- Email: [email protected]
Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs
Veterinary Anaesthesia and Analgesia, 2007, 34, 209–212
doi:10.1111/j.1467-2995.2006.00324.x
BRIEF COMMUNICATION
Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs Bruno H Pypendop DrMedVet, DrVetSci, Diplomate ACVA, Adrian Solano Jan E Ilkiw BVSc, PhD, Diplomate ECVA
DVM,
Pedro Boscan
DVM, PhD, Diplomate ACVA
&
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA Correspondence: Bruno Pypendop, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA. E-mail: [email protected]
Abstract Objective To characterize the shape of the relationship between plasma ketamine concentration and minimum alveolar concentration (MAC) of isoflurane in dogs. Study design Retrospective analysis of previous data. Animals Four healthy adult dogs. Methods The MAC of isoflurane was determined at five to six different plasma ketamine concentrations. Arterial blood samples were collected at the time of MAC determination for measurement of plasma ketamine concentration. Plasma concentration/effect data from each dog were fitted to a sigmoid inhibitory maximum effect model in which MACmin ÞC MACc ¼ MAC0 ðMAC0EC , where C is the 50 þC plasma ketamine concentration, MACc is the MAC of isoflurane at plasma ketamine concentration C, MAC0 is the MAC of isoflurane without ketamine, MACmin is the lowest MAC predicted during ketamine administration, EC50 is the plasma ketamine concentration producing 50% of the maximal MAC reduction, and c is a sigmoidicity factor. Nonlinear regression was used to estimate MACmin, EC50, and c. Results Mean ± SEM MACmin, EC50 and c were estimated to be 0.11 ± 0.01%, 2945 ± 710 ng mL)1 and 3.01 ± 0.84, respectively.
Mean ± SEM maximal MAC reduction predicted by the model was 92.20 ± 1.05%. Conclusions The relationship between plasma ketamine concentration and its effect on isoflurane MAC has a classical sigmoid shape. Maximal MAC reduction predicted by the model is less than 100%, implying that high plasma ketamine concentrations may not totally abolish gross purposeful movement in response to noxious stimulation in the absence of inhalant anesthetics. Clinical relevance The parameter estimates reported in this study will allow clinicians to predict the expected isoflurane MAC reduction from various plasma ketamine concentrations in an average dog. Keywords dog, dose–effect relationship, isoflurane, ketamine, minimum alveolar concentration, pharmacodynamics.
Introduction Ketamine is a dissociative anesthetic that acts at the phencyclidine site of the N-methyl-D-aspartate receptor where it antagonizes the effect of the excitatory amino acid glutamate (Kohrs & Durieux 1998). Ketamine produces anesthesia and analgesia, and has been reported to decrease the minimum alveolar concentration (MAC) of inhalant anesthetics in rats, mice, horses, and dogs (White et al. 1975; Daniell 1990; Schwieger et al. 1991; Muir & Sams 1992). We recently reported the effects of 209
Concentration/effect of ketamine on isoflurane MAC BH Pypendop et al.
various plasma ketamine concentrations on the MAC of isoflurane in six dogs (Solano et al. 2006). Results from that study showed that ketamine dosedependently decreased MAC, and that the response had a linear and a nonlinear component. To our knowledge, the shape of the relationship between plasma ketamine concentration and its effect on the MAC of inhalant anesthetics has not been reported. The aim of this study was to characterize the shape of that relationship in dogs and to estimate the maximal MAC reduction produced by ketamine as well as the plasma concentrations producing 50% and 95% of that maximal MAC reduction (EC50 and EC95). Materials and methods In a separately reported study (Solano et al. 2006), the MAC of isoflurane and plasma ketamine concentration was measured simultaneously at six different plasma ketamine concentrations in six dogs. Methods are reported in detail elsewhere (Solano et al. 2006). Briefly, anesthesia was induced and maintained with isoflurane in oxygen. Esophageal temperature was continuously monitored, and external heating or cooling was provided to maintain body temperature between 38 and 39 °C. Before each MAC determination, heart rate, and systolic, diastolic, and mean arterial pressures were recorded. An arterial blood sample was collected for immediate determination of PO2, PCO2 and pH, and for measurement of plasma ketamine concentration at a later time. End-tidal gas was sampled by hand for determination of isoflurane concentration using an infrared analyzer (LB2 Medical Gas Analyzer; Beckman Instruments Inc., Anaheim, CA, USA) calibrated daily with isoflurane primary standards of known concentrations. The MAC was determined in triplicate without ketamine and at six plasma ketamine concentrations using the tail clamp technique, and was defined as the mean of two consecutive concentrations not different by more than 10%, one preventing and one allowing gross purposeful movement in response to tail clamping. Ketamine was administered with a target-controlled infusion system using a syringe pump (PHD 22/2000; Harvard Apparatus, Hollinston, MA, USA) and computer software (Rugloop I; Demed, Temse, Belgium). Target plasma ketamine concentrations were 500, 1000, 2000, 5000, 8000, and 11000 ng mL)1. Individual pharmacokinetic 210
parameters, obtained in a separate experiment, were used for the target-controlled infusion. Plasma ketamine concentrations were determined using liquid chromatography/mass spectrometry. Ketamine concentrations producing maximal MAC reduction, defined as concentrations at which MAC was reduced by more than 85% compared with control MAC and/or as concentration at which MAC cannot be further reduced by increasing the plasma ketamine concentration, were observed in four of the six dogs used in a previous study (Solano et al. 2006). Data from these four dogs were used in the present study. MAC–concentration data were fitted to a sigmoid inhibitory effect model (Gabrielsson & Weiner 2000) in which MACmin ÞCc MACc ¼ MAC0 ðMAC0 EC , where C is the c þCc 50 plasma ketamine concentration, MACc is the MAC of isoflurane at plasma ketamine concentration C, MAC0 is the MAC of isoflurane without ketamine, MACmin is the lowest MAC predicted during ketamine administration, EC50 is the plasma ketamine concentration producing 50% of the maximal MAC reduction, and c is a sigmoidicity factor. The standard sigmoid inhibitory maximum effect model was modified to fix MAC0 to the observed control MAC, rather than using the model to estimate that parameter. Nonlinear regression was used to estimate MACmin, EC50, and c, using WinNonLin Pro 5.0 (Pharsight, Cary, NC, USA) and a user-written model. Adequacy of the model was judged based on visual assessment of the fit and of the residual plot, on the coefficient of variation of final estimates and on the sum of squares of the residuals. Results are reported as mean ± SEM. Results The MAC values at various plasma ketamine concentrations are reported elsewhere (Solano et al. 2006). Mean ± SEM MAC0 was 1.44 ± 0.09%. MAC–concentration data fitted the sigmoid inhibitory model well. Maximal MAC reduction produced by ketamine was predicted to be 92.20 ± 1.05%. MACmin, EC50, and c were estimated to be 0.11 ± 0.01%, 2945 ± 710 ng mL)1, and 3.01 ± 0.84, respectively. The MAC of isoflurane at plasma ketamine concentration C can therefore be calculated 1:33C3:01 as MACc ¼ 1:44 ð2:7710 10 ÞþC3:01 . According to the model, EC95 was estimated to be 10745 ± 3145 ng mL)1. Figure 1 shows the individual and average concentration–MAC relationships.
Ó 2007 The Authors. Journal Compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 209–212
Concentration/effect of ketamine on isoflurane MAC BH Pypendop et al.
Figure 1 Actual and predicted isoflurane MAC as a function of plasma ketamine concentration in four dogs.
Discussion The present study reports pharmacodynamic parameters that predict the effect of any plasma ketamine concentration on isoflurane MAC in an average dog. The results show that the relationship between plasma ketamine concentration and isoflurane MAC in dogs has a classical inverted sigmoid shape. The model suggests that the EC50 is around 3 lg mL)1. Interestingly, Boscan et al. (2005) showed that ketamine, when administered as an adjunct to isoflurane anesthesia in dogs, produced the most beneficial cardiorespiratory effects when plasma concentration was 2–3 lg mL)1. The present study predicts that MAC reduction at the higher end of these plasma ketamine concentrations is expected to be around 47%. Mean maximal MAC reduction predicted by the model is around 92%. The 95% confidence interval for that mean is 88.9–95.5%. This maximal MAC reduction lower than 100% would suggest that, in the absence of inhalant anesthetics, ketamine alone may not totally abolish gross purposeful movement in response to a supramaximal noxious stimulus, even when high plasma concentrations are reached. This may be partly explained by the findings that spontaneous movement was observed at high plasma ketamine concentrations, making the assessment of the movement response to noxious stimulation difficult (Boscan et al. 2005; Solano et al. 2006). The significance of spontaneous move-
ment when high doses of ketamine are administered is unknown. In cats it has been shown that even though organized motor responses were not observed, withdrawal reflexes were preserved when ketamine was administered at doses that eliminated autonomic responses to noxious stimulation, and total and low-frequency electroencephalographic power (Taylor & Vierck 2003). Finally, the results of the present study show that EC95 is highly variable between dogs. Boscan et al. (2005) suggested that at the concentrations required to produce 95% of the maximal effect on MAC, significant undesirable effects would be produced, making these concentrations of little clinical interest. This high variability in EC95 between dogs may also explain why maximal MAC reduction was not observed in two dogs in the study of Solano et al. (2006). Interestingly, in these two dogs, the highest actual plasma ketamine concentration reached was lower than 8000 ng mL)1. It is therefore possible that, had higher concentrations been reached, the model used in the present study would have adequately described the data from these two dogs. However, because we cannot determine where the lower plateau of the relationship between plasma ketamine concentration and isoflurane MAC is situated, the data cannot be fitted to an inhibitory maximum effect model. The differences in individual responses shown in Fig. 1 underline that, even though our model may
Ó 2007 The Authors. Journal Compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 209–212
211
Concentration/effect of ketamine on isoflurane MAC BH Pypendop et al.
allow predictions to be made for an average dog, the effects of ketamine on isoflurane MAC in any particular individual may be significantly different from that average prediction. In conclusion, the effect of ketamine on the MAC of isoflurane in dogs has a classical sigmoid shape. In an average dog, 50% of the maximal MAC reduction induced by ketamine is expected to be reached at a plasma ketamine concentration around 3 lg mL)1. Acknowledgements This study was funded by the Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis. The authors thank Scott Stanley, PhD, for the plasma ketamine concentration determinations. References Boscan P, Pypendop BH, Solano AM et al. (2005) Cardiovascular and respiratory effects of ketamine infusions in isoflurane-anesthetized dogs before and during noxious stimulation. Am J Vet Res 66, 2122–2129. Daniell LC (1990) The noncompetitive N-methyl-D-aspartate antagonists, MK-801, phencyclidine and ketamine,
212
increase the potency of general anesthetics. Pharmacol Biochem Behav 36, 111–115. Gabrielsson J, Weiner D (2000) Pharmacodynamic concepts. In: Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts & Applications (3rd edn). Gabrielsson J, Weiner D (eds). Swedish Pharmaceutical Press, Stockholm, Sweden, pp. 175–259. Kohrs R, Durieux ME (1998) Ketamine: teaching an old drug new tricks. Anesth Analg 87, 1186–1193. Muir WW 3rd, Sams R (1992) Effects of ketamine infusion on halothane minimal alveolar concentration in horses. Am J Vet Res 53, 1802–1806. Schwieger IM, Szlam F, Hug CC Jr (1991) The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokinet Biopharm 19, 145–156. Solano AM, Pypendop BH, Boscan PL et al. (2006) Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 67, 21–25. Taylor JS, Vierck CJ (2003) Effects of ketamine on electroencephalographic and autonomic arousal and segmental reflex responses in the cat. Vet Anaesth Analg 30, 237– 249. White PF, Johnston RR, Pudwill CR (1975) Interaction of ketamine and halothane in rats. Anesthesiology 42, 179–186. Received 9 June 2006; accepted 9 August 2006.
Ó 2007 The Authors. Journal Compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 209–212
doi:10.1111/j.1467-2995.2006.00324.x
BRIEF COMMUNICATION
Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs Bruno H Pypendop DrMedVet, DrVetSci, Diplomate ACVA, Adrian Solano Jan E Ilkiw BVSc, PhD, Diplomate ECVA
DVM,
Pedro Boscan
DVM, PhD, Diplomate ACVA
&
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA Correspondence: Bruno Pypendop, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA. E-mail: [email protected]
Abstract Objective To characterize the shape of the relationship between plasma ketamine concentration and minimum alveolar concentration (MAC) of isoflurane in dogs. Study design Retrospective analysis of previous data. Animals Four healthy adult dogs. Methods The MAC of isoflurane was determined at five to six different plasma ketamine concentrations. Arterial blood samples were collected at the time of MAC determination for measurement of plasma ketamine concentration. Plasma concentration/effect data from each dog were fitted to a sigmoid inhibitory maximum effect model in which MACmin ÞC MACc ¼ MAC0 ðMAC0EC , where C is the 50 þC plasma ketamine concentration, MACc is the MAC of isoflurane at plasma ketamine concentration C, MAC0 is the MAC of isoflurane without ketamine, MACmin is the lowest MAC predicted during ketamine administration, EC50 is the plasma ketamine concentration producing 50% of the maximal MAC reduction, and c is a sigmoidicity factor. Nonlinear regression was used to estimate MACmin, EC50, and c. Results Mean ± SEM MACmin, EC50 and c were estimated to be 0.11 ± 0.01%, 2945 ± 710 ng mL)1 and 3.01 ± 0.84, respectively.
Mean ± SEM maximal MAC reduction predicted by the model was 92.20 ± 1.05%. Conclusions The relationship between plasma ketamine concentration and its effect on isoflurane MAC has a classical sigmoid shape. Maximal MAC reduction predicted by the model is less than 100%, implying that high plasma ketamine concentrations may not totally abolish gross purposeful movement in response to noxious stimulation in the absence of inhalant anesthetics. Clinical relevance The parameter estimates reported in this study will allow clinicians to predict the expected isoflurane MAC reduction from various plasma ketamine concentrations in an average dog. Keywords dog, dose–effect relationship, isoflurane, ketamine, minimum alveolar concentration, pharmacodynamics.
Introduction Ketamine is a dissociative anesthetic that acts at the phencyclidine site of the N-methyl-D-aspartate receptor where it antagonizes the effect of the excitatory amino acid glutamate (Kohrs & Durieux 1998). Ketamine produces anesthesia and analgesia, and has been reported to decrease the minimum alveolar concentration (MAC) of inhalant anesthetics in rats, mice, horses, and dogs (White et al. 1975; Daniell 1990; Schwieger et al. 1991; Muir & Sams 1992). We recently reported the effects of 209
Concentration/effect of ketamine on isoflurane MAC BH Pypendop et al.
various plasma ketamine concentrations on the MAC of isoflurane in six dogs (Solano et al. 2006). Results from that study showed that ketamine dosedependently decreased MAC, and that the response had a linear and a nonlinear component. To our knowledge, the shape of the relationship between plasma ketamine concentration and its effect on the MAC of inhalant anesthetics has not been reported. The aim of this study was to characterize the shape of that relationship in dogs and to estimate the maximal MAC reduction produced by ketamine as well as the plasma concentrations producing 50% and 95% of that maximal MAC reduction (EC50 and EC95). Materials and methods In a separately reported study (Solano et al. 2006), the MAC of isoflurane and plasma ketamine concentration was measured simultaneously at six different plasma ketamine concentrations in six dogs. Methods are reported in detail elsewhere (Solano et al. 2006). Briefly, anesthesia was induced and maintained with isoflurane in oxygen. Esophageal temperature was continuously monitored, and external heating or cooling was provided to maintain body temperature between 38 and 39 °C. Before each MAC determination, heart rate, and systolic, diastolic, and mean arterial pressures were recorded. An arterial blood sample was collected for immediate determination of PO2, PCO2 and pH, and for measurement of plasma ketamine concentration at a later time. End-tidal gas was sampled by hand for determination of isoflurane concentration using an infrared analyzer (LB2 Medical Gas Analyzer; Beckman Instruments Inc., Anaheim, CA, USA) calibrated daily with isoflurane primary standards of known concentrations. The MAC was determined in triplicate without ketamine and at six plasma ketamine concentrations using the tail clamp technique, and was defined as the mean of two consecutive concentrations not different by more than 10%, one preventing and one allowing gross purposeful movement in response to tail clamping. Ketamine was administered with a target-controlled infusion system using a syringe pump (PHD 22/2000; Harvard Apparatus, Hollinston, MA, USA) and computer software (Rugloop I; Demed, Temse, Belgium). Target plasma ketamine concentrations were 500, 1000, 2000, 5000, 8000, and 11000 ng mL)1. Individual pharmacokinetic 210
parameters, obtained in a separate experiment, were used for the target-controlled infusion. Plasma ketamine concentrations were determined using liquid chromatography/mass spectrometry. Ketamine concentrations producing maximal MAC reduction, defined as concentrations at which MAC was reduced by more than 85% compared with control MAC and/or as concentration at which MAC cannot be further reduced by increasing the plasma ketamine concentration, were observed in four of the six dogs used in a previous study (Solano et al. 2006). Data from these four dogs were used in the present study. MAC–concentration data were fitted to a sigmoid inhibitory effect model (Gabrielsson & Weiner 2000) in which MACmin ÞCc MACc ¼ MAC0 ðMAC0 EC , where C is the c þCc 50 plasma ketamine concentration, MACc is the MAC of isoflurane at plasma ketamine concentration C, MAC0 is the MAC of isoflurane without ketamine, MACmin is the lowest MAC predicted during ketamine administration, EC50 is the plasma ketamine concentration producing 50% of the maximal MAC reduction, and c is a sigmoidicity factor. The standard sigmoid inhibitory maximum effect model was modified to fix MAC0 to the observed control MAC, rather than using the model to estimate that parameter. Nonlinear regression was used to estimate MACmin, EC50, and c, using WinNonLin Pro 5.0 (Pharsight, Cary, NC, USA) and a user-written model. Adequacy of the model was judged based on visual assessment of the fit and of the residual plot, on the coefficient of variation of final estimates and on the sum of squares of the residuals. Results are reported as mean ± SEM. Results The MAC values at various plasma ketamine concentrations are reported elsewhere (Solano et al. 2006). Mean ± SEM MAC0 was 1.44 ± 0.09%. MAC–concentration data fitted the sigmoid inhibitory model well. Maximal MAC reduction produced by ketamine was predicted to be 92.20 ± 1.05%. MACmin, EC50, and c were estimated to be 0.11 ± 0.01%, 2945 ± 710 ng mL)1, and 3.01 ± 0.84, respectively. The MAC of isoflurane at plasma ketamine concentration C can therefore be calculated 1:33C3:01 as MACc ¼ 1:44 ð2:7710 10 ÞþC3:01 . According to the model, EC95 was estimated to be 10745 ± 3145 ng mL)1. Figure 1 shows the individual and average concentration–MAC relationships.
Ó 2007 The Authors. Journal Compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 209–212
Concentration/effect of ketamine on isoflurane MAC BH Pypendop et al.
Figure 1 Actual and predicted isoflurane MAC as a function of plasma ketamine concentration in four dogs.
Discussion The present study reports pharmacodynamic parameters that predict the effect of any plasma ketamine concentration on isoflurane MAC in an average dog. The results show that the relationship between plasma ketamine concentration and isoflurane MAC in dogs has a classical inverted sigmoid shape. The model suggests that the EC50 is around 3 lg mL)1. Interestingly, Boscan et al. (2005) showed that ketamine, when administered as an adjunct to isoflurane anesthesia in dogs, produced the most beneficial cardiorespiratory effects when plasma concentration was 2–3 lg mL)1. The present study predicts that MAC reduction at the higher end of these plasma ketamine concentrations is expected to be around 47%. Mean maximal MAC reduction predicted by the model is around 92%. The 95% confidence interval for that mean is 88.9–95.5%. This maximal MAC reduction lower than 100% would suggest that, in the absence of inhalant anesthetics, ketamine alone may not totally abolish gross purposeful movement in response to a supramaximal noxious stimulus, even when high plasma concentrations are reached. This may be partly explained by the findings that spontaneous movement was observed at high plasma ketamine concentrations, making the assessment of the movement response to noxious stimulation difficult (Boscan et al. 2005; Solano et al. 2006). The significance of spontaneous move-
ment when high doses of ketamine are administered is unknown. In cats it has been shown that even though organized motor responses were not observed, withdrawal reflexes were preserved when ketamine was administered at doses that eliminated autonomic responses to noxious stimulation, and total and low-frequency electroencephalographic power (Taylor & Vierck 2003). Finally, the results of the present study show that EC95 is highly variable between dogs. Boscan et al. (2005) suggested that at the concentrations required to produce 95% of the maximal effect on MAC, significant undesirable effects would be produced, making these concentrations of little clinical interest. This high variability in EC95 between dogs may also explain why maximal MAC reduction was not observed in two dogs in the study of Solano et al. (2006). Interestingly, in these two dogs, the highest actual plasma ketamine concentration reached was lower than 8000 ng mL)1. It is therefore possible that, had higher concentrations been reached, the model used in the present study would have adequately described the data from these two dogs. However, because we cannot determine where the lower plateau of the relationship between plasma ketamine concentration and isoflurane MAC is situated, the data cannot be fitted to an inhibitory maximum effect model. The differences in individual responses shown in Fig. 1 underline that, even though our model may
Ó 2007 The Authors. Journal Compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 209–212
211
Concentration/effect of ketamine on isoflurane MAC BH Pypendop et al.
allow predictions to be made for an average dog, the effects of ketamine on isoflurane MAC in any particular individual may be significantly different from that average prediction. In conclusion, the effect of ketamine on the MAC of isoflurane in dogs has a classical sigmoid shape. In an average dog, 50% of the maximal MAC reduction induced by ketamine is expected to be reached at a plasma ketamine concentration around 3 lg mL)1. Acknowledgements This study was funded by the Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis. The authors thank Scott Stanley, PhD, for the plasma ketamine concentration determinations. References Boscan P, Pypendop BH, Solano AM et al. (2005) Cardiovascular and respiratory effects of ketamine infusions in isoflurane-anesthetized dogs before and during noxious stimulation. Am J Vet Res 66, 2122–2129. Daniell LC (1990) The noncompetitive N-methyl-D-aspartate antagonists, MK-801, phencyclidine and ketamine,
212
increase the potency of general anesthetics. Pharmacol Biochem Behav 36, 111–115. Gabrielsson J, Weiner D (2000) Pharmacodynamic concepts. In: Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts & Applications (3rd edn). Gabrielsson J, Weiner D (eds). Swedish Pharmaceutical Press, Stockholm, Sweden, pp. 175–259. Kohrs R, Durieux ME (1998) Ketamine: teaching an old drug new tricks. Anesth Analg 87, 1186–1193. Muir WW 3rd, Sams R (1992) Effects of ketamine infusion on halothane minimal alveolar concentration in horses. Am J Vet Res 53, 1802–1806. Schwieger IM, Szlam F, Hug CC Jr (1991) The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokinet Biopharm 19, 145–156. Solano AM, Pypendop BH, Boscan PL et al. (2006) Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 67, 21–25. Taylor JS, Vierck CJ (2003) Effects of ketamine on electroencephalographic and autonomic arousal and segmental reflex responses in the cat. Vet Anaesth Analg 30, 237– 249. White PF, Johnston RR, Pudwill CR (1975) Interaction of ketamine and halothane in rats. Anesthesiology 42, 179–186. Received 9 June 2006; accepted 9 August 2006.
Ó 2007 The Authors. Journal Compilation Ó 2007 Association of Veterinary Anaesthetists, 34, 209–212