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Total intravenous anesthesia with propofol and S(+)-ketamine in rabbits
Veterinary Anaesthesia and Analgesia, 2010, 37, 116–122
doi:10.1111/j.1467-2995.2009.00513.x
RESEARCH PAPER
Total intravenous anesthesia with propofol and S(+)-ketamine in rabbits Fernando SF Cruz*, Adriano B Carregaro, Alceu G Raiser, Marina Zimmerman, Rafael Lukarsewski & Renata PB Steffen *Pharmacology Graduate Program, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil Departamento de Clı´nica de Pequenos Animais, Centro de Cieˆncias Rurais, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
Correspondence: Adriano B Carregaro, Departamento de Clı´nica de Pequenos Animais, Centro de Cieˆncias Rurais, Universidade Federal de Santa Maria, UFSM, Av. Roraima 1000, Santa Maria, Rio Grande do Sul, Brazil CEP 97105-900. E-mail: [email protected]
Abstract Objective To evaluate total intravenous anesthesia with propofol alone or in combination with S(+)ketamine in rabbits undergoing surgery. Study design Prospective, randomized, blinded trial. Animals Nine 6-month-old New Zealand white rabbits, weighing 2.5–3 kg. Methods Animals received acepromazine (0.1 mg kg)1) and buprenorphine (20 lg kg)1) IM, and anesthesia was induced with propofol (2 mg kg)1) and S(+)-ketamine (1 mg kg)1) IV. Rabbits received two of three treatments: propofol (0.8 mg kg)1 minute)1) (control treatment, P), propofol (0.8 mg kg)1 minute)1) + S(+)-ketamine (100 lg kg)1 minute)1) (PK100) or propofol (0.8 mg kg)1 minute)1) + S(+)-ketamine (200 lg kg)1 minute)1) (PK200). All animals received 100% O2 during anesthesia. Heart rate, mean arterial pressure, hemoglobin oxygen saturation and respiratory rate were measured every 5 minutes for 60 minutes. Blood-gas parameters were measured at zero time and 60 minutes. Additional propofol injections, if necessary, and recovery time were recorded. Results An increase in heart rate was observed in P and PK200 up to 10 minutes after induction of anesthesia. Blood pressure decreased from baseline 116
values during the first 10 minutes in P and PK200, and during the first 15 minutes and between 45 and 55 minutes in PK100. A reduction in respiratory rate was observed after 5 minutes in all treatments. Respiratory acidosis was observed in all treatments. Six (2.8) [median (interquartile range)] further propofol injections were necessary in P, which differed statistically from PK100 [1 (0.2)] and PK200 [2 (0.6)]. Recovery time was shorter in P compared with PK100 and PK200, being [7.5 minutes (4.11)], [17.5 minutes (10.30)], and [12 minutes (10.30)], respectively. Conclusions and clinical relevance S(+)-ketamine potentiates propofol-induced anesthesia in rabbits, providing better maintenance of heart rate. All of these techniques were accompanied by clinically significant respiratory depression. Keywords intravenous anesthesia, propofol, rabbit, S(+)-ketamine.
Introduction Rodents and lagomorphs are considered standard animals in biomedical research especially with regard to pharmacology, toxicology, surgery and genetics. Rabbits are the third most commonly anaesthetized species but have at least seven times more risks of anaesthetic-related death compared to dogs and cats (Brodbelt 2009). In relation to its
TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
oropharyngeal anatomy, certain aspects stand out, such as narrow oral cavity, large incisor teeth, thick and protruding tongue, and low mobility of the temporomandibular articulation, which makes intubation in this species difficult (Smith et al. 2004; Bateman et al. 2005). This practice can cause trauma to the larynx, laryngospasm and tracheal lesions (Bateman et al. 2005), requiring the anesthetist to have ample experience and dexterity. One alternative to endotracheal intubation is the use of a face mask, which does not prevent airway obstruction (Bateman et al. 2005), and can contribute to the exposure of the anesthetist to anesthetic waste gases (Smith 1993). Total intravenous anesthesia can be used instead of inhalants. The combination of ketamine and xylazine, which was very popular in the past, causes hemodynamic depression (Wyatt et al. 1989; Popilskis et al. 1991; Dupras et al. 2001; Henke et al. 2005) The combination tiletamine-zolazepam also is frequently used for anesthesia in rabbits. When xylazine was added to tiletamine-zolazepam there also was intense cardiopulmonary depression (Popilskis et al. 1991). Moreover, there are reports that tiletamine is nephrotoxic in rabbits, which could cause tubular necrosis and nephrosis at doses commonly used for anesthetic induction or chemical restraint (Brammer et al. 1991; Doerning et al. 1992). In humans total intravenous anesthesia has some advantages when compared to inhalant anesthesia, such as greater hemodynamic and anesthetic plane stability, and faster and more predictable recovery (Eyres 2004). Propofol commonly is used as a continuous infusion as a result of its pharmacokinetic characteristics, which allows anesthetic maintenance for prolonged periods and rapid recoveries (Flaherty et al. 1997; Glowaski & Wetmore 1999; Horn & Nesbit 2004). However, propofol causes dose-dependent hypotension, negative inotropy, and decreased systemic vascular resistance, resulting in decreased cardiac output (Glowaski & Wetmore 1999; Lerche et al. 2000; Baumgartner et al. 2007). According to Aeschbacher & Webb (1993), the use of propofol as the only anesthetic agent for long periods of anesthesia in rabbits must be avoided, because of intense hypotension and hypoxemia. Lerche et al. (2000), reported that the effects of propofol are related to the dose used, where combinations with other anesthetic agents or adjuvants are extremely beneficial in reducing the dose and minimizing side effects.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, acting on opioid and muscarinic receptors as well (Hustveit et al. 1995). The S(+) isomer seems to demonstrate greater affinity to l and j opioid receptors (Hirota et al. 1999; Sarton et al. 2001), as well as producing hemodynamic stability during anesthesia as a result of the stimulatory effect on the sympathetic nervous system (Stoelting 1999). Another advantage S(+)-ketamine is its greater plasma clearance compared to the R(-) isomer when administered alone in dogs (Henthorn et al. 1999), thus explaining why animals anesthetized with S(+)-ketamine show faster recovery. The combination of propofol and ketamine has been used in humans and in veterinary patients for total intravenous anesthesia (Hui et al. 1995; Lerche et al. 2000; Kogan et al. 2003; Umar et al. 2006). Some advantages of the combination include intraoperative hemodynamic stability, and, when compared to the combination of fentanyl and propofol, less respiratory depression during the recovery phase (Hui et al. 1995). The aim of this study was to evaluate total intravenous anesthesia with propofol alone or combined with S(+)-ketamine in rabbits. Materials and methods Nine New Zealand white rabbits, six males and three females, 6 months old and weighing between 2.5 and 3 kg, were used. The animals were maintained in individual cages with dimensions of 60 · 60 · 60 cm, for at least 15 days before the experiments for acclimation, where they were fed with commercial pellet food and water ad libitum. The study was approved by the Animal Care Committee of the Universidade Federal de Santa Maria (46/2006). The animals were submitted to surgery for insertion and later extraction of latex membranes on the abdominal muscles for biocompatibility evaluation (parallel study). In this case, each animal was submitted to two anesthetic procedures, therefore taking part in two of the three experimental treatments, distributed in a 3 · 2 Latinsquare design, with a minimum 15-day interval between each one. The anesthetic time was standardized, employing 30 minutes for each side, totaling 60 minutes for the procedure. The treatments were performed using a blind study method where the animals were randomly distributed into three treatments maintained under
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
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TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
total intravenous anesthesia: 0.8 mg kg)1 minute)1 of propofol (Propovan, Crista´lia Produtos Quı´micos e Farmaceˆuticos Ltda., Itapira, Brazil), being the control treatment (P); a combination of 0.8 mg kg)1 minute)1 of propofol and 100 lg kg)1 minute)1 of S(+)-ketamine (Ketamin S (+), Crista´lia Produtos Quı´micos e Farmaceˆuticos Ltda., Itapira, Brazil) (PK100); or 0.8 mg kg)1 minute)1 of propofol and 200 lg kg)1 minute)1 of S(+)-ketamine (PK200). The anesthetics were administered by infusion pump (Uniset NB 400, Biosensor Indu´stria e Come´rcio Ltda., Americana, Brazil). After 2-hour fasting, the animals received 0.1 mg kg)1 of acepromazine (Acepran 0.2%, Vetnil Indu´stria e Come´rcio Produtos Veterina´rios Ltda., Sa˜o Paulo, Brazil) combined with 20 lg kg)1 of buprenorphine (Temgesic, Schering-Plough Produtos Farmaceˆuticos Ltda., Rio de Janeiro, Brazil) IM, as preanesthetic medication. After 15 minutes, 22-gauge catheters were inserted into the left auricular marginal vein to administer the treatment drugs, and into the left auricular marginal artery, which was connected to a fluid-filled pressure transducer (Model PX 260, Baxter Healthcare Corp., CA, USA) zeroed at the level of the heart to measure mean arterial pressure (MAP) in mmHg. Electrodes were positioned on their thoracic and pelvic legs to evaluate heart rate and cardiac rhythm by electrocardiography (lead II), and a sensor was used on the right ear to obtain arterial hemoglobin oxygen saturation (SpO2) (Monitor Modular Ma´ximo, Ecafix Indu´stria Comercial, Sa˜o Paulo, Brazil). The respiratory rate (fR) was determined by the observation of thoracic movements. After 20 minutes, the physiological parameters were recorded (zero time), and afterwards, a combination of 2 mg kg)1 of propofol and 1 mg kg)1 of S(+)-ketamine was administered IV, followed immediately by starting the continuous infusion of the specified treatment, for 60 minutes. The total volume of propofol administered, as well as propofol and S(+)-ketamine, was standardized at 10 mL kg)1 hour)1, and the anesthetics were diluted in 0.9% sodium chloride (Soluc¸a˜o de Cloreto de So´dio 0.9%, JP Indu´stria Farmaceˆutica S.A., Ribeira˜o Preto, Brazil). Physiologic parameters were measured at 5-minute intervals, up to 60 minutes. At zero time and 60 minutes, pH, arterial tension of CO2 (PaCO2), arterial tension of O2 (PaO2) and bicarbonate concentration (HCO3)) were measured by arterial blood-gas analysis (Omni C, Roche Diagno´stica Brasil, Brazil). Recovery time was recorded as the time from discontinuation of the 118
infusion until the animal was in sternal recumbency, and also recorded was the number of additional propofol injections (1 mg) for maintenance of an adequate anesthetic plane, in case of muscle hypertonia or presence of spontaneous blinking. All animals received 100% O2 supplementation via face mask during the entire anesthetic period. Statistical analysis was performed by the GraphPad Prism 4 program (GraphPad Prism, GraphPad Software Inc., CA, USA). Repeated measures analysis of variance (ANOVA) was used and Dunnett’s test was carried out afterward for comparison of means within each treatment in relation to time zero, for HR, MAP, SpO2 and fR, and Student’s t-test for blood-gas values. For comparisons among treatments at each time, a one-way ANOVA was carried out, followed by Tukey’s test. ANOVA followed by the Kruskal–Wallis test was used for additional injections and recovery variables. The differences were considered significant when p < 0.05. The parametric results are expressed in means ± SD and the nonparametric in medians and interquartile range (IQR). Results After induction of anaesthesia, an increase in heart rate was observed in P at all times, which did not occur in PK100, where it remained stable until the end of observation. An increase in heart rate was observed in PK200 only up to 10 minutes after induction. Comparing the treatments, P differed from PK100 after 10 minutes and from PK200 after 30 minutes. There were no alterations in cardiac rhythm. In comparison with zero time, MAP was lower only during the first 10 minutes in P and PK200. In PK100 MAP decreased from baseline values during the first 15 minutes and between 45 and 55 minutes. When comparing the treatments over time, there were no significant differences among them (Table 1). A reduction in respiratory rate was observed after 5 minutes in all treatments, and this was maintained throughout the anesthetic period, with the exception of the 10-minute observation for PK200, when there was no significant difference. There was no significant difference in respiratory rates among the treatments at any time. Since baseline values were measured when rabbits were not anesthetized and were breathing room air, and oxygen was administered during the anesthetic period, SpO2 and PaO2 values were always higher than basal levels
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
P PK100 PK200 P PK100 PK200 P PK100 PK200 P PK100 PK200
Treatment
189 182 179 76 76 75 41 48 39 96 94 95
± ± ± ± ± ± ± ± ± ± ± ±
0
9 14 14 5 13 6 11 20 6 1 2 2
212 188 194 54 57 62 17 20 27 99 96 97
± ± ± ± ± ± ± ± ± ± ± ±
5
9* 26 20* 13* 19* 12* 14* 13* 6* 0 2 2
209 182 192 56 58 63 19 17 33 99 97 96
± ± ± ± ± ± ± ± ± ± ± ±
10
8* 24 10* 16* 17* 10* 13* 5* 7 0 4 4
207 180 187 66 62 67 23 24 32 99 97 98
± ± ± ± ± ± ± ± ± ± ± ±
15
7* 18 10 7 17* 10 10* 8* 9* 1 3 1
206 176 185 67 65 73 23 27 30 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
20
7* 6 11 5 15 7 7* 11* 8* 0 2* 1
203 178 190 66 67 73 25 23 30 98 98 99
± ± ± ± ± ± ± ± ± ± ± ±
25
7* 12 13 8 10 5 6* 7* 10* 1 2* 1
203 177 185 70 66 74 25 24 27 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
30
4* 9 16 9 8 5 7* 7* 5* 0 1* 1
207 175 182 73 64 73 26 24 28 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
35
7* 5 12 9 8 6 7* 5* 5* 1 1* 1
209 176 179 74 64 69 24 24 28 98 98 98
± ± ± ± ± ± ± ± ± ± ± ±
40
6* 7 11 8 7 6 7* 7* 6* 2 1* 1
205 174 184 71 63 72 24 23 28 98 98 98
± ± ± ± ± ± ± ± ± ± ± ±
45
8* 8 8 10 6* 6 7* 6* 6* 1 1* 1
207 175 189 71 64 72 24 22 29 98 98 98
± ± ± ± ± ± ± ± ± ± ± ±
50
7* 7 7 6 5* 8 8* 5* 5* 1* 2* 1
203 177 192 69 62 70 23 23 30 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
55
7* 5 6 8 6* 8 8* 6* 7* 1* 1* 2
201 177 189 68 63 71 24 22 28 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
60
4* 7 6 8 5 7 9* 5* 6* 1* 1* 1
Baseline (time 0) values were collected while rabbits were sedated but not anaesthetized and were breathing room air and values for times 5–60 were collected when rabbits were anaesthetized and receiving O2 supplementation. *Significant difference (p < 0.05) from baseline (0 minute); significant difference (p < 0.05) from P.
SpO2 (%)
fR (breaths minute)1)
Mean arterial pressure (mmHg)
HR (beats minute)1)
Variable
Time (minutes)
Table 1 Cardio-respiratory effects of total intravenous anesthesia with propofol 0.8 mg kg)1 minute)1 (P) or in association with 100 (PK100) or 200 (PK200) lg kg)1 minute)1 (S+)ketamine in rabbits
TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
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TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
Table 2 Blood-gas values in rabbits submitted to total intravenous anesthesia with propofol (P) in association of (S+)-ketamine (PK100 and PK200) in rabbits
Time (minutes)
Variable
Treatment
pH
P PK100 PK200 PaCO2 mmHg (kPa) P PK100 PK200 PaO2 mmHg (kPa) P PK100 PK200 HCO3) (mmol L)1) P PK100 PK200
0
7.41 7.41 7.42 41.2 43.0 40.3 79.2 71.3 77.4 26.0 27.2 25.8
± ± ± ± ± ± ± ± ± ± ± ±
60
0.025 7.29 ± 0.068* 0.031 7.21 ± 0.070* 0.031 7.16 ± 0.076* 2.8 (5.49 ± 0.3) 59.8 ± 10* (7.97 ± 1.3) 5.0 (5.73 ± 0.6) 71.3 ± 9.9* (9.50 ± 1.3) 5.0 (5.41 ± 0.6) 66.5 ± 9.9* (8.86 ± 1.3) 9.7 (10.55 ± 1.3) 264.9 ± 169.5* (35.31 ± 22.6) 11 (9.50 ± 1.4) 350.2 ± 126.5* (46.69 ± 16.8) 11 (10.31 ± 1.4) 283.0 ± 120.6* (37.73 ± 16.1) 2.7 27.6 ± 2.4 3.3 27.9 ± 2.1 3.3 27.1 ± 2.1
Baseline (time 0) values were collected while rabbits were sedated and breathing room air and values for time 60 were collect when rabbits were anaesthetized and receiving O2 supplementation. *Significant difference (p < 0.05) from baseline (0 minute); significant difference (p < 0.05) from P.
after induction (Tables 1 and 2). There was a significant decrease in pH in all treatments after 60 minutes, with no difference among the treatments. PaO2 as well as PaCO2 increased significantly in all treatments. When comparing the three treatments, no differences were found for these variables. Bicarbonate remained unaltered in all treatments during the experiment (Table 2). The number of propofol supplementations necessary in P [6 (IQR:2.8)], was statistically different from that for PK100 [1 (0.2)] and PK200 [2 (0.6)]. However, recovery time was significantly shorter in P when compared to PK100 and PK200, being 7.5 (4.11), 17.5 (10.30) and 12 (10.30) minutes, respectively. Discussion In the present study, a greater need for additional propofol was observed in P than in PK100 and PK200 for maintenance of the animals at an adequate anesthetic plane. This is consistent with the results of other studies in other species (Hui et al. 1995; Lerche et al. 2000; Kogan et al. 2003; Umar et al. 2006) showing that ketamine increases anesthetic depth. During induction of anesthesia using propofol alone, hypotension is a common occurrence as a result of the negative inotropic effect and a reduction in systemic vascular resistance, causing dosedependent hypotension (Glowaski & Wetmore 1999; Lerche et al. 2000; Baumgartner et al. 120
2007). Moreover, propofol causes sympathetic inhibition, leading to a reduction in cardiac output (Furuya et al. 2001). The decrease in blood pressure can vary between 13% and 32% during anesthetic induction with the usual doses of 2–2.5 mg kg)1 in humans (Skues & Prys-Roberts 1989), which is similar to the 17–29% decrease of blood pressure observed at 5 minutes after anesthetic induction. When administered as part of balanced anesthesia, ketamine allows a dose-dependent reduction of other anesthetic requirements (Hui et al. 1995; Lerche et al. 2000; Horn & Nesbit 2004), with improved hemodynamic function (Bettschart-Wolfensberger & Larenza 2007). One of the main effects of ketamine, in humans, is an increase in peripheral vascular resistance and tachycardia because of its stimulating action on the sympathetic nervous system (Tweed et al. 1972), which could explain the higher values of MAP found in PK200. However, the 100 lg kg)1 dose of S(+)-ketamine used in PK100 did not seem to be sufficient to overcome the depressing hemodynamic effects of propofol. As a result of the mechanism of action of S(+)-ketamine and because of its action on opioid receptors, especially at low doses (Horn & Nesbit 2004; Bettschart-Wolfensberger & Larenza 2007), it is likely that a lower dose of ketamine will have greater analgesic effect than stimulatory effect on the sympathetic nervous system. The increase in heart rate continued throughout the anesthetic period in P, whereas in PK200 it
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
occurred during the first 10 minutes, with no alterations occuring in PK100, showing that the dose was likely insufficient to maintain an adequate plane of anesthesia in P, confirmed by the number of extra propofol injections required. Besides, the other fact that could have contributed to higher HR values in P was the use of acepromazine, which promotes tachycardia in response to the decrease in blood pressure (Turner et al. 1974), even though the baroreceptor response is supposed to be blunted by propofol (Glowaski & Wetmore 1999). Buprenorphine has no influence on HR in rabbits (Shafford & Schadt 2008). MAP and HR stability during PK100 and PK200 confirm the findings of Lerche et al. (2000) who did not observe significant alterations in the hemodynamic parameters using 2 mg kg)1 of ketamine combined with the same dose of propofol. A reduction in respiratory rate was observed in all treatments throughout the anesthetic period. According to Glowaski & Wetmore (1999) propofol causes bradypnea, or even apnea, as a main adverse effect. Ketamine also causes respiratory depression (Lerche et al. 2000) which is observed with both agents and is dose-dependent (Flaherty et al. 1997; Glowaski & Wetmore 1999; Lerche et al. 2000). The bradypnea caused by propofol is likely due to the depression of the respiratory center and to the inhibition of the response to hypercapnea (Adetunji et al. 2002), culminating in respiratory acidosis, since HCO3) levels remained unaltered during the study. When ketamine is used in infusions (BettschartWolfensberger & Larenza 2007) or administered slowly (Craven 2007), it results in minimal respiratory depression with moderate hypercapnea. Hypoxia and hypercapnea are alterations commonly observed when high doses or combinations with central nervous system-depressing agents are used (O¨klu¨ et al. 2003). Hypoxia may occur without O2 supplementation, as reported by other authors (Peeters et al. 1988; Hellebrekers et al. 1997), but was not observed in the present study, since O2 was administered during the anesthetic period. The biotransformation of propofol is dependent on the liver and extra-hepatic mechanisms (Glowaski & Wetmore 1999; Horn & Nesbit 2004). In the liver, propofol undergoes hydroxylation and conjugation with glucuronide and sulfate (Horn & Nesbit 2004). As a result of its high lipophilic property, propofol is rapidly redistributed (Adetunji et al. 2002),
which contributes to a short period of action, hence the, rapid recovery observed in P. Unlike propofol, ketamine undergoes N-demethylation into its primary metabolite, norketamine (Woolf & Adams 1987; Hijazi & Boulieu 2002). Norketamine has a third of the potency of ketamine, and is subsequently hydroxylated, producing hydroxynorketamine, facilitating its excretion as a result of its water-solubility. Knobloch et al. (2006) reported in ponies that prolonged infusion of ketamine can result in excessive formation of norketamine and ketamine build up in the adipose and muscle tissues, and that S(+)ketamine has a faster plasma clearance than R())ketamine. If the metabolism is similar in rabbits this could explain the longer recovery periods seen in PK100 and PK200 than in P. Conclusion S(+)-ketamine potentiates the anesthesia induced by propofol alone in rabbits, decreasing the need for additional doses and resulting in better maintenance of heart rate. However, there is respiratory depression, which should be given special attention. References Adetunji A, Ajadi RA, Adewoye CO et al. (2002) Total intravenous anaesthesia with propofol: repeat bolus versus continuous propofol infusion technique in xylazine – premedicated dogs. Israel J Vet Med 52, 139. Aeschbacher G, Webb AI (1993) Propofol in rabbits. 2 Long-term anesthesia. Lab Anim Sci 43, 328–335. Bateman L, Ludders JW, Gleed RD et al. (2005) Comparison between face mask and laryngeal mask airway in rabbits during isoflurane anesthesia. Vet Anaesth Analg 32, 280–288. Baumgartner C, Bollerhey M, Henke J et al. (2007) Effects of propofol on ultrasonic indicators of haemodynamic function in rabbits. Vet Anaesth Analg 35, 100–112. Bettschart-Wolfensberger R, Larenza MP (2007) Balanced anesthesia in the equine. Clin Tech Equine Pract 6, 104–110. Brammer DW, Doerning BJ, Chrisp CE et al. (1991) Anesthetic and nephrotoxic effects of Telazol in New Zealand white rabbits. Lab Anim Sci 41, 432–435. Brodbelt D (2009) Perioperative mortality in small animal anaesthesia. Vet J 182, 152–61. Craven R (2007) Ketamine. Anesthesia 62(Suppl. 1), 48–53. Doerning BJ, Brammer DW, Chrisp CE et al. (1992) Nephrotoxicity of tiletamine in New Zealand white rabbits. Lab Anim Sci 42, 267–269.
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
121
TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
Dupras J, Vachon P, Cuvelliez S et al. (2001) Anesthesia of the New Zealand rabbit using the combination of tiletamine-zolazepam and ketamine-midazolam with or without xylazine. Can Vet J 42, 455–460. Eyres R (2004) Update on TIVA. Paediatr Anaesth 14, 374–379. Flaherty D, Reid J, Welsh E et al. (1997) A pharmacodynamic study of propofol or propofol and ketamine infusions in ponies undergoing surgery. Res Vet Sci 62, 179–184. Furuya A, Matsukawa T, Ozaki M et al. (2001) Intravenous ketamine attenuates arterial pressure changes during the induction of anesthesia with propofol. Eur J Anaesth 18, 88–92. Glowaski MM, Wetmore A (1999) Propofol: application in veterinary sedation and anesthesia. Clin Tech Small Anim Pract 14, 1–9. Henke J, Astner S, Brill T et al. (2005) Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits. Vet Anaesth Analg 32, 261–270. Hellebrekers LJ, de Boer EJ, van Zuylen MA et al. (1997) A comparison between medetomidine-ketamine and medetomidine-propofol anaesthesia in rabbits. Lab Anim 31, 58–69. Henthorn TK, Krejcie TC, Niemann C. (1999) Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective. Anesthesiology 91, 1733–1743. Hijazi Y, Boulieu R (2002) Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 30, 853–858. Hirota K, Okawa H, Appadu BL et al. (1999) Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology 90, 174–182. Horn E, Nesbit SA (2004) Pharmacology and pharmacokinetics of sedatives and analgesics. Gastrointest Endosc Clin N Am 14, 247–268. Hui TW, Short TG, Hong W et al. (1995) Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 82, 641–648. Hustveit O, Maurset A, Oye I (1995) Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol 77, 355–359. Knobloch M, Portier CJ, Levionnois OL et al. (2006) Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion. Toxicol Appl Pharmacol 216, 373–386. Kogan A, Efrat R, Katz J et al. (2003) Propofol-ketamine mixture for anesthesia in pediatric patients undergoing cardiac catheterization. J Cardiothorac Vasc Anesth 17, 691–693.
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Lerche P, Nolan AM, Reid J (2000) Comparative study of propofol or propofol and ketamine for the induction of anesthesia in dogs. Vet Rec 146, 571–574. O¨klu¨ E, Bulutcu FS, Yalc¸ın Y et al. (2003) Which anesthetic agent alters the hemodynamic status during pediatric catheterization? Comparison of propofol versus ketamine J Cardiothorac Vasc Anesth 17, 686–690. Peeters ME, Gil D, Teske E et al. (1988) Four methods for general anaesthesia in the rabbit: a comparative study. Lab Anim 22, 355–360. Popilskis SJ, Oz MC, Gorman P et al. (1991) Comparison of xylazine with tiletamine-zolazepam (Telazol) and xylazine-ketamine anesthesia in rabbits. Lab Anim Sci 41, 51–53. Sarton E, Teppema LJ, Olievier C et al. (2001) The involvement of the mu-opioid receptor in ketamineinduced respiratory depression and antinociception. Anesth Analg 93, 1495–1500. Shafford HL, Schadt JC (2008) Respiratory and cardiovascular effects of buprenorphine in conscious rabbits. Vet Anaesth Analg 35, 326–332. Skues MA, Prys-Roberts C (1989) The pharmacology of propofol. J Clin Anesth 1, 387–400. Smith JA (1993) Anesthetic pollution and waste anesthetic gas scavenging. Semin Vet Med Surg Small Anim 8, 90– 103. Smith JC, Robertson LD, Auhll A et al. (2004) Endotracheal tubes versus laryngeal mask airways in rabbit inhalation anesthesia: ease of use and waste gas emissions. Contemp Top Lab Anim Sci 43, 22–25. Stoelting RK (1999) Nonbarbiturate induction drugs. In: Pharmacology & Physiology in Anesthetic Practice. (3rd edn) Stoelting RK (ed). Lippincott-Raven, Philadelphia, PA, USA. pp. 140–157. Turner DM, Ilkiw JE, Rose RJ et al. (1974) Respiratory and cardiovascular effects of five drugs used as sedatives in the dog. Aust Vet J 50, 260–265. Tweed WA, Minuck MS, Mymin D (1972) Circulatory response to ketamine anesthesia. Anesthesiology 37, 613–619. Umar MA, Yamashita K, Kushiro T et al. (2006) Evaluation of total intravenous anesthesia with propofol or ketamine-medetomidine-propofol combination in horses. J Am Vet Med Assoc 228, 1221–1227. Woolf TF, Adams JD (1987) Biotransformation of ketamine, (Z)-6-hydroxyketamine and (E)-6-hydroxyketamine by rat, rabbit and human liver microsomal preparations. Xenobiotica 17, 839–847. Wyatt JD, Scott RA, Richardson ME (1989) The effects of prolonged ketamine-xylazine intravenous infusion on arterial blood pH, blood gases, mean arterial blood pressure, heart and respiratory rates, rectal temperature and reflex in the rabbit. Lab Anim Sci 39, 411–416. Received 11 July 2008; accepted 15 March 2009.
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
doi:10.1111/j.1467-2995.2009.00513.x
RESEARCH PAPER
Total intravenous anesthesia with propofol and S(+)-ketamine in rabbits Fernando SF Cruz*, Adriano B Carregaro, Alceu G Raiser, Marina Zimmerman, Rafael Lukarsewski & Renata PB Steffen *Pharmacology Graduate Program, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil Departamento de Clı´nica de Pequenos Animais, Centro de Cieˆncias Rurais, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
Correspondence: Adriano B Carregaro, Departamento de Clı´nica de Pequenos Animais, Centro de Cieˆncias Rurais, Universidade Federal de Santa Maria, UFSM, Av. Roraima 1000, Santa Maria, Rio Grande do Sul, Brazil CEP 97105-900. E-mail: [email protected]
Abstract Objective To evaluate total intravenous anesthesia with propofol alone or in combination with S(+)ketamine in rabbits undergoing surgery. Study design Prospective, randomized, blinded trial. Animals Nine 6-month-old New Zealand white rabbits, weighing 2.5–3 kg. Methods Animals received acepromazine (0.1 mg kg)1) and buprenorphine (20 lg kg)1) IM, and anesthesia was induced with propofol (2 mg kg)1) and S(+)-ketamine (1 mg kg)1) IV. Rabbits received two of three treatments: propofol (0.8 mg kg)1 minute)1) (control treatment, P), propofol (0.8 mg kg)1 minute)1) + S(+)-ketamine (100 lg kg)1 minute)1) (PK100) or propofol (0.8 mg kg)1 minute)1) + S(+)-ketamine (200 lg kg)1 minute)1) (PK200). All animals received 100% O2 during anesthesia. Heart rate, mean arterial pressure, hemoglobin oxygen saturation and respiratory rate were measured every 5 minutes for 60 minutes. Blood-gas parameters were measured at zero time and 60 minutes. Additional propofol injections, if necessary, and recovery time were recorded. Results An increase in heart rate was observed in P and PK200 up to 10 minutes after induction of anesthesia. Blood pressure decreased from baseline 116
values during the first 10 minutes in P and PK200, and during the first 15 minutes and between 45 and 55 minutes in PK100. A reduction in respiratory rate was observed after 5 minutes in all treatments. Respiratory acidosis was observed in all treatments. Six (2.8) [median (interquartile range)] further propofol injections were necessary in P, which differed statistically from PK100 [1 (0.2)] and PK200 [2 (0.6)]. Recovery time was shorter in P compared with PK100 and PK200, being [7.5 minutes (4.11)], [17.5 minutes (10.30)], and [12 minutes (10.30)], respectively. Conclusions and clinical relevance S(+)-ketamine potentiates propofol-induced anesthesia in rabbits, providing better maintenance of heart rate. All of these techniques were accompanied by clinically significant respiratory depression. Keywords intravenous anesthesia, propofol, rabbit, S(+)-ketamine.
Introduction Rodents and lagomorphs are considered standard animals in biomedical research especially with regard to pharmacology, toxicology, surgery and genetics. Rabbits are the third most commonly anaesthetized species but have at least seven times more risks of anaesthetic-related death compared to dogs and cats (Brodbelt 2009). In relation to its
TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
oropharyngeal anatomy, certain aspects stand out, such as narrow oral cavity, large incisor teeth, thick and protruding tongue, and low mobility of the temporomandibular articulation, which makes intubation in this species difficult (Smith et al. 2004; Bateman et al. 2005). This practice can cause trauma to the larynx, laryngospasm and tracheal lesions (Bateman et al. 2005), requiring the anesthetist to have ample experience and dexterity. One alternative to endotracheal intubation is the use of a face mask, which does not prevent airway obstruction (Bateman et al. 2005), and can contribute to the exposure of the anesthetist to anesthetic waste gases (Smith 1993). Total intravenous anesthesia can be used instead of inhalants. The combination of ketamine and xylazine, which was very popular in the past, causes hemodynamic depression (Wyatt et al. 1989; Popilskis et al. 1991; Dupras et al. 2001; Henke et al. 2005) The combination tiletamine-zolazepam also is frequently used for anesthesia in rabbits. When xylazine was added to tiletamine-zolazepam there also was intense cardiopulmonary depression (Popilskis et al. 1991). Moreover, there are reports that tiletamine is nephrotoxic in rabbits, which could cause tubular necrosis and nephrosis at doses commonly used for anesthetic induction or chemical restraint (Brammer et al. 1991; Doerning et al. 1992). In humans total intravenous anesthesia has some advantages when compared to inhalant anesthesia, such as greater hemodynamic and anesthetic plane stability, and faster and more predictable recovery (Eyres 2004). Propofol commonly is used as a continuous infusion as a result of its pharmacokinetic characteristics, which allows anesthetic maintenance for prolonged periods and rapid recoveries (Flaherty et al. 1997; Glowaski & Wetmore 1999; Horn & Nesbit 2004). However, propofol causes dose-dependent hypotension, negative inotropy, and decreased systemic vascular resistance, resulting in decreased cardiac output (Glowaski & Wetmore 1999; Lerche et al. 2000; Baumgartner et al. 2007). According to Aeschbacher & Webb (1993), the use of propofol as the only anesthetic agent for long periods of anesthesia in rabbits must be avoided, because of intense hypotension and hypoxemia. Lerche et al. (2000), reported that the effects of propofol are related to the dose used, where combinations with other anesthetic agents or adjuvants are extremely beneficial in reducing the dose and minimizing side effects.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, acting on opioid and muscarinic receptors as well (Hustveit et al. 1995). The S(+) isomer seems to demonstrate greater affinity to l and j opioid receptors (Hirota et al. 1999; Sarton et al. 2001), as well as producing hemodynamic stability during anesthesia as a result of the stimulatory effect on the sympathetic nervous system (Stoelting 1999). Another advantage S(+)-ketamine is its greater plasma clearance compared to the R(-) isomer when administered alone in dogs (Henthorn et al. 1999), thus explaining why animals anesthetized with S(+)-ketamine show faster recovery. The combination of propofol and ketamine has been used in humans and in veterinary patients for total intravenous anesthesia (Hui et al. 1995; Lerche et al. 2000; Kogan et al. 2003; Umar et al. 2006). Some advantages of the combination include intraoperative hemodynamic stability, and, when compared to the combination of fentanyl and propofol, less respiratory depression during the recovery phase (Hui et al. 1995). The aim of this study was to evaluate total intravenous anesthesia with propofol alone or combined with S(+)-ketamine in rabbits. Materials and methods Nine New Zealand white rabbits, six males and three females, 6 months old and weighing between 2.5 and 3 kg, were used. The animals were maintained in individual cages with dimensions of 60 · 60 · 60 cm, for at least 15 days before the experiments for acclimation, where they were fed with commercial pellet food and water ad libitum. The study was approved by the Animal Care Committee of the Universidade Federal de Santa Maria (46/2006). The animals were submitted to surgery for insertion and later extraction of latex membranes on the abdominal muscles for biocompatibility evaluation (parallel study). In this case, each animal was submitted to two anesthetic procedures, therefore taking part in two of the three experimental treatments, distributed in a 3 · 2 Latinsquare design, with a minimum 15-day interval between each one. The anesthetic time was standardized, employing 30 minutes for each side, totaling 60 minutes for the procedure. The treatments were performed using a blind study method where the animals were randomly distributed into three treatments maintained under
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TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
total intravenous anesthesia: 0.8 mg kg)1 minute)1 of propofol (Propovan, Crista´lia Produtos Quı´micos e Farmaceˆuticos Ltda., Itapira, Brazil), being the control treatment (P); a combination of 0.8 mg kg)1 minute)1 of propofol and 100 lg kg)1 minute)1 of S(+)-ketamine (Ketamin S (+), Crista´lia Produtos Quı´micos e Farmaceˆuticos Ltda., Itapira, Brazil) (PK100); or 0.8 mg kg)1 minute)1 of propofol and 200 lg kg)1 minute)1 of S(+)-ketamine (PK200). The anesthetics were administered by infusion pump (Uniset NB 400, Biosensor Indu´stria e Come´rcio Ltda., Americana, Brazil). After 2-hour fasting, the animals received 0.1 mg kg)1 of acepromazine (Acepran 0.2%, Vetnil Indu´stria e Come´rcio Produtos Veterina´rios Ltda., Sa˜o Paulo, Brazil) combined with 20 lg kg)1 of buprenorphine (Temgesic, Schering-Plough Produtos Farmaceˆuticos Ltda., Rio de Janeiro, Brazil) IM, as preanesthetic medication. After 15 minutes, 22-gauge catheters were inserted into the left auricular marginal vein to administer the treatment drugs, and into the left auricular marginal artery, which was connected to a fluid-filled pressure transducer (Model PX 260, Baxter Healthcare Corp., CA, USA) zeroed at the level of the heart to measure mean arterial pressure (MAP) in mmHg. Electrodes were positioned on their thoracic and pelvic legs to evaluate heart rate and cardiac rhythm by electrocardiography (lead II), and a sensor was used on the right ear to obtain arterial hemoglobin oxygen saturation (SpO2) (Monitor Modular Ma´ximo, Ecafix Indu´stria Comercial, Sa˜o Paulo, Brazil). The respiratory rate (fR) was determined by the observation of thoracic movements. After 20 minutes, the physiological parameters were recorded (zero time), and afterwards, a combination of 2 mg kg)1 of propofol and 1 mg kg)1 of S(+)-ketamine was administered IV, followed immediately by starting the continuous infusion of the specified treatment, for 60 minutes. The total volume of propofol administered, as well as propofol and S(+)-ketamine, was standardized at 10 mL kg)1 hour)1, and the anesthetics were diluted in 0.9% sodium chloride (Soluc¸a˜o de Cloreto de So´dio 0.9%, JP Indu´stria Farmaceˆutica S.A., Ribeira˜o Preto, Brazil). Physiologic parameters were measured at 5-minute intervals, up to 60 minutes. At zero time and 60 minutes, pH, arterial tension of CO2 (PaCO2), arterial tension of O2 (PaO2) and bicarbonate concentration (HCO3)) were measured by arterial blood-gas analysis (Omni C, Roche Diagno´stica Brasil, Brazil). Recovery time was recorded as the time from discontinuation of the 118
infusion until the animal was in sternal recumbency, and also recorded was the number of additional propofol injections (1 mg) for maintenance of an adequate anesthetic plane, in case of muscle hypertonia or presence of spontaneous blinking. All animals received 100% O2 supplementation via face mask during the entire anesthetic period. Statistical analysis was performed by the GraphPad Prism 4 program (GraphPad Prism, GraphPad Software Inc., CA, USA). Repeated measures analysis of variance (ANOVA) was used and Dunnett’s test was carried out afterward for comparison of means within each treatment in relation to time zero, for HR, MAP, SpO2 and fR, and Student’s t-test for blood-gas values. For comparisons among treatments at each time, a one-way ANOVA was carried out, followed by Tukey’s test. ANOVA followed by the Kruskal–Wallis test was used for additional injections and recovery variables. The differences were considered significant when p < 0.05. The parametric results are expressed in means ± SD and the nonparametric in medians and interquartile range (IQR). Results After induction of anaesthesia, an increase in heart rate was observed in P at all times, which did not occur in PK100, where it remained stable until the end of observation. An increase in heart rate was observed in PK200 only up to 10 minutes after induction. Comparing the treatments, P differed from PK100 after 10 minutes and from PK200 after 30 minutes. There were no alterations in cardiac rhythm. In comparison with zero time, MAP was lower only during the first 10 minutes in P and PK200. In PK100 MAP decreased from baseline values during the first 15 minutes and between 45 and 55 minutes. When comparing the treatments over time, there were no significant differences among them (Table 1). A reduction in respiratory rate was observed after 5 minutes in all treatments, and this was maintained throughout the anesthetic period, with the exception of the 10-minute observation for PK200, when there was no significant difference. There was no significant difference in respiratory rates among the treatments at any time. Since baseline values were measured when rabbits were not anesthetized and were breathing room air, and oxygen was administered during the anesthetic period, SpO2 and PaO2 values were always higher than basal levels
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
P PK100 PK200 P PK100 PK200 P PK100 PK200 P PK100 PK200
Treatment
189 182 179 76 76 75 41 48 39 96 94 95
± ± ± ± ± ± ± ± ± ± ± ±
0
9 14 14 5 13 6 11 20 6 1 2 2
212 188 194 54 57 62 17 20 27 99 96 97
± ± ± ± ± ± ± ± ± ± ± ±
5
9* 26 20* 13* 19* 12* 14* 13* 6* 0 2 2
209 182 192 56 58 63 19 17 33 99 97 96
± ± ± ± ± ± ± ± ± ± ± ±
10
8* 24 10* 16* 17* 10* 13* 5* 7 0 4 4
207 180 187 66 62 67 23 24 32 99 97 98
± ± ± ± ± ± ± ± ± ± ± ±
15
7* 18 10 7 17* 10 10* 8* 9* 1 3 1
206 176 185 67 65 73 23 27 30 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
20
7* 6 11 5 15 7 7* 11* 8* 0 2* 1
203 178 190 66 67 73 25 23 30 98 98 99
± ± ± ± ± ± ± ± ± ± ± ±
25
7* 12 13 8 10 5 6* 7* 10* 1 2* 1
203 177 185 70 66 74 25 24 27 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
30
4* 9 16 9 8 5 7* 7* 5* 0 1* 1
207 175 182 73 64 73 26 24 28 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
35
7* 5 12 9 8 6 7* 5* 5* 1 1* 1
209 176 179 74 64 69 24 24 28 98 98 98
± ± ± ± ± ± ± ± ± ± ± ±
40
6* 7 11 8 7 6 7* 7* 6* 2 1* 1
205 174 184 71 63 72 24 23 28 98 98 98
± ± ± ± ± ± ± ± ± ± ± ±
45
8* 8 8 10 6* 6 7* 6* 6* 1 1* 1
207 175 189 71 64 72 24 22 29 98 98 98
± ± ± ± ± ± ± ± ± ± ± ±
50
7* 7 7 6 5* 8 8* 5* 5* 1* 2* 1
203 177 192 69 62 70 23 23 30 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
55
7* 5 6 8 6* 8 8* 6* 7* 1* 1* 2
201 177 189 68 63 71 24 22 28 99 98 98
± ± ± ± ± ± ± ± ± ± ± ±
60
4* 7 6 8 5 7 9* 5* 6* 1* 1* 1
Baseline (time 0) values were collected while rabbits were sedated but not anaesthetized and were breathing room air and values for times 5–60 were collected when rabbits were anaesthetized and receiving O2 supplementation. *Significant difference (p < 0.05) from baseline (0 minute); significant difference (p < 0.05) from P.
SpO2 (%)
fR (breaths minute)1)
Mean arterial pressure (mmHg)
HR (beats minute)1)
Variable
Time (minutes)
Table 1 Cardio-respiratory effects of total intravenous anesthesia with propofol 0.8 mg kg)1 minute)1 (P) or in association with 100 (PK100) or 200 (PK200) lg kg)1 minute)1 (S+)ketamine in rabbits
TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
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TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
Table 2 Blood-gas values in rabbits submitted to total intravenous anesthesia with propofol (P) in association of (S+)-ketamine (PK100 and PK200) in rabbits
Time (minutes)
Variable
Treatment
pH
P PK100 PK200 PaCO2 mmHg (kPa) P PK100 PK200 PaO2 mmHg (kPa) P PK100 PK200 HCO3) (mmol L)1) P PK100 PK200
0
7.41 7.41 7.42 41.2 43.0 40.3 79.2 71.3 77.4 26.0 27.2 25.8
± ± ± ± ± ± ± ± ± ± ± ±
60
0.025 7.29 ± 0.068* 0.031 7.21 ± 0.070* 0.031 7.16 ± 0.076* 2.8 (5.49 ± 0.3) 59.8 ± 10* (7.97 ± 1.3) 5.0 (5.73 ± 0.6) 71.3 ± 9.9* (9.50 ± 1.3) 5.0 (5.41 ± 0.6) 66.5 ± 9.9* (8.86 ± 1.3) 9.7 (10.55 ± 1.3) 264.9 ± 169.5* (35.31 ± 22.6) 11 (9.50 ± 1.4) 350.2 ± 126.5* (46.69 ± 16.8) 11 (10.31 ± 1.4) 283.0 ± 120.6* (37.73 ± 16.1) 2.7 27.6 ± 2.4 3.3 27.9 ± 2.1 3.3 27.1 ± 2.1
Baseline (time 0) values were collected while rabbits were sedated and breathing room air and values for time 60 were collect when rabbits were anaesthetized and receiving O2 supplementation. *Significant difference (p < 0.05) from baseline (0 minute); significant difference (p < 0.05) from P.
after induction (Tables 1 and 2). There was a significant decrease in pH in all treatments after 60 minutes, with no difference among the treatments. PaO2 as well as PaCO2 increased significantly in all treatments. When comparing the three treatments, no differences were found for these variables. Bicarbonate remained unaltered in all treatments during the experiment (Table 2). The number of propofol supplementations necessary in P [6 (IQR:2.8)], was statistically different from that for PK100 [1 (0.2)] and PK200 [2 (0.6)]. However, recovery time was significantly shorter in P when compared to PK100 and PK200, being 7.5 (4.11), 17.5 (10.30) and 12 (10.30) minutes, respectively. Discussion In the present study, a greater need for additional propofol was observed in P than in PK100 and PK200 for maintenance of the animals at an adequate anesthetic plane. This is consistent with the results of other studies in other species (Hui et al. 1995; Lerche et al. 2000; Kogan et al. 2003; Umar et al. 2006) showing that ketamine increases anesthetic depth. During induction of anesthesia using propofol alone, hypotension is a common occurrence as a result of the negative inotropic effect and a reduction in systemic vascular resistance, causing dosedependent hypotension (Glowaski & Wetmore 1999; Lerche et al. 2000; Baumgartner et al. 120
2007). Moreover, propofol causes sympathetic inhibition, leading to a reduction in cardiac output (Furuya et al. 2001). The decrease in blood pressure can vary between 13% and 32% during anesthetic induction with the usual doses of 2–2.5 mg kg)1 in humans (Skues & Prys-Roberts 1989), which is similar to the 17–29% decrease of blood pressure observed at 5 minutes after anesthetic induction. When administered as part of balanced anesthesia, ketamine allows a dose-dependent reduction of other anesthetic requirements (Hui et al. 1995; Lerche et al. 2000; Horn & Nesbit 2004), with improved hemodynamic function (Bettschart-Wolfensberger & Larenza 2007). One of the main effects of ketamine, in humans, is an increase in peripheral vascular resistance and tachycardia because of its stimulating action on the sympathetic nervous system (Tweed et al. 1972), which could explain the higher values of MAP found in PK200. However, the 100 lg kg)1 dose of S(+)-ketamine used in PK100 did not seem to be sufficient to overcome the depressing hemodynamic effects of propofol. As a result of the mechanism of action of S(+)-ketamine and because of its action on opioid receptors, especially at low doses (Horn & Nesbit 2004; Bettschart-Wolfensberger & Larenza 2007), it is likely that a lower dose of ketamine will have greater analgesic effect than stimulatory effect on the sympathetic nervous system. The increase in heart rate continued throughout the anesthetic period in P, whereas in PK200 it
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TIVA with propofol and S(+)-ketamine in rabbits FSF Cruz et al.
occurred during the first 10 minutes, with no alterations occuring in PK100, showing that the dose was likely insufficient to maintain an adequate plane of anesthesia in P, confirmed by the number of extra propofol injections required. Besides, the other fact that could have contributed to higher HR values in P was the use of acepromazine, which promotes tachycardia in response to the decrease in blood pressure (Turner et al. 1974), even though the baroreceptor response is supposed to be blunted by propofol (Glowaski & Wetmore 1999). Buprenorphine has no influence on HR in rabbits (Shafford & Schadt 2008). MAP and HR stability during PK100 and PK200 confirm the findings of Lerche et al. (2000) who did not observe significant alterations in the hemodynamic parameters using 2 mg kg)1 of ketamine combined with the same dose of propofol. A reduction in respiratory rate was observed in all treatments throughout the anesthetic period. According to Glowaski & Wetmore (1999) propofol causes bradypnea, or even apnea, as a main adverse effect. Ketamine also causes respiratory depression (Lerche et al. 2000) which is observed with both agents and is dose-dependent (Flaherty et al. 1997; Glowaski & Wetmore 1999; Lerche et al. 2000). The bradypnea caused by propofol is likely due to the depression of the respiratory center and to the inhibition of the response to hypercapnea (Adetunji et al. 2002), culminating in respiratory acidosis, since HCO3) levels remained unaltered during the study. When ketamine is used in infusions (BettschartWolfensberger & Larenza 2007) or administered slowly (Craven 2007), it results in minimal respiratory depression with moderate hypercapnea. Hypoxia and hypercapnea are alterations commonly observed when high doses or combinations with central nervous system-depressing agents are used (O¨klu¨ et al. 2003). Hypoxia may occur without O2 supplementation, as reported by other authors (Peeters et al. 1988; Hellebrekers et al. 1997), but was not observed in the present study, since O2 was administered during the anesthetic period. The biotransformation of propofol is dependent on the liver and extra-hepatic mechanisms (Glowaski & Wetmore 1999; Horn & Nesbit 2004). In the liver, propofol undergoes hydroxylation and conjugation with glucuronide and sulfate (Horn & Nesbit 2004). As a result of its high lipophilic property, propofol is rapidly redistributed (Adetunji et al. 2002),
which contributes to a short period of action, hence the, rapid recovery observed in P. Unlike propofol, ketamine undergoes N-demethylation into its primary metabolite, norketamine (Woolf & Adams 1987; Hijazi & Boulieu 2002). Norketamine has a third of the potency of ketamine, and is subsequently hydroxylated, producing hydroxynorketamine, facilitating its excretion as a result of its water-solubility. Knobloch et al. (2006) reported in ponies that prolonged infusion of ketamine can result in excessive formation of norketamine and ketamine build up in the adipose and muscle tissues, and that S(+)ketamine has a faster plasma clearance than R())ketamine. If the metabolism is similar in rabbits this could explain the longer recovery periods seen in PK100 and PK200 than in P. Conclusion S(+)-ketamine potentiates the anesthesia induced by propofol alone in rabbits, decreasing the need for additional doses and resulting in better maintenance of heart rate. However, there is respiratory depression, which should be given special attention. References Adetunji A, Ajadi RA, Adewoye CO et al. (2002) Total intravenous anaesthesia with propofol: repeat bolus versus continuous propofol infusion technique in xylazine – premedicated dogs. Israel J Vet Med 52, 139. Aeschbacher G, Webb AI (1993) Propofol in rabbits. 2 Long-term anesthesia. Lab Anim Sci 43, 328–335. Bateman L, Ludders JW, Gleed RD et al. (2005) Comparison between face mask and laryngeal mask airway in rabbits during isoflurane anesthesia. Vet Anaesth Analg 32, 280–288. Baumgartner C, Bollerhey M, Henke J et al. (2007) Effects of propofol on ultrasonic indicators of haemodynamic function in rabbits. Vet Anaesth Analg 35, 100–112. Bettschart-Wolfensberger R, Larenza MP (2007) Balanced anesthesia in the equine. Clin Tech Equine Pract 6, 104–110. Brammer DW, Doerning BJ, Chrisp CE et al. (1991) Anesthetic and nephrotoxic effects of Telazol in New Zealand white rabbits. Lab Anim Sci 41, 432–435. Brodbelt D (2009) Perioperative mortality in small animal anaesthesia. Vet J 182, 152–61. Craven R (2007) Ketamine. Anesthesia 62(Suppl. 1), 48–53. Doerning BJ, Brammer DW, Chrisp CE et al. (1992) Nephrotoxicity of tiletamine in New Zealand white rabbits. Lab Anim Sci 42, 267–269.
2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 116–122
121
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Dupras J, Vachon P, Cuvelliez S et al. (2001) Anesthesia of the New Zealand rabbit using the combination of tiletamine-zolazepam and ketamine-midazolam with or without xylazine. Can Vet J 42, 455–460. Eyres R (2004) Update on TIVA. Paediatr Anaesth 14, 374–379. Flaherty D, Reid J, Welsh E et al. (1997) A pharmacodynamic study of propofol or propofol and ketamine infusions in ponies undergoing surgery. Res Vet Sci 62, 179–184. Furuya A, Matsukawa T, Ozaki M et al. (2001) Intravenous ketamine attenuates arterial pressure changes during the induction of anesthesia with propofol. Eur J Anaesth 18, 88–92. Glowaski MM, Wetmore A (1999) Propofol: application in veterinary sedation and anesthesia. Clin Tech Small Anim Pract 14, 1–9. Henke J, Astner S, Brill T et al. (2005) Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits. Vet Anaesth Analg 32, 261–270. Hellebrekers LJ, de Boer EJ, van Zuylen MA et al. (1997) A comparison between medetomidine-ketamine and medetomidine-propofol anaesthesia in rabbits. Lab Anim 31, 58–69. Henthorn TK, Krejcie TC, Niemann C. (1999) Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective. Anesthesiology 91, 1733–1743. Hijazi Y, Boulieu R (2002) Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 30, 853–858. Hirota K, Okawa H, Appadu BL et al. (1999) Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology 90, 174–182. Horn E, Nesbit SA (2004) Pharmacology and pharmacokinetics of sedatives and analgesics. Gastrointest Endosc Clin N Am 14, 247–268. Hui TW, Short TG, Hong W et al. (1995) Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 82, 641–648. Hustveit O, Maurset A, Oye I (1995) Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol 77, 355–359. Knobloch M, Portier CJ, Levionnois OL et al. (2006) Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion. Toxicol Appl Pharmacol 216, 373–386. Kogan A, Efrat R, Katz J et al. (2003) Propofol-ketamine mixture for anesthesia in pediatric patients undergoing cardiac catheterization. J Cardiothorac Vasc Anesth 17, 691–693.
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Lerche P, Nolan AM, Reid J (2000) Comparative study of propofol or propofol and ketamine for the induction of anesthesia in dogs. Vet Rec 146, 571–574. O¨klu¨ E, Bulutcu FS, Yalc¸ın Y et al. (2003) Which anesthetic agent alters the hemodynamic status during pediatric catheterization? Comparison of propofol versus ketamine J Cardiothorac Vasc Anesth 17, 686–690. Peeters ME, Gil D, Teske E et al. (1988) Four methods for general anaesthesia in the rabbit: a comparative study. Lab Anim 22, 355–360. Popilskis SJ, Oz MC, Gorman P et al. (1991) Comparison of xylazine with tiletamine-zolazepam (Telazol) and xylazine-ketamine anesthesia in rabbits. Lab Anim Sci 41, 51–53. Sarton E, Teppema LJ, Olievier C et al. (2001) The involvement of the mu-opioid receptor in ketamineinduced respiratory depression and antinociception. Anesth Analg 93, 1495–1500. Shafford HL, Schadt JC (2008) Respiratory and cardiovascular effects of buprenorphine in conscious rabbits. Vet Anaesth Analg 35, 326–332. Skues MA, Prys-Roberts C (1989) The pharmacology of propofol. J Clin Anesth 1, 387–400. Smith JA (1993) Anesthetic pollution and waste anesthetic gas scavenging. Semin Vet Med Surg Small Anim 8, 90– 103. Smith JC, Robertson LD, Auhll A et al. (2004) Endotracheal tubes versus laryngeal mask airways in rabbit inhalation anesthesia: ease of use and waste gas emissions. Contemp Top Lab Anim Sci 43, 22–25. Stoelting RK (1999) Nonbarbiturate induction drugs. In: Pharmacology & Physiology in Anesthetic Practice. (3rd edn) Stoelting RK (ed). Lippincott-Raven, Philadelphia, PA, USA. pp. 140–157. Turner DM, Ilkiw JE, Rose RJ et al. (1974) Respiratory and cardiovascular effects of five drugs used as sedatives in the dog. Aust Vet J 50, 260–265. Tweed WA, Minuck MS, Mymin D (1972) Circulatory response to ketamine anesthesia. Anesthesiology 37, 613–619. Umar MA, Yamashita K, Kushiro T et al. (2006) Evaluation of total intravenous anesthesia with propofol or ketamine-medetomidine-propofol combination in horses. J Am Vet Med Assoc 228, 1221–1227. Woolf TF, Adams JD (1987) Biotransformation of ketamine, (Z)-6-hydroxyketamine and (E)-6-hydroxyketamine by rat, rabbit and human liver microsomal preparations. Xenobiotica 17, 839–847. Wyatt JD, Scott RA, Richardson ME (1989) The effects of prolonged ketamine-xylazine intravenous infusion on arterial blood pH, blood gases, mean arterial blood pressure, heart and respiratory rates, rectal temperature and reflex in the rabbit. Lab Anim Sci 39, 411–416. Received 11 July 2008; accepted 15 March 2009.
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