o clock positions. Cyanoacrylate adhesive was placed at the entry point of the needles to prevent leakage of aqueous humor. Throughout the procedure, leakage around the needles was not observed. The effect of the needles on corneal curvature was negligible. The needle placed at 9 o clock or 3 o clock was connected to the pressure transducer, and the needle at 2 o clock or 11 o clock was connected via an infusion set to a 500 ml bag of isotonic saline (Plasmalyte A, Baxter Healthcare, Deerfield, IL). A third 25-gauge needle connected to a separate bag of isotonic saline was placed through the skin above the eye to provide corneal lubrication by continuous drip irrigation throughout the testing session. Initially, the IOP was set at 5 mmhg and was then increased in 5 mmhg increments from 5 to 40 mmhg and by 10 mmhg increments from 40 to 80 mmhg. IOP was adjusted by raising the height of the fluid bag. At each IOP, an unmasked observer obtained three consecutive instrument-derived, valid IOP readings in each eye with each tonometer; the Tono-Pen VET TM, TonoLab â, and TonoVet â (the latter used at both the d setting and the p setting). The order of tonometers used was varied randomly by the operator throughout the experiment to limit bias. Care was taken to hold the Tono-Pen VET TM to ensure that the probe tip contacted the axial cornea perpendicularly. Only readings that displayed <5% standard deviation indicated on the Tono-Pen VET TM display were recorded. Similar care was taken with the TonoLab â and TonoVet â to ensure the instrument was held perpendicular to the ground, with the probe directed horizontally, and that the probe tip contacted the axial cornea perpendicularly. Only readings that displayed no to slight deviation were recorded as indicated by the absence of an error bar or only one bar displayed at the bottom of the TonoVet â and TonoLab â instrument screens. Intraocular pressure survey in vivo A TonoVet â tonometer set on the d setting was used to acquire triplicate IOP readings which were then averaged in 60 chinchillas, in one afternoon, at a single breeding facility. Healthy subjects were preselected by the breeder to provide a representative sample of different coat and eye colors (37 dark brown irides and 23 slate/heterochromic irides), sex (34 females and 26 males), span a broad range of ages (8 weeks to 16 years, median = 4.1 years old) and with bodyweights ranging from an estimated 200 g to 1100 g. Only readings that

3 6 snyder ET AL. displayed <2.5 mmhg variance were recorded, as indicated by the absence of an error bar or only one bar displayed at the bottom of the instrument screen. A random number generator was used to assign an even or odd value to each chinchilla to determine the order in which each eye was tested in an effort to limit bias. The TonoVet â tonometer probe was replaced after every five animals to minimize error. Chinchillas were gently manually restrained, held cradled against the assistant s upper body, with the animal s legs resting on one arm of the assistant and the ears very gently held together to facilitate IOP measurement and ophthalmic examination. No pressure was applied around the head or neck, or periocularly during restraint for IOP measurement. Immediately after IOP measurement, an ACVO board certified veterinary ophthalmologist (GJM) examined both eyes by slit-lamp biomicroscopy, and when warranted, indirect funduscopy. Any ocular abnormalities identified on ophthalmic examination excluded the affected chinchilla from the study. Statistical analysis GRAPHPAD PRISM v7 (Graphpad Software Inc, La Jolla, CA) was used for linear regression analysis (IOP reading analyses ex vivo and in vivo), paired t-test (Right Eye vs. Left eye in vivo), two-tailed unpaired t-test (variables as a determinant of IOP in vivo), and one-way repeated measures ANOVA (IOP readings vs. manometry ex vivo). A P-value of 0.05 or less was considered significant. Bland Altman plots were also used to evaluate tonometer IOP measurement in agreement with manometric IOP. RESULTS Manometry and tonometer validation The Tono-Pen VET TM and TonoVet â d tonometer readings showed strong linear correlation with manometric IOP across a wide range of IOP values; Tono-Pen VET TM : y = 0.922x , r 2 = 0.922; TonoVet â d : y = 0.693x , r 2 = (Fig. 1a,b). Within a narrower, clinically relevant range of 0 50 mmhg, the Tono- Pen VET TM and TonoVet â d values exhibited stronger linear trends; y = 1.03x 3.014, r 2 = and y = 0.856x , r 2 = 0.998, respectively (Fig. 1c,d). Readings obtained with the TonoVet â p setting (Fig. 2) also exhibited a linear correlation with true manometric IOP, but grossly underestimated IOP; y = 0.451x , r 2 = The TonoLab â tonometer grossly overestimated IOP compared to manometry (Fig. 3); y = 0.971x , r 2 = Bland Altman plots revealed a trend toward underestimation of IOP by the TonoVet â d and Tono-Pen VET TM, with increasing underestimation at higher IOPs (40 80 mmhg) (Figs 4 and 5). The Tono-Pen VET TM readings exhibited greater variability compared to the TonoVet â d readings that were more consistent throughout the range of IOPs evaluated. Figure 1. Tono-Pen VET TM and TonoVet â d derived intraocular pressure (IOP) values showed strong linear correlation with manometric IOP. Scatter plot of nine values (triplicate values for each of three chinchillas) measured by the tonometers (y-axis), plotted at each manometric IOP (x-axis). Some data points are superimposed. Linear regression lines are plotted as dashed lines, with y = x shown as a solid line for reference. (a) Tono-Pen VET TM IOP readings from 5 to 80 mmhg, showing linear regression line (y = x , r 2 = ) (b) TonoVet â d IOP readings from 5 to 80 mmhg, showing linear regression line (y = x , r 2 = ). (c) Tono-Pen VET TM IOP readings from 5 to 50 mmhg, showing linear line (y = 1.031x 3.014, r 2 =0.994). (d) TonoVet â d measured IOP readings from 5 to 50 mmhg, showing linear regression line (y = x , r 2 = 0.998).

4 tonometry and iop in the normal chinchilla 7 Figure 2. TonoVet â p underestimated intraocular pressure (IOP) (mmhg) vs. Manometric IOP (mmhg) up to 80 mmhg. Scatter plot shows nine values (triplicate values for each of three chinchillas; some data points are superimposed) measured by the TonoVet â p (y-axis) plotted against each increment of manometric IOP (x-axis). Linear regression dashed line (y = x , r 2 = ) is plotted, with y = x shown as a solid line for reference. Figure 4. TonoVet â d intraocular pressure (IOP) values show a trend toward underestimation (mmhg) relative to manometric IOP up to 80 mmhg. The x-axis shows the average for each of nine values (triplicate values for each of three chinchillas) measured by TonoVet â d and gold standard manometric IOP, while values plotted on the y-axis represent the extent of departure of TonoVet â d -derived IOP values from true manometric IOP (some data points are superimposed). Linear regression line (y = 0.35x , r 2 = ) is plotted. There is an increasing tendency to underestimate IOP above 40 mmhg, although values remain relatively precise, even at higher IOP values. Figure 3. TonoLab â overestimated intraocular pressure (IOP) (mmhg) vs. manometric IOP (mmhg) up to 80 mmhg. Scatter plot shows nine values (triplicate values for each of three chinchillas; some data points are superimposed) measured by the TonoLab â (y-axis) plotted against each increment in manometric IOP (x-axis). Linear regression dashed line (y = x , r 2 = ) is plotted, with y = x shown as a solid line for reference. No significant difference was observed when comparing IOP readings of the Tono-Pen VET TM and TonoVet â d tonometers to manometric IOP (P = and P = 0.632, respectively) or to each other (P = 0.979). The TonoLab â and TonoVet â p IOP readings were significantly different from manometric IOP (P < and P = , respectively). Intraocular pressure survey in vivo No clinical evidence of ocular disease was identified in the 57 chinchillas included in this study. Three of 60 chinchillas examined were excluded from the study due to clinical evidence of ocular disease that included corneal opacity/scarring, uveitis, and conjunctivitis. No significant difference was observed when comparing IOP between the right and left eyes, P = 0.96 (Fig. 6). Consequently, the Figure 5. Tono-Pen VET TM intraocular pressure (IOP) values show a trend toward underestimation (mmhg) relative to manometric IOP up to 80 mmhg. The x-axis shows the average for each of nine values (triplicate values for each of three chinchillas) measured by Tono-Pen VET TM and gold standard manometric IOP, while values plotted on the y-axis represent the departure of Tono-Pen VET TM measured IOP from true manometric IOP. Linear regression line (y = x , r 2 = ) is plotted. Some data points are superimposed. Note the increasing underestimation of IOP that occurs after IOP rises above 50 mmhg, as well as relative imprecision of readings at IOPs over 15 mmhg. mean of triplicate IOP readings from right and from left eyes was averaged to provide a single IOP value for each subject. Within this entire cohort of chinchillas, mean IOP standard deviation was mmhg, 95% reference interval was mmhg (range; 5 to 18 mmhg). No significant linear correlation was observed between age of chinchilla and IOP (y = 0.04x , r 2 = 0.004). IOP readings were not significantly different between males (n = 23) and females (n = 34), P = 0.61,

5 8 snyder ET AL. IOP (mmhg) and there was no apparent association evident between iris color (dark brown, slate gray/brown or ruby/pink or heterochromic) and IOP, P = DISCUSSION OS Figure 6. IOP values for right (OD) and left (OS) eyes of 57 normal chinchillas show no significant difference, measured by the TonoVet â in d setting. Mean IOP values for OD and OS were not significantly different (P = 0.96). Mean SD IOP values were mmhg OD and mmhg OS. Some data points are superimposed. In summary, the TonoVet â d and the Tono-Pen VET TM provided IOP readings within a physiologic and clinically relevant range in situ that were significantly more accurate than IOP readings obtained with either the TonoLab â or the TonoVet â when used in the p setting. The TonoVet â d showed greater precision but slightly underestimated true IOP across the range of IOP, while the Tono-Pen VET TM readings showed greater variance with IOP values measured both well above and below true IOP. Some difficulty was experienced in obtaining valid Tono-Pen VET TM readings at 5 mmhg in the ex vivo chinchilla eyes, but more readily provided IOP readings at 10 mmhg. The TonoVet â reliably measured IOP at manometrically determined IOP of 5 mmhg, and no difficulty was experienced in obtaining reproducible readings in the low end of the IOP range tested. The small size of the probe tip in the TonoVet â relative to the Tono-Pen VET TM seemed to facilitate its application in the chinchilla eye. The smaller probe has less corneal contact than the Tono-Pen VET TM, and was therefore considered most applicable in a clinical setting in this species, and was selected for use in determining the reference range for IOP in conscious chinchillas in vivo. The probe size of the TonoLab â is primarily designed for use in smaller rodents and is not designed or calibrated for the larger and thicker cornea of the chinchilla. Central corneal thickness (CCT) has been reported previously ranging from lm 33 to 170 lm 34 in mice and approximately 130 lm in three different strains of rats. 35 In contrast, CCT in the chinchilla has been reported to be approximately /- 30 lm, 9 that is, 2 3 times OD OS OD thicker than the reported CCT of laboratory mice. The chinchilla s greater corneal thickness is likely responsible for the inaccurate IOP values obtained with the TonoLab â in this study. There are published and anecdotal reports of use by veterinarians of the TonoVet â in the unassigned p calibration mode in nonconventional species. It is clear this calibration mode severely underestimated IOP in the present study and should not be used to measure IOP in chinchillas. In the cohort of normal chinchillas studied, averaged afternoon IOP values in individuals with no clinical evidence of anterior segment disease varied across a wide range from 5 to 18 mmhg. These IOP values are consistent with normal TonoVet-derived IOP values previously reported for a broad range of mammalian species, including rabbits. 36 TonoVet-derived IOP values in the present study were higher than very low values reported previously using this instrument and lower than Tono-Pen-derived IOP values reported in another study However, the time of day at which IOP measurements were obtained was not reported in previous studies and could account for differences in observed IOP ranges between studies, due to circadian variation in IOP. The effect of ocular disease on IOP readings was not examined in this species and warrants further investigation. CONCLUSIONS Intraocular pressure measurement by both the Tono- Pen VET TM and TonoVet â tonometers provide values in the chinchilla that are generally representative of true IOP in a physiologic and clinically relevant range of 0 50 mmhg. While slightly more accurate, values obtained with the Tono-Pen VET TM displayed greater variance than those obtained with the TonoVet â. Further, the Tono-Pen VET TM was more challenging to use in eyes with low IOP ex vivo and typically necessitates the use of a topical anesthetic in vivo. The TonoVet â d setting was the most precise across an extended range of IOPs and was therefore selected for further evaluation of IOP in a population of normal chinchillas in vivo. The TonoVet â was readily applicable and well tolerated by conscious chinchillas and provided a reference range for IOP in this species in a clinical setting. ACKNOWLEDGMENTS We extend our gratitude to Brenda Walter for access to her chinchilla colony to obtain IOP measurements. GRANT SUPPORT Dr. McLellan receives support from an unrestricted grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness.

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