Experimental and clinical evidence suggest that several injectable anesthetic drugs, including ketamine, etomidate, and propofol, increase IOP in healthy dogs.1–5 Any increase in IOP can facilitate the loss of globe contents through traumatic or surgical openings because the orbital globe is a relatively noncompliant sphere encased by a rigid orbital rim.6 Furthermore, IOP values > 25 mm Hg can decrease optic nerve axoplasmic flow, potentially leading to blindness.7 The primary factors that determine IOP in mammalian species include aqueous fluid production and drainage and increased scleral rigidity, which is greatly influenced by extraocular muscle tone.6–8 Less critical factors that can influence IOP include pupillary diameter, autonomic tone, arterial blood pressure, and Pco28–10; however, these latter factors are rarely deranged enough to produce clinically relevant effects on IOP in otherwise healthy animals. For example, miosis widens the drainage apparatus, causing an increase in aqueous humor outflow that decreases IOP, whereas mydriasis increases IOP.11 Similarly, alteration in cardiorespiratory values (eg, heart rate or arterial blood pressure) and blood gases (eg, Po2 and Pco2) during anesthesia is unlikely to be responsible for substantial changes in IOP.9,10 Inadvertent compression of both jugular veins, changes in globe position, contraction of the extraocular muscles, and eyeball retraction can produce significant increases in IOP in dogs.12 Forceful contraction of the orbicularis oculi in humans has been shown to increase IOP to > 50 mm Hg.6
Increases in IOP are significantly blunted in healthy dogs when midazolam (0.2 mg/kg [0.09 mg/lb], IV) is coadministered with ketamine (15 mg/kg [6.8 mg/lb], IV),13 suggesting that the increase in IOP observed in dogs administered ketamine might be caused by extraocular factors such as muscle tone.1,14,15 Propofol, a noncumulative, short-acting anesthetic administered IV, is noted for producing rapid, uneventful anesthetic induction and recovery.16,17 However, at a dose of 4.67 ± 1.20 mg/kg (2.12 ± 0.55 mg/lb), propofol has been shown to increase IOP in dogs that received midazolam (0.15 mg/kg [0.07 mg/lb]).4 Furthermore, hypoventilation, apnea, and hypotension are temporary but frequently observed adverse effects associated with IV propofol administration16–18 that could influence IOP.
The objective of the study reported here was to determine the effects of propofol on IOP in premedicated and nonpremedicated dogs admitted to a specialty referral hospital for surgical correction of ocular and extraocular diseases. We hypothesized that propofol administration, independent of preanesthetic medication, would not be associated with a significant increase in IOP in dogs. We also sought to determine IOP in a large population of healthy dogs as a basis for establishing a definition of glaucoma for study purposes. To the authors' knowledge, IOP values considered normal in dogs without ocular disease have been determined on the basis of author experience,12 and no specific values that can be used as evidence of glaucoma have been established in this species.
Materials and Methods
Animals and study design
Dogs evaluated at MedVet Medical and Cancer Centers for Pets (Columbus, Ohio) from January 1, 2014, to October 1, 2014, were eligible for study enrollment. Dogs were prospectively enrolled into 2 groups; the first group included 113 healthy dogs that were used to establish a working set of IOP values in healthy dogs. These dogs were client-owned dogs recruited for the study during regular physical examination. The second group comprised 121 dogs scheduled for ophthalmic surgical procedures; these dogs were randomly assigned to treatment subgroups (premedicated or nonpremedicated) with a random number generator for unequal groups.
The same experienced veterinary ophthalmology technician recorded pertinent history in a standardized manner and performed a Schirmer tear testa and applanation tonometryb for all dogs. A general physical examination and complete bilateral ocular examination that included fluorescein staining,c slit-lamp biomicroscopy, and indirect ophthalmoscopy with pupillary dilation were performed for all dogs by 1 of 2 experienced, board-certified ophthalmologists (TRW or MW). To be included in the healthy group, dogs were required to have normal physical examination results with no evidence of ocular disease and CBC results within the reference ranges; dogs receiving medications were excluded. All dogs scheduled to undergo ophthalmic surgery with general anesthesia were eligible for inclusion in the surgery group.
Dogs undergoing anesthesia and surgery were assigned an American Society of Anesthesiologists physical status on the basis of results of physical examination and hematologic (Hct, RBC count, WBC count, platelet count, and hemoglobin concentration) and biochemical (BUN concentration; serum creatinine, glucose, total protein, sodium, and potassium concentrations; and serum alanine aminotransferase, alkaline phosphatase, and lipase activities) tests.19 The physical examination was repeated, and baseline IOP determinations were performed in the morning on the day of anesthesia for this group.
All procedures were performed after obtaining signed owner consent. The facility's clinical studies and animal care committee approved the study.
Anesthesia of surgical patients
A 20-gauge, 2.5-cm IV cathetere was placed in a cephalic vein. Dogs assigned to be premedicated had midazolam (0.1 mg/kg [0.045 mg/lb], IV) and butorphanol (0.1 to 0.2 mg/kg, IV) coadministered 10 to 15 minutes before anesthetic induction. Nonpremedicated dogs received a placebo treatment (lactated Ringer solution [3 mL]) at the same time point.
All dogs were administered supplemental oxygen by face mask for ≥ 3 minutes immediately before propofolf (10% solution) was delivered for induction of anesthesia. The drug was administered over 60 seconds, to effect, until loss of jaw tone was detected. Dogs were orotracheally intubated immediately after propofol administration, and anesthesia was maintained with isoflurane in oxygen. Midazolam (0.1 mg/kg, IV) and butorphanol (0.2 mg/kg, IV) were administered to nonpremedicated dogs 7 to 10 minutes after propofol administration during stabilization of isoflurane anesthesia but before surgery to enhance analgesia during the surgical procedure and recovery from anesthesia.
All dogs were kept in sternal or lateral recumbency during anesthesia, with the head slightly elevated (above the level of the heart). Lactated Ringer solution (5 mL/kg/h [2.72 mg/lb/h]) was infused throughout anesthesia. Heart rate, an ECG, respiratory rate, Spo2, ETco2, and indirect oscillometric mean arterial blood pressure measurements were displayed on a multiparameter physiologic monitorg and recorded by a certified veterinary anesthesia technician. All physiologic variables were recorded before propofol administration and at 5-minute intervals throughout anesthesia. An ultrasonic transcutaneous Doppler flow detection probe,h blood pressure cuff, and sphygmomanometer were used to determine blood pressure in dogs that weighed < 2.5 kg (5.5 lb). The flow detection probe was placed over the plantar aspect of a digital artery and secured with adhesive tape after the hair had been trimmed from the area and ultrasonographic gel had been applied. A blood pressure cuff (size, approx 40% of limb circumference) was placed proximal to a metatarsus and attached to the sphygmomanometer. Heart rate was determined by the ECG. Respiratory rate was determined by counting chest wall movement for 30 seconds. Adverse effects including bradycardia (heart rate, < 40 bpm), apnea (respiratory rate of 0 for > 30 seconds), myoclonus, regurgitation, vomiting, salivation, and abnormal behaviors were recorded before, during, and after anesthesia.
Tonometry
The same tonometerb was used throughout the study. The tonometer was manually calibrated electronically each day before IOP determination. One drop of 0.5% proparacaine solutiond was topically applied to each eye before IOP measurement. All IOP measurements were performed by the same technician with the dog standing, sitting, or in sternal recumbency and its head slightly raised; care was taken not to apply pressure to the neck and skin on the dog's face or place pressure on the globe while retracting the eyelids. The technician was blinded to group assignment. At least 3 IOP measurements that were within 10% of each other were recorded, and the mean of these measurements was used as the IOP value. The head was kept in a natural position (above the level of the heart) for each measurement.
For patients undergoing surgery, the baseline IOP was determined as described 1 to 3 minutes before the IV administration of preanesthetic medication (midazolam-butorphanol) or placebo as applicable. Another IOP measurement was obtained 5 to 10 minutes after preanesthetic medication or placebo administration (time 1), and another was determined 2 to 4 minutes after induction of general anesthesia with propofol (time 2). The time 2 measurement was obtained before the administration of midazolam and butorphanol to nonpremedicated dogs. The IOP measurements after preanesthetic or placebo treatment and after anesthetic induction with propofol were performed with dogs in sternal recumbency.
Determination of glaucoma on the basis of IOP
An IOP > 3 SD above the mean for the population of healthy dogs7 was defined as evidence of glaucoma in the present study. This cutoff value was used because it included 99.7% of the IOP values that lie around the mean measurement obtained from healthy dogs.
Statistical analysis
Values of P < 0.05 were considered significant for all comparisons. The primary outcome variable investigated was a change in IOP. Assessment with the Kolmogorov-Smirnov test indicated that the data from healthy dogs were normally distributed. An a priori power analysis was performed with data from healthy dogs and dogs without glaucoma that had other naturally occurring ocular diseases to determine the number of dogs required to identify a > 2 mm Hg change in IOP, with an α of 0.05 and β of 0.2. The results of this analysis established that the data from dogs without glaucoma were normally distributed and that no more than 8 dogs in each of the 2 groups receiving propofol (premedicated and nonpremedicated) would be needed to detect this difference. Data are expressed as mean ± SD unless otherwise indicated. A 1-way ANOVA for repeated measures was used to evaluate within-group changes in IOP, heart rate, respiratory rate, Spo2, ETco2, and mean arterial blood pressure over time. Bonferroni-adjusted multiple t tests were used when the ANOVA revealed significant differences.
The IOPs were compared between left and right eyes of 113 healthy dogs and between left and right eyes at each measurement time point for 98 dogs without glaucoma undergoing ophthalmic surgery; analysis by paired Student t tests revealed no significant differences. No IOP outliers were recorded. The data from left and right eyes in each group were consequently pooled for subsequent analysis.
Results
The group of 113 healthy dogs used to establish normal IOPs for study purposes included dogs of 31 breeds and both sexes (54 males and 59 females). Ages of these dogs ranged from 0.5 to 15 years. Mean IOP obtained from the 113 healthy dogs (226 eyes) was 13.9 ± 3.7 mm Hg. On the basis of this value, an IOP > 25 mm Hg (13.9 mm Hg + 3 SD = 25 mm Hg) was calculated as evidence for glaucoma.
The group of surgical patients included 121 dogs with an American Society of Anesthesiologists physical status of I (n = 102) or II (19). There were 31 breeds represented in this group, which included 54 males and 67 females from 0.5 to 15 years of age.
Surgical patients without glaucoma
Ninety-eight surgical patients (87 and 11 in the premedicated and nonpremedicated subgroups, respectively) had no evidence of glaucoma (Table 1). The baseline IOP was 13.0 ± 3.4 mm Hg in the premedicated group (170 eyes; 4 dogs had 1 eye) and 13.2 ± 2.7 mm Hg in the nonpremedicated group (22 eyes); these values did not differ significantly.
Mean ± SD IOP measurements determined by applanation tonometry for 113 healthy dogs and for 121 dogs that underwent ophthalmic surgery under anesthesia induced by propofol and maintained with isoflurane, with or without premedication.
| Â | Â | Â | IOP (mm Hg) | |
|---|---|---|---|---|
| Group | No. of eyes | Baseline | Time 1 | Time 2 |
| Healthy dogs (n = 113) | 226 | 13.9 ± 3.7 | — | — |
| Surgical patients (n = 121) | ||||
|   No evidence of glaucoma | ||||
|     Premedicated dogs (n = 87) | 170 | 13.0 ± 3.4 | 11.1 ± 3.6* | 12.3 ± 3.9 |
|   Nonpremedicated dogs (n = 11) | 22 | 13.2 ± 2.7 | 13.3 ± 3.1 | 16.5 ± 3.2* |
|   Glaucoma in ≥ 1 eye | ||||
|   Premedicated dogs (n = 15) | 29 |  |  |  |
|     Glaucomatous eye | 15 | 43.7 ± 14.1 | 36.1 ± 13.7* | 30.7 ± 10.9†|
|     Unaffected eye | 14 | 13.1 ± 2.3 | 11.8 ± 3.3 | 13.1 ± 3.5 |
|   Nonpremedicated dogs (n = 8) | 16 |  |  |  |
|   Glaucomatous eye | 10 | 36.9 ± 12.9 | 35.6 ± 112 | 35.0 ± 8.9 |
|   Unaffected eye | 6 | 17.2 ± 2.4 | 16.8 ± 2.6 | 18.9 ± 2.3 |
Baseline IOP measurements in healthy dogs were obtained during routine ophthalmic examinations. Baseline data for surgical patients were obtained 1 to 3 minutes before administration of preanesthetic medication (midazolam [0.1 mg/kg {0.045 mg/lb}, IV] coadministered with butorphanol [0.1 to 0.2 mg/kg {0.045 to 0.09 mg/lb}, IV]; premedicated dogs) or a placebo treatment (lactated Ringer solution; nonpremedicated dogs). Time 1 measurements were obtained 5 to 10 minutes after the preanesthetic or placebo treatment was given, and time 2 measurements were obtained 2 to 4 minutes after anesthetic induction with propofol was completed. For study purposes, an IOP > 3 SD above the mean value for the 113 healthy dogs (ie, 25 mm Hg) was considered evidence of glaucoma.
Within a row, value is significantly (P < 0.05) different from the baseline value.
Within a row, value is significantly different from those at baseline and time 1.
— = Not applicable.
The mean IOP was significantly decreased from the baseline value in the premedicated group after administration of preanesthetic medication (Table 1). The mean IOP was significantly increased after administration of propofol (2.4 ± 1.6 mg/kg [1.1 ± 0.73 mg/lb], IV), compared with that recorded after preanesthetic administration, but was not different from the baseline value for this group.
For nonpremedicated dogs, the mean IOP after placebo treatment was not different from the baseline value (Table 1). The mean IOP for this group was significantly increased after propofol administration (4.4 ± 2.1 mg/kg [2 ± 0.95 mg/lb], IV), compared with the baseline value.
Surgical patients with glaucoma
Twenty-three dogs undergoing ophthalmic surgery had evidence of glaucoma (IOP > 25 mm Hg) in ≥ 1 eye at baseline (Table 1). This included 15 and 8 dogs in the premedicated and nonpremedicated groups, respectively.
For premedicated dogs, the mean baseline IOP was 43.7 ± 14.1 mm Hg in 15 glaucomatous eyes (9 right and 6 left) and 13.1 ± 2.3 in 14 nonglaucomatous eyes (1 dog had 1 eye). The mean IOP for glaucomatous eyes in this group was significantly decreased from the baseline value following administration of preanesthetic medication and was significantly decreased, compared with baseline, following propofol administration (3.0 ± 1.4 mg/kg [1.4 ± 0.6 mg/lb], IV). The mean IOP for nonglaucomatous eyes did not differ significantly from the baseline value following preanesthetic treatment or propofol administration in this group.
For nonpremedicated dogs, the mean baseline IOP was 36.9 ± 12.9 mm Hg in 10 glaucomatous eyes (7 right and 3 left) and 17.2 ± 2.4 in 6 nonglaucomatous eyes (2 dogs had bilateral glaucoma; Table 1). The mean IOP for glaucomatous or nonglaucomatous eyes after propofol administration (4.2 ± 2.2 mg/kg [1.9 ± 1.0 mg/lb], IV) in this group did not differ significantly from the baseline value.
Cardiorespiratory effects and anesthetic recovery
Heart rate, respiratory rate, Spo2, and ETco2 values were within the respective reference ranges, and there were no significant within-group changes in these variables over time.20 The ECG data were considered normal for most dogs during isoflurane anesthesia. Twelve dogs had transient decreases in mean arterial blood pressure to < 50 mm Hg during isoflurane anesthesia. Twenty-seven dogs had transient decreases in heart rate to < 50 beats/min, and 7 dogs had evidence for single premature ventricular depolarizations during isoflurane anesthesia. All dogs were treated appropriately (eg, by administration of dopamine, atropine, or lidocaine).
Seven dogs with glaucoma had signs of mild myoclonus and disorientation during recovery from anesthesia and responded to acepromazine (0.1 mg/kg, IV). No dog had signs of regurgitation, vomiting, or excessive salivation.
Discussion
To the authors' knowledge, the present study was the first to evaluate the effects of IV propofol administration, with or without preanesthetic medication, on IOP in a large population of dogs with naturally occurring ocular diseases including glaucoma. Our data from a large number of healthy dogs without evidence of ocular disease established an IOP value > 25 mm Hg as evidence for glaucoma. We accepted the null hypothesis that propofol would not increase IOP, compared with baseline values, in premedicated dogs with or without glaucoma and in nonpremedicated dogs with glaucoma. We rejected the null hypothesis for nonpremedicated dogs without glaucoma.
Multiple physiologic and operational factors influence IOP during anesthesia, including drug-related adverse effects (hypertension, vomiting, and retching).13,21,22 Marked changes in heart rate (tachycardia), arterial blood pressure, and cardiac index produce minimal changes in IOP.9,23 Increases in arterial Pco2 can increase choroidal and retrobulbar blood volumes, which can result in an increase in IOP.10 We used ETco2 as a surrogate for arterial Pco2, and we did not observe changes in ETco2 or arterial blood pressure that would produce an important change in the measured IOPs.10 Other authors have found that eyelid manipulation, compression of both jugular veins, increases in central venous pressure, and positioning in dorsal recumbency can increase IOP in clinically normal dogs.12 We attempted to minimize stress and anxiety associated with the anesthetic procedures and techniques by maintaining a friendly, interactive environment and preventing each dog's exposure to other animals during IOP measurements and during administration of preanesthetic drugs and propofol. In addition, physical restraint was minimized and compression of the neck was avoided for all dogs during the preanesthetic and anesthetic induction periods.
Results of several studies3,5,24,25 suggest that IOP changes produced by anesthesia vary among species and are influenced by anesthetic drugs, drug dosages, and the rate of drug administration, independent of operational factors. Contradictory data, however, have been generated from multiple studies1,2,13,26 that investigated the effects of specific drugs and drug combinations on IOP in dogs. Topical local anesthesia with proparacaine had no effect on IOP values in dogs.27 Anticholinergic drugs (glycopyrrolate and atropine) caused no change or a small increase (approx 2 mm Hg) in IOP values approximately 30 minutes after IV administration.28,29 Inhalation anesthetics such as isoflurane or nitrous oxide produced minimal effects on IOP in normocapnic dogs, although it was suggested that IOP may increase minimally with time (an effect likely related to vasodilation associated with hypercapnia).9,30 The nondepolarizing neuromuscular blocking drug atracurium (0.2 mg/kg, IV) did not change IOP in isoflurane-anesthetized dogs.31 Morphine, hydromorphone, buprenorphine, butorphanol, and isoflurane produced no change or a minimal decrease in IOP in dogs, and their co-administration with acepromazine decreased IOP.11,32,i The α2-adrenergic receptor agonists are not considered to increase IOP, although butorphanol used in combination with α2-adrenergic receptor agonists (eg, medetomidine or dexmedetomidine) resulted in a transient increase (3 to 4 mm Hg) in IOP 10 minutes after IV administration.33–35 This effect was followed by a decrease (1 to 2 mm Hg) in IOP from baseline values at later times.35 Benzodiazepines such as midazolam or diazepam produced minimal or no changes in IOP; however, these drugs may blunt increases in IOP caused by IV administration of propofol or ketamine.1,36,37 Thiopental (18 mg/kg [8.1 mg/lb], IV, to effect) produced minimal changes in IOP in normal dogs, whereas propofol (8 mg/kg [3.6 mg/lb], IV, to effect) increased IOP, an effect that was not exaggerated or blunted by repeated administration of graduated doses.3 Propofol (6 mg/kg [2.7 mg/lb], IV) and alfaxalone (3 mg/kg [1.6 mg/lb], IV) initially produced a slight but insignificant increase in IOP (1 to 2 mm Hg) in healthy nonpremedicated dogs immediately after orotracheal intubation, and this was followed by a significant decrease in IOP.38 Other investigators identified an increase in IOP in dogs administered propofol (4 mg/kg [1.8 mg/lb], IV) and alfaxalone (2 mg/kg [0.9 mg/lb], IV) after premedication with hydromorphone and acepromazine.5 Similarly, IOP was significantly increased (4 to 5 mm Hg) from baseline values in healthy, client-owned dogs administered midazolam (0.2 mg/kg) and etomidate (1 to 3 mg/kg [0.45 to 1.6 mg/lb], IV).4 Ketamine is generally considered to increase IOP in healthy dogs, whether or not it is administered in conjunction with diazepam; however, the results of 1 study13 revealed no clinically important effect on IOP in dogs when midazolam (0.2 mg/kg, IV) and ketamine (15 mg/kg, IV) were coadministered.
In the present study, nonpremedicated dogs without glaucoma had a small but significant increase in IOP relative to baseline after propofol was administered. In premedicated dogs without glaucoma, a decrease in IOP from baseline after administration of butorphanol and midazolam was followed by an increase in IOP (back to baseline values) after propofol was administered. For premedicated dogs with glaucoma, premedication and propofol administration were each associated with a significant decrease in IOP from the baseline value for affected eyes, but no significant changes from baseline were observed in nonglaucomatous eyes. These results suggested that premedication with midazolam-butorphanol blunted the increase in IOP that can be produced by propofol in dogs without glaucoma. It may also prevent the potential increase in IOP produced by propofol in dogs with glaucoma; however, propofol administration had no significant effect on IOP in nonpremedicated dogs with glaucoma in our study.
To what extent the choices of species, preanesthetic medication, propofol dose, or presence of primary or secondary glaucoma influenced our results is unknown, although previous studies2,4,39,40 have shown that propofol does not increase IOP in normal sheep or people but is likely to increase IOP in dogs, regardless of whether preanesthetic medication is administered.1–5 Collectively, the data suggest that species differences, experimental design, and preexisting IOP influence the response to anesthetic drugs. In addition, the administration of preanesthetic medication with muscle-relaxing properties likely blunts or prevents an increase in IOP produced by propofol and other injectable anesthetic drugs.1–5,10,12
The present study had several limitations. We selected an IOP range for healthy dogs that incorporated 99.7% of results for a population of 113 and calculated an IOP > 25 mm Hg (3 SDs above the mean) as evidence for glaucoma. This value was identical to the IOP value of 25 mm Hg reported by others on the basis of clinical experience.12 We do not know to what extent the effects of preanesthetic oxygen delivery or the different doses of propofol among groups influenced our results, and the study was not designed to identify the mechanism whereby midazolam, butorphanol, and propofol changed IOP or whether their effects were additive, supra-additive, or antagonistic. The IOP values were recorded 2 to 4 minutes after the IV administration of propofol, a time that was previously shown to be associated with the maximum increase in IOP values,1,5,26 but we did not record IOP at later times. Finally, the numbers of nonpremedicated dogs without glaucoma and premedicated or nonpremedicated dogs with glaucoma were small; thus, the findings may not accurately reflect the response of a larger population, particularly considering that the variability in the glaucomatous eyes was marked.
Acknowledgments
The authors thank Megan Masterson, Chelsea Dotter, Shannon Klein, Galie Bowersmith, and Keali Stewart for technical assistance.
ABBREVIATIONS
| ETco2 | End-tidal concentration of carbon dioxide |
| IOP | Intraocular pressure |
| Spo2 | Oxygen saturation as measured by pulse oximetry |
Footnotes
Schering-Plough Animal Health Corp, Union, NJ.
Tonopen XL, Medtronic Solan, Jacksonville, Fla.
Fluor-I-Strip-AT, Bausch & Lomb Pharmaceuticals Inc, Tampa, Fla.
Bausch & Lomb Pharmaceuticals Inc, Tampa, Fla.
SureFlo, Terumo Medical Corp, Elkton, Md.
Abbott Laboratories, North Chicago, Ill.
Advisor V9204, Surgivet, Waukesha, Wis.
Model 915-BL Doppler ultrasound, Parks Medical Electronics Inc, Aloha, Ore.
Blaze C, Pirie CG, Casey E, et al. The effect of intravenous hydromorphone, butorphanol, morphine, and buprenorphine on pupil size and intraocular pressure in normal dogs (abstr), in Proceedings. 10th World Cong Vet Anesth, 2009.
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