The effects of intravenous alfaxalone with and without premedication on intraocular pressure in healthy dogs

Abstract

The objective of this study was to investigate the effects of intravenous alfaxalone with and without premedication on intraocular pressure (IOP) in healthy dogs. Thirty-three dogs were randomized to receive 1 of 3 treatments: acepromazine [0.03 mg/kg body weight (BW)] with butorphanol (0.2 mg/kg BW) intramuscularly (IM), followed by intravenous (IV) alfaxalone (1.5 mg/kg BW); dexmedetomidine (0.002 mg/kg BW) with hydromorphone (0.1 mg/kg BW) IM, followed by alfaxalone (1 mg/kg BW) IV; and saline 0.9% (0.02 mL/kg BW) IM, followed by alfaxalone (3 mg/kg BW) IV. Intraocular pressure (IOP) was measured at baseline, 15 min, and 30 min after premedication, after pre-oxygenation, after administration of alfaxalone, and after intubation. After induction and after intubation, the IOP was significantly increased in all groups compared to baseline. While premedication with acepromazine/butorphanol or dexmedetomidine/hydromorphone did not cause a significant increase in IOP, the risk of vomiting and the associated peak in IOP after dexmedetomidine/hydromorphone should be considered when selecting an anesthetic protocol for dogs with poor tolerance for transient increases in IOP.

Introduction

Intraocular pressure (IOP) is maintained by a balance between the production of aqueous humor and its outflow (1). Anesthetic agents can alter intraocular pressure by changing the rate of aqueous production or outflow or by increasing extraocular muscle tone (2). When choosing an anesthetic protocol for intraocular surgeries, the effect of the protocol on intraocular pressure must be taken into account (2,3). Abrupt increases in IOP throughout anesthesia of patients undergoing ophthalmic surgery can have significant effects. For example, minimal increases in IOP (30 to 35 mmHg) in glaucomatous animals can significantly lower axoplasmic flow within the optic nerve, resulting in further nerve injury (4). Inadvertent perforation of a deep corneal ulcer before or during surgery due to IOP elevations can complicate the surgical procedure and worsen the postoperative prognosis (5,6).

Alfaxalone is a synthetic neuroactive steroidal anesthetic that is injectable and acts as an agonist at gamma-aminobutyric acid A (GABA_A) receptors within the central nervous system (CNS) (7). Alfaxalone was first introduced into veterinary medicine in 1971 (8) and is currently licensed as Alfaxan (Jurox, Kansas City, Missouri, USA) for use in several countries, including Canada, Australia, and most of Europe. Anesthesia can be induced and maintained with alfaxalone, producing rapid and smooth induction with excellent muscle relaxation (9–11). The cardiopulmonary effects of alfaxalone have been well-investigated in dogs (9–12). The reported effects of alfaxalone on IOP in dogs are varied (13,14). In 1 study without pre-anesthetic medication, a single bolus of alfaxalone induced a transient nonsignificant increase in IOP, followed by a significant reduction in IOP (14). In another study, a significant increase in IOP was observed when alfaxalone was administered after premedication with acepromazine and hydromorphone (13).

Pre-anesthetic medication is commonly used to calm the patient, reduce anesthetic requirements, promote smooth induction and recovery from anesthesia, and provide analgesia (15). Combinations of acepromazine and butorphanol or dexmedetomidine and hydromorphone are commonly used as pre-anesthetic medications in dogs (15,16). Although the effect of combined acepromazine and butorphanol on IOP has been evaluated in 1 study (17), the combination of dexmedetomidine and hydromorphone on IOP has not yet been studied. The objective of this study was to determine the effects on IOP in healthy dogs after the administration of alfaxalone alone compared with alfaxalone administered after pre-anesthetic medication with acepromazine-butorphanol and dexmedetomidine-hydromorphone.

Materials and methods

Thirty-three healthy shelter and client-owned dogs undergoing elective surgery procedures were used for this study. Informed owner consent was obtained and the protocol was approved by the University of Saskatchewan’s Animal Research Ethics Board and followed the guidelines provided by the Canadian Council on Animal Care. Breed, gender, and body weight were recorded. Age was not recorded as definitive age could not be established for most patients, but all dogs were considered adults on the basis of physical and dental examination. Pre-anesthetic physical examination and blood work consisting of packed cell volume (PCV), total protein (TP), blood glucose, and blood urea nitrogen (BUN) were conducted in all cases and dogs were classified according to the American Society of Anesthesiologists (ASA) classification.

Before entering the study, all dogs underwent a complete ophthalmic examination (Schirmer tear tests, intraocular pressure measurement with rebound tonometry, slit lamp biomicroscopy, and indirect ophthalmoscopy) by a veterinary ophthalmologist (BB) who was blinded to the treatment group. Dogs that were deemed unhealthy on physical examination or with abnormal PCV, TP, BUN, or ophthalmic examination were excluded from the study. Brachycephalic breeds and aggressive dogs that were difficult to restrain were also excluded from the study.

All IOP measurements were taken by a veterinary ophthalmologist (BB) using rebound tonometry (Tonovet; Icare Finland Oy, Helsinki, Finland) and both eyes [oculus uterque (OU)] were measured in all subjects at all time points. Each IOP obtained was an average of 6 readings and only measurements with < 2.5% variance were used. All animals were restrained in sternal position with the head raised, avoiding pressure against the globe, jugular veins, or eyelids.

Dogs were allocated into 1 of 3 treatment groups by random drawing, using an envelope containing the assignment to a treatment. The main investigators (BA and BB) were unaware of which premedication combination had been administered. The 3 treatment groups were: Group ABA — acepromazine [0.03 mg/kg body weight (BW)] (Atravet; Ayerst Laboratories, Montreal, Quebec) with butorphanol (0.2 mg/kg BW) (Torbugesic; Wyeth Animal Health, Guelph, Ontario) intramuscularly (IM), followed by intravenous (IV) alfaxalone (1.5 mg/kg BW) (Alfaxan; Abbott Laboratories, Saint Laurent, Quebec); Group DHA — dexmedetomidine (0.002 mg/kg BW) (Dexdomitor; Pfizer Canada, Mississauga, Ontario) with hydromorphone (0.1 mg/kg BW) (Hydromorphone HCl; Sandoz Canada, Quebec City, Quebec) IM, followed by alfaxalone (1 mg/kg BW) IV; and Group SA — saline 0.9% (0.02 mL/kg BW) (0.9% Sodium Chloride; Hospira, Montreal, Quebec) IM, followed by alfaxalone (3 mg/kg BW) IV.

After pre-medication, an intravenous catheter was placed in a cephalic vein and dogs were pre-oxygenated with a fitting face mask for 3 min. If dogs did not tolerate the application of the face mask, i.e., became agitated and struggled, pre-oxygenation was discontinued and procedures were paused for 3 min. Anesthesia was then induced with intravenous alfaxalone. The prepared dose of alfaxalone was administered by hand injection over 60 s, after which jaw tone was assessed by a board-certified anesthesiologist (BA). If jaw tone was not lost after 20 s, further boluses of 0.5 mg/kg BW of alfaxalone were given over 20 s until jaw tone was absent such that intubation could be achieved. After induction was complete, post-induction intraocular pressures were obtained right away, followed immediately by intubation by a board-certified anesthesiologist (BA). The number of attempts and any difficulty in orotracheal intubation were recorded. Intraocular pressures were measured at the following 6 time points: baseline at initial ophthalmic examination (BL); 15 min after premedication (15); 30 min after premedication (30); after pre-oxygenation and before induction (Post O₂); immediately after administration of alfaxalone (Post A); and after intubation, before connection to the anesthetic breathing system (Post INT).

Quality of sedation at time point 30, anesthesia induction, and intubation was scored by a board-certified anesthesiologist (BA) blinded to the treatment (Appendix 1). Behavior after premedication was observed and any incidences of vomiting or retching were recorded. After the final IOP measurement, dogs continued on to the planned surgical procedure. All procedures were carried out by the same 2 people (BA and BB) between 0800 and 1400 h.

Appendix.

Scores for Sedation, Induction, and Intubation [from Maddern et al (32)]

Sedation Score No discernable effect Mild sedation: appears sleepy Moderate sedation: very sleepy may be recumbent, but could be aroused Heavy sedation: recumbent, difficulty rousing Profound sedation: lateral recumbency, not arousable

Anesthesia Induction Score Smooth uneventful induction Some mild paddling, twitching, excitement Poor induction, pronounced paddling, twitching, excitement

Tracheal Intubation Score Smooth intubation Some mild coughing Pronounced coughing Swallowing, coughing, gagging — failed attempt

Statistical analysis

A commercially available software package (Graph Pad Prism 6 for MAC OS X; Graph Pad Software, San Diego, California, USA) was used for statistical analyses. Normality was tested by the Kolmogorov-Smirnov test. A paired t-test was done to compare IOP between right and left eye at each time point. A 1-way analysis of variance (ANOVA) with Tukey’s post-hoc test was used to evaluate within-group changes in IOP. Between-treatment effects in IOP were analyzed with 2-way repeated measures ANOVA with Tukey’s post-hoc test. Data are reported as mean ± standard deviation (SD). Sedation, induction, and intubation scores were compared with a Mann-Whitney test and data are presented as a median. Population and drug data were compared among groups with independent t-tests. A value of P < 0.05 was considered significant.

Results

Thirty-three dogs were initially included in the study, but 2 dogs in the saline group were excluded from data processing due to significant differences between the IOP in the right and left eye. As there were no significant differences between the right and left eye in the remaining 31 dogs at any time point, the data from both eyes were pooled for subsequent analysis. Of the 31 dogs included in the data analysis, there were 17 mixed breed, 3 border collies, 3 Weimaraners, 2 Siberian huskies, 2 Australian shepherds, 1 Labrador retriever, 1 Staffordshire terrier, 1 Rottweiler, and 1 Portuguese water dog.

Body weight, sedation, induction and intubation scores, baseline IOP, and the number of dogs requiring alfaxalone top-ups, and alfaxalone top-up dose are provided in Table I. There were no significant differences in body weight and baseline IOP (P > 0.05) among groups. Sedation scores were significantly different between the ABA [median 3 (2 to 4)] and SA groups (median 1) (P < 0.0001) and between the DHA [median 2 (1 to 3)] and SA groups (median 1) (P = 0.0002), but not between the ABA and DHA groups (P = 0.09). Two dogs in the DHA group vomited, but no other side effects were observed. All anesthetic regimes were successful in eliminating laryngeal reflex and preventing cough; 4 dogs required alfaxalone top ups (Table I). There were no difficulties in carrying out orotracheal intubation. All dogs were successfully intubated on the first attempt and all subjects were intubated within 2 min of the beginning of the alfaxalone injection.

Table I.

Baseline characteristics for dogs administered ABA (acepromazine, butorphanol, alfaxalone) (n = 11), DHA (dexmedetomidine, hydromorphone, alfaxalone) (n = 11), and SA (saline, alfaxalone) (n = 9)

Variable	ABA group	DHA group	SA group
Body weight (kg)	20.1 ± 10.4	18.4 ± 6.0	17.8 ± 7.3
Baseline IOP (mmHg)	15.9 ± 2.1	16.0 ± 2.9	16.9 ± 3.4
Sedation score (1 to 5)	3 (2 to 4)*	2 (1 to 3)*	1*
Induction score (1 to 3)	1	1 (1 to 2)	1 (1 to 2)
Intubation score (1 to 4)	1 (1 to 2)	1 (1 to 2)	1 (1 to 2)
Number of dogs requiring alfaxalone top up	2	1	1
Alfaxalone top-up dose (mg/kg)	1 ± 0.5	1	0.5

Data are expressed as mean ± SD or median (range). Treatment groups were compared with unpaired t-test (body weight), 2-way analysis of variance (ANOVA) for repeated measures [intraocular pressure (IOP)], and Mann-Whitney test (sedation scores, induction, and intubation scores).

No significant differences were observed among treatments, except for sedation scores.

^*Sedation scores between SA and ABA and between SA and DHA were significantly different.

P-values < 0.05 were considered significant.

When comparing IOP among groups, a significant difference was observed between the SA (15.4 ± 3.7 mmHg) and ABA (19.0 ± 2.6 mmHg) groups (P < 0.01) at 15 min (Table II). No other significant differences were observed among treatment groups (P > 0.05, Table II). In the ABA group, IOP was significantly different among BL (15.9 ± 2.1 mmHg) and post A (20.3 ± 3.9 mmHg, P < 0.05) and post INT (22.3 ± 4.0 mmHg, P < 0.001); among 15 (19.0 ± 2.6 mmHg) and 30 (15.3 ± 4.6 mmHg, P < 0.01) and post O₂ (14.5 ± 3.4 mmHg, P < 0.001); among 30 and post A (P < 0.0001) and post INT (P < 0.0001), among post O₂ and post A (P < 0.0001) and post INT (P < 0.0001). In the DHA group, IOP did not differ among BL (16.0 ± 2.9 mmHg) and 15 min (16.3 ± 3.4 mmHg) or 30 min (16.2 ± 4.3 mmHg) after premedication (P > 0.05). There was, however, a significant difference among BL and post A (19.6 ± 3.5 mmHg, P < 0.01) and post INT (22.2 ± 3.5 mmHg, P < 0.0001); among post O₂ (15.3 ± 4.4 mmHg) and post A (P < 0.01) and post INT (P < 0.0001); between 15 and post INT (P < 0.0001); and between 30 and post INT (P < 0.0001). For the SA group, IOP was significantly different between BL (16.9 ± 3.4 mmHg) and post A (21.8 ± 3.9 mmHg, P < 0.001) and post INT (22.4 ± 3.9 mmHg, P < 0.0001); between 15 (15.4 ± 3.7 mmHg) and post A and post INT (P < 0.0001); between 30 (15.4 ± 3.5 mmHg) and post A and post INT (P < 0.0001); between post O₂ (15.9 ± 3.1 mmHg) and post A and post INT (P < 0.0001).

Table II.

Mean ± SD values for intraocular pressure (mmHg) recorded at different time points in healthy dogs receiving either ABA (acepromazine, butorphanol, alfaxalone) (n = 11), DHA (dexmedetomidine, hydromorphone, alfaxalone) (n = 11), or SA (saline, alfaxalone) (n = 9)

	Treatments
Time points	SA	ABA	DHA
BL	16.9 ± 3.4	15.9 ± 2.1	16.0 ± 2.9
15	15.4 ± 3.7*	19.0 ± 2.6	16.3 ± 3.4
30	15.4 ± 3.5	15.3 ± 4.6b	16.2 ± 4.3
Post O2	15.9 ± 3.1	14.5 ± 3.4b	15.3 ± 4.4
Post A	21.8 ± 3.9aaa,bbbb,cccc,dddd	20.3 ± 3.9a,ccc,dddd	19.6 ± 3.5aa,dd
Post INT	22.4 ± 3.9aaa,bbbb,ccccc,dddd	22.3 ± 4.0aaa,cccc,ddd	22.2 ± 3.5aaa,b,cccc,dddd

P-values < 0.05 were considered significant.

BL — Baseline; 15 to 15 min after premedication; 30 to 30 min after premedication; Post O₂ — Post pre-oxygenation; Post A — Post alfaxalone administration; and Post INT — Post intubation.

^*Values are significantly different between group ABA and SA (P < 0.01).

^aSignificantly different from baseline value for the respective treatment.

^bSignificantly different from (15) value for the respective treatment.

^cSignificantly different from (30) value for the respective treatment.

^dSignificantly different from post O₂ value for the respective treatment.

(^a) P < 0.05; (^aa) P < 0.01;(^aaa) P < 0.001; (^aaaa) P < 0.0001.

Discussion

This was a clinical study that investigated the effects of 2 common pre-anesthetic medication protocols, followed by induction with alfaxalone, on IOP in healthy dogs scheduled for routine surgery. The drug combinations and doses used in this study were those routinely used to achieve a level of sedation and induction necessary for intubation. The baseline IOP values obtained in this study before treatment are in agreement with the generally accepted normal range for IOP in dogs (15 to 18 mmHg) (18).

It has previously been reported that IOP does not significantly increase after IM administration of combined acepromazine/butorphanol (17) or acepromazine/hydromorphone (13,19). Our results using combined acepromazine/butorphanol show a significant difference in IOP at 15 min. Although statistically significant, we do not believe that this is clinically significant. Our results also demonstrate that no significant elevation in IOP occurs with the IM administration of dexmedetomidine in combination with hydromorphone.

To the authors’ knowledge, there are no previous reports evaluating the effects on IOP of this particular drug protocol. One study, however, demonstrated an elevated IOP in dogs in lateral recumbency after IV administration of dexmedetomidine and butorphanol (20). This study compared IV medetomidine (0.3 mg/m²) with butorphanol (6 mg/m²) to IV dexmedetomidine (0.3 mg/m²) with butorphanol (6 mg/m²) and, although both groups demonstrated significant increases in IOP relative to baseline, the dexmedetomidine/butorphanol group was significantly higher than the medetomidine/butorphanol group (20). It was proposed that the significant differences between the groups was due to the potency of the dexmedetomidine dose chosen for the dexmedetomidine/butorphanol group. The IOP elevation noted by Rauser et al (20) in both groups was deemed to be due to elevations in systemic vascular resistance and blood pressure indirectly influencing IOP. These IOP increases were not determined to be clinically significant, however, as the IOPs did not exceed 20 mmHg. In contrast, Artigas et al (21) determined that IV dexmedetomidine (0.005 mg/kg BW) given alone did not significantly increase IOP of healthy dogs in sternal recumbency (21). While low doses of dexmedetomidine should not increase systemic vascular resistance enough to increase IOP, the dose used by Rauser et al (20) (approximately 0.01 mg/kg BW, IV) was sufficient to cause an increase in IOP in dogs.

Our study demonstrated that there is no increase in IOP at a 0.002 mg/kg BW dose of dexmedetomidine. The overall effect of dexmedetomidine combined with hydromorphone on IOP is minimal at the time points at which IOP was measured, which suggests that IM sedation with dexmedetomidine/hydromorphone at these dosages is a satisfactory option for surgical premedication when an increase in IOP is undesirable. However, the adverse effects of this combination need to be considered. Two out of 11 dogs in our study vomited shortly after sedation with dexmedetomidine and hydromorphone. Coughing, retching, and vomiting and any maneuver that increases central venous pressure may induce a dramatic increase in IOP (2). This elevation in central venous pressure results in a steep increase in choroidal blood volume and IOP. Emesis and the associated increase in IOP is a possible side-effect of administering systemic μ-opioid receptor agonist (22) and alpha-2 adrenergic receptor agonist (23). The risk of vomiting and the associated elevation in IOP after administration of dexmedetomidine and hydromorphone should be considered when selecting an anesthetic protocol for a patient at risk of globe rupture.

When comparing IOP among all 3 treatment groups, a statistically significant difference was observed between SA (15.4 ± 3.7 mmHg) and ABA (19.0 ± 2.6 mmHg) at 15 min after premedication. Given that IOP changes within the respective groups were not statistically significant compared to baseline values and remained within the normal range at the measured time points, this finding was deemed not clinically relevant. A significant increase in IOP has been demonstrated after induction of anesthesia in healthy dogs with propofol (13,24,25), alfaxalone (13), and a combination of ketamine, diazepam, and ketamine/diazepam (26). Our study findings are similar as IV induction with alfaxalone resulted in a statistically significant increase in IOP relative to baseline and 30 min post-premedication in all study groups. These results are consistent with the findings of Hasiuk et al (13), in which 1.5 mg/kg BW of IV alfaxalone was used for induction following premedication with IV acepromazine and hydromorphone in dogs and IOPs were measured in sitting or sternal recumbency.

In contrast to these findings, a more recent study observed a transient nonsignificant increase in IOP, followed by a significant reduction in IOP after a single bolus of 3 mg/kg BW of alfaxalone was administered to healthy non-premedicated dogs (14). There are several possible explanations for this difference in IOP after alfaxalone. Dogs in our study and in the study by Hasiuk et al (13) were sedated with acepromazine/butorphanol or dexmedetomidine/hydromorphone and acepromazine-hydromorphone, respectively. The simultaneous use of pre-anesthetic medication could have induced pharmacologic or pharmacokinetic interactions, which promoted an increase in IOP. Another more likely explanation is the different duration of the 3 studies. Costa et al (14) monitored IOP for 30 min after alfaxalone administration, whereas measurements of IOP pressure were stopped after orotracheal intubation in our dogs as well as in the study by Hasiuk et al (13). It is possible that a reduction in IOP at a later time point was missed due to the shorter monitoring window after alfaxalone administration.

Another difference between studies is orotracheal intubation following alfaxalone administration. Dogs in the study by Costa et al (14) were not intubated, while dogs in our study and in the study by Hasiuk et al (13) were intubated. Although intubation criteria were met for all the dogs herein and no obvious response to orotracheal intubation, such as gagging or coughing, was observed, IOP increased further in all 3 treatment groups post-intubation. This observation is consistent with the findings of Hasiuk et al (13). An increase in IOP of 5 mmHg secondary to laryngoscopy and intubation has been described in humans (27). Hofmeister et al (25) reported a significant increase in IOP in dogs after intubation. This increase in IOP is most likely related to the cardiovascular response to intubation. Laryngoscopy and tracheal intubation can cause tachycardia and hypertension due to sympathetic discharge caused by stimulation of the upper respiratory tract (28). While brief elevation of IOP during intubation is normally of little consequence, it can be harmful to patients with penetrating globe injuries.

Intraocular pressure during anesthesia can be affected in several ways. Anesthetic agents can alter intraocular pressures by changing the rate of aqueous production or outflow or by increasing extraocular muscle tone and scleral rigidity (2). It has been suggested that extraocular muscle tone has a minimal effect on IOP during induction of anesthesia in healthy dogs when propofol or alfaxalone are used (13). Aqueous humor production and outflow can be affected by changes in central nervous system (CNS) output, blood pressure (BP), central venous pressure (CVP), partial pressure of oxygen in arterial blood (PaO₂), and partial pressure of carbon dioxide in arterial blood (PaCO₂) (2). Hofmeister et al (24,29) demonstrated that in unpremedicated dogs, hypercapnea did not play a role in IOP changes with propofol. Although BP, CVP, PaO₂, and PaCO₂ were not specifically evaluated in this study, Ambros et al (10) determined that, in dogs premedicated with acepromazine and hydromorphone, PaCO₂ increases significantly post-induction with alfaxalone or propofol and that PaO₂ is unaltered. A limitation of the present study is that PaO₂ and PaCO₂ were not measured and it is therefore possible that hypoventilation and hypercapnea may have played a role in the IOP alterations noted in our dogs.

Changes in CNS control of the production and outflow of aqueous humor may also play a role in alfaxalone induction in dogs similar to propofol induction in humans (30). As alfaxalone induces significant respiratory depression (10), it is possible that hypoxemia or elevated CVP during induction could also contribute to the increase in IOP observed in our study. All dogs were given oxygen for at least 3 min before induction, however, and were intubated within 2 min of the beginning of the alfaxalone injection. In our study, the pre-oxygenation had no significant effects on IOP as expected and hypoxemia would not be expected to develop within 2 min of the onset of apnea after pre-oxygenation (31). With regard to CVP, to avoid affecting ocular venous drainage, no pressure was placed on either external jugular vein during handling of the patients.

In conclusion, the results of this study show a statistically significant increase in IOP after induction with alfaxalone, with or with out pre-anesthetic medication. Premedication with acepromazine/butorphanol or dexmedetomidine/hydromorphone did not cause a significant increase in IOP and are satisfactory pre-anesthetic combinations to use alone or before anesthesia induction in dogs. The risk of vomiting and the associated elevation in IOP after dexmedetomdine and hydromorphone are administered should be considered when selecting an anesthetic protocol for a patient with limited tolerance for short-lived increases in IOP. Additional studies are needed to evaluate the effect of alfaxalone on the eyes of patients with ocular diseases, such as glaucoma.