Repetitive Propofol Administration in Dogs and Cats
A bolus of propofol was administered to 10 dogs (6 mg/kg intravenously [IV]) and 10 cats (10 mg/kg IV) on three consecutive days. The occurrence of apnea, heart and respiratory rates, blood pressure, time to movement, and changes in a complete blood count and biochemical profile were recorded. Apnea was not seen in the dogs but was seen in three cats. Slight increases in the number of Heinz bodies were seen in six cats, but the increases were not considered clinically significant. No apparent cumulative adverse effects were seen from a bolus of bisulfite-containing propofol, administered on three consecutive days.
Introduction
Although propofol is approved for use in dogs and cats and has been used extensively for sedation, short- and long-term anesthesia, and with numerous preanesthetic medications, there are few reports describing the effects of propofol administered on consecutive days. One study in cats reported that recovery time increased after a second administration, and the number of Heinz bodies increased after a third administration.1 To the authors’ knowledge, no similar study exists in dogs.
Recently, a sodium metabisulfite-containing propofol product has been introduced to the veterinary market. The sodium metabisulfite is added as a bacterial retardant. Since the pH of this formulation is lower (pH 4.5 to 6.4), it has been reported to cause less pain on injection than other formulations (pH 7.0 to 8.5).2 The purpose of this study was to evaluate the anesthetic and cardiopulmonary effects of specific doses of bisulfite-containing propofol administered on three consecutive days to dogs and cats.
Materials and Methods
All procedures were approved by the Texas A & M University Laboratory Animal Care Committee. Ten healthy research dogs and 10 healthy research cats participated in the trial.
Study Animals
The 10 dogs ranged in age from 1 to 11 years (mean 4.8 years) and in weight from 9.1 to 29.5 kg (mean 19.3 kg). The seven females (intact) and three males (two intact, one castrated) included five mixed-breed dogs, four hounds (two black and tan; one red-bone; one Walker), and a beagle. Dogs were determined to be healthy on the basis of physical examination, 2-week observation of behavior and appetite, a baseline complete blood count (CBC), heartworm test, and serum biochemical profile.
The 10 cats ranged in age from 10 months to 8 years (mean 4.2 years) and in weight from 1.8 to 5.5 kg (mean 3.4 kg). The eight females (three spayed, five intact) and two neutered males included one domestic longhair and nine domestic shorthair cats. Cats were determined to be healthy on the basis of physical examination, 2-week observation of behavior and appetite, a baseline CBC, and serum biochemical profile.
Anesthesia Protocol
All animals were fasted for 6 hours, and water was withheld for 3 hours prior to anesthesia. Baseline measurements of rectal temperature, heart rate, respiratory rate, and body weight were made on each day of the study. Atropine (0.05 mg/kg subcutaneously [SC]) was given at least 10 minutes prior to induction, unless heart rate was >180 beats per minute. An intravenous (IV) catheter was placed in a cephalic vein before induction of anesthesia on the first day and maintained until the third day. Anesthesia was induced by administration of 6 mg/kg propofola in dogs and 10 mg/kg in cats. The propofol was given through the IV catheter over 70 seconds. These doses were selected because they fell in the midrange of doses recommended for induction of dogs and cats with no premedication (based on the package insert). Following induction, animals were intubated (when depth of anesthesia allowed) with an appropriately sized endotracheal tube.
Monitoring and Data Collection
Monitored parameters included the electrocardiogram (ECG),b noninvasive blood pressurec using a cuff applied to the forelimb, and hemoglobin saturation with oxygen (SpO2) using a pulse oximeterd with a probe attached to a peripheral site (e.g., ear pinnae, toe web, or tongue). Heart rate, respiratory rate (recorded from observation of respirations), blood pressures (systolic, mean [MAP], diastolic), and SpO2 were recorded at 2-minute intervals until the animal moved spontaneously (i.e., moved head or limb). Animals were observed for the presence and duration of apnea (defined as no spontaneous breathing for >1 minute after the propofol injection had been completed). If apnea occurred, a resuscitator bag was available to assist respiration. If the SpO2 fell to <90% for >1 minute, oxygen (2 to 3 L per minute) was administered through the endotracheal tube (for animals that were intubated) or via flow-by systems (for the animals that were not intubated). Oxygen was discontinued when SpO2 returned to 90%.
Depth of anesthesia was subjectively evaluated as inadequate (intubation not possible because of movement of head or limbs, animal appeared conscious); light (animal appeared to be unconscious but still maintained brisk corneal and palpebral reflexes, moderate jaw tone); moderate (animal unconscious with no movement, palpebral reflex lost but corneal reflex maintained); deep (animal unconscious with no movement, palpebral and corneal reflexes lost, pronounced muscle relaxation); and excessive (profound muscle relaxation, all reflexes lost, respiration and heart rates decreased, hypotension). Data collection was discontinued when spontaneous movement occurred. Animals were extubated and were observed until they were able to stand and walk.
All the above procedures were repeated on days 2 and 3. Following the third dose of propofol (usually 18 to 24 hours after recovery), animals were evaluated by physical examination, observation of attitude and appetite, CBC, and serum biochemical profile (blood samples were obtained from jugular veins).
Data Analysis
Subjective data (i.e., depth of anesthesia) was summarized for both the dogs and cats. A mixed model,e which accounted for serial correlation with repeated measures by animal assuming a compound symmetry covariance matrix, was used to evaluate each animal’s time to movement (in minutes) following anesthesia. Time to movement was used as the dependent variable, and day of anesthesia (i.e., day 1, 2, or 3) was used as the independent variable. Measurements of heart rate, respiratory rate, SpO2, systolic, diastolic, and MAP were compared at 2-minute intervals for a total of 12 minutes, or until recovery, for all anesthetic periods (days 1, 2, and 3). No comparisons of blood pressure values at similar time points in the cats were made, because of the inconsistency of numbers obtained and the frequent failure to obtain readings. Analysis of the physiological measurements taken during anesthesia was performed by using a similar mixed-model analysis (repeated measures by animal with a compound symmetry covariance matrix). At each time point, a specific physiological value (e.g., heart rate) was used as the dependent variable, and the day of anesthetic treatment was used as the independent variable. Differences were reported as least square means. A P value <0.05 was considered significant. No statistical evaluation of the laboratory data was performed.
Results
Dogs
Mean values (±standard deviation [SD]) for heart and respiratory rates, blood pressures, and SpO2 during each day’s administration of propofol are shown in Table 1. When fewer than three animals were available for measurement, values were not reported. Heart rates were significantly higher on day 1 compared to day 2 on the 2-minute (P=0.03) and 6-minute (P=0.05) readings. For the 4-minute readings, heart rates were higher (P=0.008) on days 1 and 3 when compared to day 2. Heart rates were significantly higher (P=0.03) on day 1 compared to days 2 or 3 at the 8-minute reading. Very few animals were available for measurement at the 8-minute reading (owing to anesthetic recovery), so the power of significance was questionable. Results, however, appeared to be consistent with earlier readings (e.g., 2-, 4-, and 6-minute readings).
No apnea was observed in any dog on any day. All dogs were intubated without difficulty, except for one dog that was not intubated on day 1. Oxygen insufflation was required each day in one dog (the oldest dog) for 2 minutes immediately after intubation to keep SpO2 >90%. On day 3 of the study, a second dog received oxygen insufflation for 1 minute after intubation. Respiratory rates were significantly higher (P=0.03) at 2 minutes on day 1 when compared to day 3. Hemoglobin saturation at 2 minutes was significantly higher (P=0.004) on day 1 compared to days 2 or 3.
Infrequent (<15 per minute, untreated), unifocal ventricular premature contractions (VPCs) were observed in one dog on all 3 days, and atropine administration was discontinued after day 1 in this dog. Subsequent examination found the same arrhythmia when the dog was awake, but echocardiography revealed no evidence of significant cardiac disease. No difficulty was experienced with intubation, and oxygen saturation values were normal in this dog.
Depth of anesthesia was subjectively rated. On day 1, two dogs were inadequately anesthetized, two dogs were considered to be at a light plane, and six dogs were at a moderate plane. On days 2 and 3, two dogs were at a light plane, six dogs were at a moderate plane, and two dogs were at a deep plane. Heart rates and blood pressures tended to decrease over time; however, no hypotension was seen. Oxygen saturation tended to increase over time. These trends were similar on all 3 days. Mean time to movement also did not vary significantly from day 1 to day 3. Mean times to movement±SD were 7.9 minutes (±4.1) on day 1, 9.5 minutes (±3.2) on day 2, and 9.4 minutes (±3.3) on day 3 of anesthesia. All dogs recovered uneventfully, although some transient (i.e., <1-minute duration) “paddling” was seen on recovery in three dogs. No adverse effects were evident on physical examination or in laboratory tests performed following recovery on day 3.
Cats
Mean values (±SD) for heart and respiratory rates, blood pressures, and SpO2 during each day’s dosage of propofol are shown in Table 2. When fewer than three animals were available for measurement, values were not reported. No significant differences between days or readings were seen for any variable. Most cats were moving within 6 to 8 minutes, so readings often could not be obtained. Atropine was not administered to the cats on any day because of high baseline heart rates (180 to 200 beats per minute). Apnea was observed in one cat on all 3 days (2-minute duration) and in two cats on the first day (1-minute duration). One cat was inadequately anesthetized on all 3 days and could not be intubated. Although all other cats were intubated, coughing and gagging were commonly observed following intubation. Oxygen insufflation was required within the first few minutes following propofol in five cats to maintain SpO2 >90%. Two cats received 2 to 3 minutes of oxygen each day, while three cats received 2 to 3 minutes of oxygen only on the first day. No cardiac arrhythmias were observed in the cats.
Depth of anesthesia was subjectively rated. On day 1, five cats were at a light plane, four cats were at a moderate plane, and one cat was at a deep plane. On day 2, three cats were at a light plane, while seven were at a moderate plane. On day 3, four cats were at a light plane, five cats were at a moderate plane, and one cat was at a deep plane. Some cats experienced lighter planes of anesthesia on each successive day, and other cats experienced deeper planes of anesthesia on each successive day. Heart rates tended to decrease slightly over time, while other variables appeared to be similar over time and from day to day. Mean time to movement did not vary significantly from day 1 to day 3. Mean times to movement ±SD were 9.6 minutes (±4.7) on day 1, 8.2 minutes (±6.3) on day 2, and 8.7 minutes (±3.1) on day 3 of anesthesia.
All cats recovered uneventfully, and no evidence of adverse effects was detected on physical examination. Some changes in the CBC were found, however. The number of Heinz bodies seen prior to propofol administration and on day 4 (12 to 24 hours after the last dose of propofol was administered) increased in six cats, decreased in one cat, and remained the same in one cat. Heinz bodies were not seen in two cats. All slides were evaluated by the same pathologist (Lovering).
Discussion
Although not specifically rated, inductions and recoveries were smooth in all cats. Inductions were smooth in all dogs, but some paddling was seen on recovery. Paddling has been previously reported with propofol, but the incidence varies widely.34 Paddling is probably more prevalent when pre-anesthetic medications are not used (as was the situation in this study).
Interestingly, no apnea was reported in the dogs in this study, yet apnea has frequently been reported when using propofol.5–8 In previous studies, the propofol dose was administered more rapidly (range, 30 to 60 seconds), which may account for the higher incidence of apnea.
The incidence of low SpO2 was higher in the cats than in the dogs and may have been associated with the higher dose of propofol administered.
Propofol has been reported as enhancing epinephrine-induced arrhythmias in dogs, and ventricular depolarizations have been reported after induction.910 In this study, the one dog with VPCs following propofol administration also had VPCs while awake. Therefore, it is unlikely that the propofol caused the arrhythmia, although it may have increased the incidence of VPCs. No obvious cause was identified to explain why heart rate was generally higher on day 1 than days 2 or 3, but the stress of IV catheter placement (day 1 only) may have contributed. If IV catheter placement contributed, however, it was unknown why the difference in heart rate was only observed in the dogs. Perhaps the cats were as disturbed by handling/restraint as by catheter placement; therefore, heart rates were consistently high each day.
Anesthesia time was short, with considerable variation in duration from individual to individual. Duration did not increase from day 1 to day 3 in either the dogs or cats. These results were different from what was reported in a previous study of consecutive-day propofol administration in cats, where an increase in recovery time was seen after day 2.1 However, in that study, anesthesia was maintained for 30 minutes via propofol infusion, so the total dose of propofol received was much higher than the dose administered to the cats in the study reported here.
The higher doses of propofol administered in the prior study may have explained the significant increase in Heinz bodies, malaise, and other adverse signs reported.1 Although the cats’ body weights were not reported in the prior study, it would appear that 17% to 33% more propofol was administered to each cat.
The number of Heinz bodies detected in the study reported here varied between cats. Generally, there was an increase in Heinz bodies from “none” to “rare” or “few” (<1%), although two cats showed an increase to 1+ (<5%). This was the largest increase seen and was considered to be morphologically significant but clinically insignificant. In the study reported by Andress et al., Heinz bodies increased significantly from 0.6% on days 1 and 2 to 1.8% on day 3, then continued to increase over the subsequent 3 days to 15%.1
Heinz body formation in cats occurs from an oxidative injury to hemoglobin caused by the limited glucuronide conjugation capability of cats. The number of Heinz bodies identified in normal cats is quite variable, which may account for no observation of Heinz bodies in two cats and decreased Heinz bodies in one cat.11 Presumably, less Heinz body formation occurred in this study because lower doses of propofol were given (compared to the dosage administered by Andress, et al.).1 Based upon this presumption, it might be concluded that low doses of propofol are safe when they are administered on consecutive days for induction, but repeated doses might not be safe when used for both induction and maintenance of anesthesia in cats. It is also possible that less Heinz body formation occurred in the study reported here because of the difference in formulation of the propofol used (i.e., metabisulfite). The authors were unable to find any information as to the likelihood of the bisulfite causing a difference in metabolism, however. Further investigation is needed to explore the differences in Heinz body formation between both preparations of propofol.
Conclusion
Overall, propofol produced smooth inductions and recoveries and short periods of anesthesia in dogs and cats. Apnea did not develop in any dogs, but it occurred in 30% of cats. Heinz bodies increased in 60% of the cats, but the increase was not considered clinically significant. No cardiopulmonary differences were detected, and no apparent cumulative effects were observed when metabisulfite propofol was administered on three consecutive days at an IV dose of 6 mg/kg in dogs and 10 mg/kg in cats.
Rapinovet; Schering-Plough Animal Health Corp., Union, NJ 07083
Propaq 106 EL; Protocol Systems, Beaverton, OR 97005
Dinamap 8300; Critikon, Tampa, FL 33631
Nellcor N-20 PAV; Nellcor-Puritan Bennett, Pleasanton, CA 94588
SAS, version 8.0; SAS Institute, Cary, NC 27513
