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Correspondence: Yael Shilo-Benjamini, Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, POB 12, Rehovot 7610001, Israel.
Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
To compare the effect of propofol, alfaxalone and ketamine on intraocular pressure (IOP) in cats.
Study design
Prospective, masked, randomized clinical trial.
Animals
A total of 43 ophthalmologically normal cats scheduled to undergo general anesthesia for various procedures.
Methods
Following baseline IOP measurements using applanation tonometry, anesthesia was induced with propofol (n = 15), alfaxalone (n = 14) or ketamine (n = 14) administered intravenously to effect. Then, midazolam (0.3 mg kg−1) was administered intravenously and endotracheal intubation was performed without application of topical anesthesia. The IOP was measured following each intervention. Data was analyzed using one-way anova and repeated-measures mixed design with post hoc analysis. A p-value <0.05 was considered significant.
Results
Mean ± standard error IOP at baseline was not different among groups (propofol, 18 ± 0.6; alfaxalone, 18 ± 0.7; ketamine, 17 ± 0.5 mmHg). Following induction of anesthesia, IOP increased significantly compared with baseline in the propofol (20 ± 0.7 mmHg), but not in the alfaxalone (19 ± 0.8 mmHg) or ketamine (16 ± 0.7 mmHg) groups. Midazolam administration resulted in significant decrease from the previous measurement in the alfaxalone group (16 ± 0.7 mmHg), but not in the propofol group (19 ± 0.7 mmHg) or the ketamine (16 ± 0.8 mmHg) group. A further decrease was measured after intubation in the alfaxalone group (15 ± 0.9 mmHg).
Conclusions and clinical relevance
Propofol should be used with caution in cats predisposed to perforation or glaucoma, as any increase in IOP should be avoided.
Induction drugs may produce intraocular pressure (IOP) spikes, which can be harmful in eyes predisposed to perforation or glaucoma. Decreases in IOP were reported in humans, horses and dogs following thiopental administration, and increases following ketamine administration. However, the effect of propofol on IOP differed among species, resulting in decreases in humans, increases in dogs and no significant change in horses (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
). Species-specific differences may be the influence of differences in ocular muscle tone, the rigidity of the sclera and/or differences in drainage or production of the aqueous humor (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
The authors are not aware of any published study reporting the effects of induction anesthetic agents administered intravenously (IV) on IOP in cats; therefore, the primary objective of this study was to compare effects of IV propofol, alfaxalone and ketamine on IOP in cats. The secondary objectives were to measure IOP in cats after midazolam administration following these drugs, and subsequently the effect of endotracheal intubation. Our hypotheses were: 1) that ketamine would increase IOP and propofol and alfaxalone would either decrease IOP or result in no significant change; 2) that subsequent administration of midazolam would decrease IOP (
This study was approved by the Internal Ethic Review Committee of the Koret School of Veterinary Medicine, The Hebrew University (KSVM–VTH/10_2013), and a written informed owner consent was obtained. Cat owners were contacted by one of the study investigators and were recruited for participation in the study. A total of 43 client-owned cats scheduled to undergo general anesthesia for various procedures were recruited for a randomized clinical trial. Inclusion criteria were: 1) aged from 5 months to 10 years; 2) healthy cats, based on history, physical examination, complete blood count and serum creatinine measurement (creatinine in cats >5 years); 3) ophthalmologically normal, based on a comprehensive ophthalmic examination by a veterinary ophthalmology specialist or resident, including direct illumination (3.5 V; Finnoff Ocular Transilluminator; Welch Allyn Inc., NY, USA), biomicroscopy (Kowa SL-15 Portable Slit-Lamp; Kowa Co. Ltd., Japan) and indirect ophthalmoscopy (Welch Allyn Inc.); 4) American Society of Anesthesiologists (ASA) Physical Status Classification System I–II; and 5) easy to handle cats, based on the ability to perform an ophthalmic examination and IOP measurement without sedation and with minimal restraint. Exclusion criteria were: 1) cats younger than 5 months and older than 10 years; 2) abnormal physical examination or blood work; 3) abnormal ophthalmic examination; 4) ASA Classification III–V; and 5) cats that could not be easily handled.
A catheter was placed in the cephalic or medial saphenous vein using restraint with a towel or following sedation with intramuscular (IM) medetomidine (0.03–0.05 mg kg−1; Domitor, 1 mg mL−1; Orion Pharma Ltd, Finland) if needed. Lactated Ringer’s solution (4 mL kg−1 hour−1; Baxter Corporation, ON, Canada) was infused IV. Cats administered medetomidine for catheter placement were then administered atipamezole (five times the dose of medetomidine; Antisedan, 5 mg mL−1; Orion Pharma Ltd) IM and anesthesia induction was performed ≥2 hours later.
Procedures
Anesthesia was scheduled in the morning to minimize the effect of circadian rhythm on IOP. Allocation sequence was assigned using an online generated random list (www.random.org/lists/; accessed on 25 February 2014) by the anesthetist according to the order of recruitment. Cats were allocated to one of three induction protocols: propofol (Diprofol 1%; Synthon Hispania S.L., Spain; n = 15), alfaxalone (Alfaxan, 10 mg mL−1; Jurox Pty Limited, NSW, Australia; n = 14) or ketamine hydrochloride (Clorketam 1000, 100 mg mL−1; Vetoquinol, France; diluted with saline 0.9% to 10 mg mL−1; n = 14) administered slowly IV to effect (Fig. 1), and the total dose was recorded. The IOP was measured when the cat assumed lateral recumbency, ceased moving and made no response when moved to sternal position. A single anesthetist aware of group assignment performed all inductions of anesthesia, and IOP was measured by one of four experienced clinicians who were unaware of the induction drug used.
Figure 1Study design to measure intraocular pressure (IOP) before and after induction of anesthesia with propofol, alfaxalone or ketamine to effect, after intravenous administration of midazolam and after endotracheal intubation in 43 cats.
Each cat was wrapped gently in a towel and placed in sternal recumbency for IOP measurement of both eyes using applanation tonometry (Tono-Pen Vet; Reichert Technologies, NY, USA), with the first eye arbitrarily selected. The tonometer was calibrated each day before the first data collection. Topical anesthesia was not applied and special care was taken to avoid any pressure on the jugular veins or eyelids, to avoid artefacts. The TonoPen collects several IOP readings and displays an average IOP and the variance. For each eye, three averaged readings with a variance <5% were collected, and the mean was calculated and used for analysis (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
IOP was measured at baseline (BL; immediately before administration of propofol, alfaxalone or ketamine), following induction of anesthesia (time point IND), after IV injection of midazolam (0.3 mg kg−1; Midolam, 5 mg mL−1; Rafa Laboratories Ltd, Israel; time point MID) and lastly after endotracheal intubation (time point INT), before administration of inhalation anesthesia (Fig. 1). Intubation was performed with the cat in sternal recumbency using a laryngoscope and a 3.5–4.0 mm internal diameter endotracheal tube, with no topical anesthetic solution. If the cat started moving, swallowing or the jaws were not sufficiently relaxed to accomplish intubation, an additional dose of the same induction drug was administered (Fig. 1). The anesthetist scored the quality of tracheal intubation using a 1–4 scale (Appendix A). Coughing following intubation was registered.
Following the last IOP measurement, the endotracheal tube was connected to a small animal anesthesia machine, and anesthesia was maintained with isoflurane in oxygen for the duration of the scheduled procedure. Analgesic drugs, such as opioids (butorphanol or methadone), were administered immediately after monitoring equipment was attached and the cat was considered to be stable under anesthesia. A local block (lidocaine, bupivacaine or ropivacaine) was performed at anesthetist's discretion before the beginning of surgical procedure, and a non-steroidal anti-inflammatory drug (meloxicam or dipyrone) was administered before recovery.
Statistical analysis
A power analysis was performed based on the effect of propofol on IOP in dogs (
), because the effect of propofol on IOP in that study was the smallest, which would ensure the maximum sample size needed. The analysis determined that 10 cats would be required in each group to detect a difference of 3.6 ± 2.5 mmHg in IOP between baseline measurement and anesthetic induction with a power of 80% and α = 0.05 (one-tailed). Several more cats were included in each group to account for excluded data, individual variability and species differences.
Statistical analysis was performed using SPSS Statistics for Windows, Version 21.0. (IBM Corp., NY, USA). Data were not tested for normality, as the sample size was greater than 30, and based on the central limit theorem, the mean follows the normal distribution. Quantitative variables are expressed as mean ± standard error (SEM) for IOP or mean ± standard deviation (SD) for other variables, such as age, weight and drug doses. Qualitative variables are expressed as median (range). Cat data were analyzed with one-way analysis of variance (anova) (parametric data) or likelihood ratio test (G-test; categorial data). Analyses of IOP from both eyes were performed with repeated measures mixed effects with random intercept at the cat level. An effect for the treatment on delta IOP was tested using one-way anova and then multiple comparison analysis with Tukey's correction. The difference between treatments in the frequency of IOP ≥ 24 mmHg at different time points was tested using Pearson’s chi-square followed by post hoc analysis by Bonferroni method. A p-value <0.05 was considered significant.
Results
All 43 recruited cats completed the study. Most cats were young and healthy and were submitted for castration or ovariohysterectomy performed by veterinary students in their final year of veterinary studies. A total of nine cats were administered medetomidine for IV catheter placement (propofol, three cats; alfaxalone, four cats; ketamine, two cats), and reversal with atipamezole was performed 2.5–17 hours prior to induction of anesthesia. Although inductions were planned to take place in the mornings, last minute changes in the schedule resulted in a longer period, between 07:30 and 14:40 hours (mean ± SD induction time: propofol, 11:45 ± 02:10; alfaxalone, 11:00 ± 02:30; ketamine, 10:55 ± 02:20 hours). No difference among groups was found in sex (p = 0.833), age (p = 0.854), body weight (p = 0.774), procedure performed (p = 0.791) or IOP evaluator (p = 0.655; Table 1).
Table 1Sex, age, body weight, procedure, intraocular pressure (IOP) evaluators (designated R, O, M and N) and doses of propofol, alfaxalone or ketamine administered for induction of anesthesia and after injection of midazolam but before endotracheal intubation. Data are presented as number of animals or mean ± standard deviation (range)
At baseline, no difference was found between the right and left eyes for all groups together (p = 0.631) or in each group separately (propofol, p = 0.141; alfaxalone, p = 0.918; ketamine, p = 0.607); therefore, the data for both eyes were pooled for statistical analysis (
). The IOP was not significantly different between groups at any time point (BL, p = 0.534; IND, p = 0.155; MID, p = 0.124; INT, p = 0.143). Following induction of anesthesia, a significant increase was observed in the propofol (p = 0.001), but not in the alfaxalone (p = 0.180) or ketamine (p = 0.331) groups. Following administration of midazolam, a significant decrease was observed in the alfaxalone group compared with IND (p = 0.001), but not in the propofol group (p = 0.062) or the ketamine group (p = 0.165). Following intubation, a decrease was observed in the alfaxalone group compared with MID (p = 0.029), but no change was observed in the propofol group (p = 0.314) or the ketamine group (p = 0.225) (Fig. 2).
Figure 2Intraocular pressure measured at baseline, immediately following induction of anesthesia with intravenous (IV) propofol (n = 15), alfaxalone (n = 14) or ketamine (n = 14), following IV administration of midazolam and following endotracheal intubation in cats undergoing general anesthesia for various procedures. Data are presented as mean ± standard error of the mean. ∗Significantly different from the previous time point in the same group (p < 0.05).
There was an effect of the treatment on IOP change between BL and IND (p = 0.013), and multiple comparison analysis showed that the change in IOP was significantly higher in the propofol group than in the ketamine group (p = 0.009; Table 2). At intubation, there was a significantly higher frequency of IOP ≥ 24 mmHg (
) in the propofol group than in the ketamine group (p = 0.024; Table 3).
Table 2Change in intraocular pressure (IOP) measured in both eyes of 43 cats before (baseline) and after induction of anesthesia by intravenous administration of propofol (4.9 ± 1.5 mg kg−1; n = 15), alfaxalone (1.5 ± 0.3 mg kg−1; n = 14) or ketamine (3.0 ± 0.6 mg kg−1; n = 14). Data are presented as mean ± standard deviation. n, number of cats
Table 3Intraocular pressure (IOP) measured in both eyes of 43 cats assigned to induction of anesthesia with propofol (n = 15), alfaxalone (n = 14) or ketamine (n = 14). IOP was recorded before anesthesia (baseline), after induction of anesthesia (induction), after injection of midazolam (midazolam) and after endotracheal intubation (intubation). Data are presented as the number of eyes with IOP ≥ 24 mmHg (individual values)
No difference was found among groups in the number of cats requiring extra induction drug for intubation (Table 1). Most intubations were excellent, with median (range) intubation quality score not significantly different between groups; propofol 4 (1–4), alfaxalone 4 (2–4) and ketamine 3.5 (1–4) (p = 0.434; Fig. 3). The number of cats coughing following intubation was similar between groups (propofol, 3; alfaxalone, 4; and ketamine, 3). Following the procedure, all cats recovered and were discharged from the hospital without any complications.
Figure 3Endotracheal intubation quality scores in cats anesthetized with propofol–midazolam (n = 15), alfaxalone–midazolam (n = 14) or ketamine–midazolam (n = 14). Score 1, poor; score 4, excellent.
The results of the present study suggest that IOP in cats can be affected by IV induction drugs, with propofol resulting in the most profound increase. Baseline IOP of all cats in the present study (mean ± SEM: 17.5 ± 0.4 mmHg) was overall similar to reference range IOP measured with applanation tonometry in cats; 18.4 ± 0.6 mmHg (
). Difference in IOP between studies can be attributed to differences in the time of measurements (circadian rhythm). Diurnal IOP was measured in the present study, which was similar to IOP recorded in the morning–noon time (16.7 ± 0.5 and 18.0 ± 0.4 mmHg, respectively) (
). Although baseline IOP was measured with gentle restraint, it is possible that the cats were stressed resulting in increased IOP. In our experience, many cats become stressed by the application of eye drops and frequently start sneezing, affecting IOP, whereas cats do not resist IOP measurement without topical anesthesia. Therefore, local anesthetic eye drops were not instilled prior to baseline IOP measurements. A study in cats reported that there is no difference in IOP if topical anesthesia is instilled or not (
In the present study, a sedative was not administered prior to induction of anesthesia because the primary aim was to study effects of the induction drugs on IOP. A study investigating the effect of topical application of xylazine (
) reported decreased IOP. However, IM administration of dexmedetomidine (7.5 μg kg−1) or medetomidine (100 μg kg−1) did not significantly affect IOP in cats (
). Methadone (0.2 mg kg−1) alone, a pure μ-agonist opioid, did not change IOP, but in combination with dexmedetomidine (7.5 or 10 μg kg−1) IOP significantly decreased (
). When atipamezole was used for reversal of 10 μg kg−1 dexmedetomidine (which caused decreased IOP), a significant increase in IOP from baseline value was observed within 30 minutes (
). In the present study, several cats from each group required medetomidine for catheterization, but atipamezole was administered several hours before induction of anesthesia. Sedation is commonly used prior to induction of anesthesia and the effects of the sedatives may alter the IOP changes that were observed in the present study.
Propofol, alfaxalone and ketamine were chosen for this study because these drugs are commonly used IV in cats for anesthetic induction (
). Therefore, in cases of cats with glaucoma or deep corneal ulcers requiring surgery, it is probable that one of these drugs will be used for induction. In the present study, propofol was the only drug that resulted in significant change of IOP, and the IOP was increased in more eyes and to a greater extent than in cats anesthetized with alfaxalone or ketamine. In humans, propofol significantly decreased IOP in multiple studies and prevented the increase in IOP during intubation (
). It appears that propofol may have a species-dependent effect. In horses, administration of xylazine decreased IOP, and subsequent propofol administration resulted in a nonsignificant IOP increase (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
Effects of morphine–alfaxalone–midazolam premedication, alfaxalone induction and sevoflurane maintenance on intraocular pressure and tear production in dogs.
). Although another study in unpremedicated dogs reported a nonsignificant increase at 2 minutes following administration, and later a significant IOP decrease (
). In the present study, alfaxalone did not affect IOP significantly, with a minimal increase in IOP immediately following induction.
In the present study there was a nonsignificant tendency of ketamine to decrease IOP. In horses, ketamine (2.2 mg kg−1) administered several minutes after xylazine, significantly decreased IOP 6 minutes after administration (
). Another study in horses reported that administration of ketamine (2 mg kg−1) after xylazine resulted in significant IOP increase, but because xylazine decreased IOP prior to ketamine administration, the increase caused by ketamine was considered less clinically important (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
). In dogs, a significant increase in IOP following IV ketamine (5 mg kg−1) was observed up to 10 minutes following induction, whereas a dose of 10 mg kg−1 resulted in a nonsignificant increase (
). Another study reported that IV ketamine (20 mg kg−1) resulted in a significant IOP increase from baseline for up to 35 minutes following administration (
). It is hypothesized that the mechanism of action of IOP increase is related to ketamine effects of increased blood pressure and increased extraocular muscle tone (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
). The difference between the results in the present study and the increase observed following ketamine in dogs may be attributed to the higher doses administered to dogs. In children, 6 mg kg−1 of ketamine resulted in significant IOP increase, whereas a dose of 3 mg kg−1 did not alter IOP (
). A study assessing IM administration of 12.5 and 25 mg kg−1 ketamine in cats reported an increase of 10% from baseline value in normal eyes and 15% increase in glaucomatous eyes using the higher dose (
). Except for the different administration routes (IM versus IV), it is possible that other factors contributed to the different outcome observed in the present study. Factors such as the dose used (3 mg kg−1 in the present study), the tonometer (the Langham pneumatic applanation tonometer versus Tono-Pen), initial stress level (cats administered IM ketamine were habituated to IOP measurement daily for 2 weeks prior to the study) and because failure to report baseline IOP (
) precluded comparisons. Future investigations of ketamine effect on IOP in cats with simultaneous monitoring of heart rate and blood pressure would add more information.
Midazolam is a water-soluble benzodiazepine with muscle relaxant, anticonvulsant and sedative properties. It is commonly used as part of anesthetic induction in veterinary medicine to reduce the doses of the induction drugs (
). In dogs, administration of diazepam (0.25 mg kg−1) IV before induction prevented the significant increase in IOP observed following administration of propofol (
). However, a different study reported that administration of midazolam (0.2 mg kg−1) IV did not affect IOP, and propofol administered 1 minute later resulted in significantly elevated IOP (
Effects of anesthetic induction with midazolam-propofol and midazolam-etomidate on selected ocular and cardiorespiratory variables in clinically normal dogs.
). In the present study, midazolam administered after alfaxalone decreased IOP but resulted in no change in IOP after propofol or ketamine administration.
Laryngoscopy and intubation were reported to increase IOP in humans, attributed to a rise in sympathetic outflow and increased blood pressure (
). In dogs, tracheal intubation results in significantly increased IOP from baseline but no difference from IOP measured after induction of anesthesia (
). However, atracurium was administered prior to intubation in some studies, which could have minimized the cough reflex and caused relaxation of the extraocular muscles (
). In the present study, intubation resulted in a significant IOP decrease in the alfaxalone group and no change in the propofol and ketamine groups. It is possible that because midazolam was administered shortly before intubation, IOP control mechanisms were still under the influence of midazolam following intubation; therefore, an increase was not observed.
Other factors affecting IOP and potentially modifying the results of the present study include age (
), which was controlled as much as possible but partly unavoidable when restraining an awake cat for baseline IOP measurement. Hypotension or hypertension will decrease or increase IOP, respectively (
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
). Anesthetic induction agents influence blood pressure via effects on vasomotor tone, heart rate and contractility and as such, they may result in an indirect effect on IOP (
). In the present study, blood pressure was not measured because it was suspected that oscillometric cuff inflation would stimulate the cat and affect IOP.
Induction doses of all drugs were generally lower than doses reported in the literature for cats: propofol (5–10 mg kg−1), alfaxalone (0.5–5.0 mg kg−1 following sedation) and ketamine (5–10 mg kg−1) (
). The difference could result from use of different end points, such as lateral recumbency compared with intubation requiring a higher dose, or inclusion of midazolam reducing drug doses for induction of anesthesia (
Study limitations include the sample size that was relatively small. Although a power analysis was performed, it was based on results from dogs and the high variability responses in cats were not expected. A narrow window of induction time to avoid effects of the circadian rhythm was not kept. The majority of cats were young and healthy, and older cats or cats with ocular disease may respond differently to these drugs. Blood pressure and end-tidal carbon dioxide tension were not measured during induction of anesthesia to avoid preanesthetic instrumentation in the client-owned cats, although that information may have explained the IOP results. In addition, the cats were not sedated because IOP may have been changed. Several IOP evaluators participated in data acquisition, and variability among the evaluators may have introduced bias. Finally, intubation quality was scored by an anesthetist who was not blinded to the group assigned, which may have introduced some bias.
Conclusion
Propofol alone should be used with caution in cats when increased IOP may be detrimental, as in animals that are predisposed to corneal perforation or glaucoma. Further investigations, such as in cats with ocular disease, or with the use of sedation prior to induction, would add more knowledge to the effects of anesthetic drugs on IOP in cats.
Authors’ contributions
YS-B: conception, study design, data acquisition and interpretation, drafting the manuscript. OP: data acquisition. WAA: data analysis. RO: conception, study design, data acquisition. All authors revised the manuscript and approved the final version.
Conflict of interest statement
The authors declare no conflict of interest
Acknowledgements
This study was presented in part at the North American Veterinary Anesthesia Society Virtual Spring Symposium, 2021. The authors thank Dr Nili Kahana and Dr Mickey Hatzav for assistance in data acquisition, and Dr Yishai Kushnir for statistical advice. No funding supported this study.
Appendix A.
Tabled
1Scoring quality of endotracheal intubation
Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses.
Effects of anesthetic induction with midazolam-propofol and midazolam-etomidate on selected ocular and cardiorespiratory variables in clinically normal dogs.
Effects of morphine–alfaxalone–midazolam premedication, alfaxalone induction and sevoflurane maintenance on intraocular pressure and tear production in dogs.
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