Cardiovascular, respiratory, electrolyte and acid base balance during continuous dexmedetomidine infusion in anesthetized dogs

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1 Veterinary Anaesthesia and Analgesia, 2013, 40, doi: /vaa RESEARCH PAPER Cardiovascular, respiratory, electrolyte and acid base balance during continuous dexmedetomidine infusion in anesthetized dogs Jonathan M Congdon*, Megan Marquez*, Sirirat Niyom* & Pedro Boscan* *Department of Clinical Sciences, College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, CO, USA Correspondence: Jonathan M Congdon, Wisconsin Veterinary Referral Center, 306 Bluemound Rd, Waukesha, WI, 53188, USA. drjoncongdon@gmail.com Abstract Objective To evaluate the cardiovascular, respiratory, electrolyte and acid-base effects of a continuous infusion of dexmedetomidine during propofol-isoflurane anesthesia following premedication with dexmedetomidine. Study design Prospective experimental study. Animals Five adult male Walker Hound dogs 1 2 years of age averaging kg. Methods Dogs were sedated with dexmedetomidine 10 lg kg 1 IM, minutes (mean SD) before general anesthesia. Anesthesia was induced with propofol ( mg kg 1 ) IV and maintained with 1.5% isoflurane. Thirty minutes later dexmedetomidine 0.5 lg kg 1 IV was administered over 5 minutes followed by an infusion of 0.5 lg kg 1 hour 1. Cardiac output (CO), heart rate (HR), ECG, direct blood pressure, body temperature, respiratory parameters, acid-base and arterial blood gases and electrolytes were measured 30 and 60 minutes after the infusion started. Data were analyzed via multiple linear regression modeling of individual variables overtime, comparedtoanesthetizedbaseline values. Data are presented as mean SD. Results No statistical difference from baseline for any parameter was measured at any time point. Baseline CO, HR and mean arterial blood pressure (MAP) before infusion were L minute 1, beats minute 1 and mmhg, respectively. During infusion CO, HR and MAP were L minute 1, beats minute 1 and mmhg, respectively. No differences were found in respiratory rates, PaO 2, PaCO 2, ph, base excess, bicarbonate, sodium, potassium, chloride, calcium or lactate measurements before or during infusion. Conclusions and clinical relevance Dexmedetomidine infusion using a loading dose of 0.5 lg kg 1 IV followed by a constant rate infusion of 0.5 lg kg 1 hour 1 does not cause any significant changes beyond those associated with an IM premedication dose of 10 lg kg 1, in propofolisoflurane anesthetized dogs. IM dexmedetomidine given minutes before onset of infusion showed typical significant effects on cardiovascular parameters. Keywords cardiac output, cardiovascular, dexmedetomidine, infusion, LiDCO, lithium dilution. Introduction The alpha-2 agonist dexmedetomidine has been recommended to provide reliable sedation, analgesia and chemical restraint in dogs (Bloor et al. 1992; Kuusela et al. 2001; Alvaides et al. 2008; Congdon 464

2 et al. 2011). It has also been shown to reduce the requirement of isoflurane when administered as a bolus (Weitz et al. 1991) and also when used as a constant rate infusion in dogs (Pascoe et al. 2006; Uilenreef et al. 2008). The cardiovascular, respiratory and acid base changes from bolus administration of alpha-2 agonists have been well characterized in dogs in other studies (Bloor et al. 1992; Lemke et al. 1993; Alvaides et al. 2008; Congdon et al. 2011). Concern for the decrease in heart rate, cardiac output and subsequent potential for decreases in oxygen delivery associated with dexmedetomidine may lead to hesitation over the use of constant rate infusions despite its analgesic effects and reduction in requirements for inhaled anesthetics. Low dose dexmedetomidine infusions in the range of lg kg 1 hour 1 have been previously investigated and reported on in the literature (Pascoe 2005; Braz et al. 2008; Lin et al. 2008; Uilenreef et al. 2008) and have generally found that even low dose infusions have the typical cardiovascular responses seen at higher doses, while there is a trend toward increasing severity and duration of side effects as dose increases. Medetomidine infusions from lg kg 1 hour 1 have also been evaluated and have shown similar results (Grimm et al. 2005; Gomez-Villamandos et al. 2008; Carter et al. 2010; Kaartinen et al. 2010) with respect to increasing severity and duration of side effects with increasing dose. Many of these studies included an intravenous bolus or loading dose of dexmedetomidine or medetomidine before beginning infusion(s), in the range of lg kg 1. Only one study used a dose of 3 lg kg 1 administered intravenously (Uilenreef et al. 2008). Despite this wealth of information about infusions of these agents at low doses with or without small loading doses, to the author s knowledge no studies have evaluated these cardiovascular parameters of a microdose dexmedetomidine bolus and subsequent infusion in dogs after a larger intramuscular dose of dexmedetomidine at or near 10 lg kg 1. The purpose of the current study then, was to characterize cardiovascular, respiratory, acid base, hemoglobin and electrolyte changes during a 1 hour infusion of dexmedetomidine at 0.5 lg kg 1 hour 1 during isoflurane anesthesia following premedication with dexmedetomidine. Methods The design and methods for the current study were approved by the University s Institutional Animal Care and Use Committee. Five 1 year old male intact Walker Hound dogs weighing kg were used in this study. The dogs were found to be healthy on physical examination, were interacted with daily, fed twice daily and water was continuously available during non-testing periods. Food was withheld the morning of experiments. The dogs were restrained in lateral recumbency and instrumented with a 20-gauge (Becton Dickinson, Insyte, 48 mm, UT, USA) in the dorsal pedal artery, and two 18-gauge venous catheters in the cephalic and lateral saphenous veins. Lidocaine 0.2 ml was infused subcutaneously over the dorsal pedal artery 5 minutes prior to catheter placement to prevent pain from arterial catheter introduction. Catheters were flushed with 2 ml heparinized saline after placement. After instrumentation, the dogs were sedated with dexmedetomidine 10 lg kg 1 IM minutes before induction of general anesthesia for an unrelated study. Cardiovascular, respiratory and blood gas data were collected before IM dexmedetomidine for this unrelated study in the exact manner as done for the current study, as described below. At the completion of this study anesthesia was induced with propofol 2 mg kg 1 IV over 5 10 seconds to allow intubation. If orotracheal intubation was not possible, additional propofol boluses of 1 mg kg 1 boluses were given every seconds until intubation was possible. Study subjects were intubated and maintained with 1.5% isoflurane in oxygen. Dogs were placed in lateral recumbency after induction and allowed to breathe spontaneously for the duration of the study. Body temperature was maintained between 37.2 and 38 C by placing the dogs on an electric warming blanket (HotDog, Augustine Biomedical, MN, USA) and covering with blankets if necessary. Lactated Ringer s solution was delivered at 3 5 mlkg 1 hour 1 during general anesthesia via the cephalic catheter. Thirty minutes were allotted after induction for stabilization of depth of anesthesia before control measurements and onset of infusion. After baseline measurements, dexmedetomidine 0.5 lg kg 1 IV was administered with a precision syringe pump via the cephalic catheter as a loading dose over 5 minutes followed by a constant rate infusion of dexmedetomidine at 0.5 lg kg 1 hour 1 for 60 minutes. The dexmedetomidine bolus was started at minutes after IM dexmedetomidine premedication. Data for the current study were measured before the dexmedetomidine bolus ( baseline ) and then at 5, 30 and 60 minutes during the infusion. Data 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

3 collected included cardiac output (CO) using the lithium dilution technique per manufacturer instructions (LiDCO, Cambridge, UK), heart rate (HR), respiratory rate (f R ), direct arterial blood pressures (systolic arterial pressure SAP, mean arterial pressure MAP, diastolic arterial pressure DAP), esophageal temperature, arterial blood gases (ph, PaCO 2, PaO 2, SBE, HCO 3 ), electrolytes (Na +, K +, Cl, ica ++ ), lactate and blood glucose (BG) as well as a manual packed cell volume (PCV) and total protein (TP). The lateral saphenous IV catheter was reserved for lithium injections for CO measurement. Arterial blood samples were obtained by use of a three way stopcock attached between the arterial catheter and lithium sensor. 3 ml of blood was scavenged from the arterial catheter before sampling for blood gas analysis to prevent dilution with heparinized saline. Arterial blood gas samples were tested immediately (ABL800, Radiometer, Denmark) after sampling. The arterial blood sample was also tested with a co-oximeter (Radiometer, Denmark) for hemoglobin and hemoglobin saturation values at all time points. All dogs were continuously monitored for heart rate, electrocardiogram, direct blood pressures and body temperature using a commercially available PC based monitoring system (LabChart 7, AD Instruments, CO, USA). The arterial pressure transducer (MLT844 Physiological Pressure Transducer, AD Instruments, CO, USA) was zeroed to the patient at the level of the sternum while in lateral recumbency. The transducer was checked against a mercury manometer each day to a maximum pressure of 150 mmhg. At the completion of the study the dexmedtomidine infusion was discontinued and the dogs were transferred to the operating room and castrated. Dogs received ketoprofen 1mgkg 1 SC and were allowed to recover from anesthesia. All dogs were adopted to families at the completion of the study. Statistical analysis Data were analyzed using simple and multiple linear regression modeling accounting for repeated measures using commercially available software (Graph- Pad Prism, GraphPad Software, Inc. CA, USA). Means and standard deviations were calculated for each variable and are presented in this way in the results. Statistical significance was accepted at p < Results There were no significant differences in any measured variable as compared to pre-infusion baseline over the 60 minute study period. Post-hoc power calculation using cardiac output data (R 2 = 0.12, probability level = 0.05, n = 5) resulted in a low statistical power of 0.11 to detect the presence of a statistical difference should one have existed. Given lack of significant differences over time based on regression analysis, results during infusion (5, 30 and 60 minute time points) were averaged, compared to baseline values and these comparisons are described in the body of the text. Data for individual time points and results of regression analysis are reported in Tables 1 3. Cardiovascular Baseline cardiac output was L minute 1 and during infusion was L minute 1 (p = 0.10) (Table 1). Total number of lithium injections for cardiac output measurement was doses over 77 9 minutes. Baseline Table 1 Cardiovascular variables before and during dexmedetomidine infusion Time (minutes) Baseline p-value CO (L minute 1 ) HR (beats minute 1 ) SAP (mmhg) MAP (mmhg) DAP (mmhg) Control data points represent data collected minutes after dexmedetomidine 10 lg kg 1 IM, propofol induction and 30 minutes of isoflurane maintenance. The reported p-value was calculated to indicate the overall significance of the association between the independent variable and the outcome for each measured variable Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

4 HR was 62 5 beats minute 1 and during infusion was beats minute 1 (p = 0.07). Baseline SAP was mmhg and during infusion was mmhg (p = 0.13). Baseline MAP was mmhg during infusion was mmhg (p = 0.06). Baseline DAP was mmhg and during infusion was mmhg (p = 0.21). Sinus arrhythmia was the only observed arrhythmia noted at any time upon review of ECG recordings after the completion of data collection. Respiratory, core temperature and arterial blood gases Baseline f R was 11 2 breaths minute 1 and during infusion was 10 3 breaths minute 1 (p = 0.10) (Table 2). Baseline temperature was C and during infusion was C(p = 0.50). Baseline PaCO 2 was mmhg and during infusion was mmhg (p = 0.08). Baseline PaO 2 was and during infusion was mmhg (p = 0.59). Baseline SaO 2 was % and during infusion was % (p = 0.59). Acid base Baseline ph was and during infusion was (p = 0.08) (Table 2). Baseline HCO 3 was meq L 1 and during infusion was meq L 1 (p = 0.40). Baseline BE was meq L 1 and during infusion was meq L 1 (p = 0.59). Electrolytes, glucose, lactate Baseline sodium was meq L 1 and during infusion was meq L 1 (p = 0.6) (Table 3). Baseline potassium was meq L 1 and during infusion was meq L 1 (p = 0.44). Baseline chloride was meq L 1 and during infusion was meq L 1 (p = 0.6). Baseline ionized calcium was meq L 1 and during infusion was meq L 1 (p = 0.66). Baseline glucose was mg dl 1 and during infusion was mg dl 1 (p = 0.76). Baseline lactate was mmol L 1 and during infusion was mmol L 1 (p = 0.1). Table 2 Respiratory, arterial blood gas and co-oximeter variables, before and during dexmedetomidine infusion Time (minutes) Baseline p-value f R (breaths minute 1 ) Temp ( C) ph PaCO 2 (mmhg) PaCO 2 (kpa) PaO 2 (mmhg) PaO 2 (kpa) HCO 3 (mmol L 1 ) SBE (mmol L 1 ) SaO 2 (%) Tot Hb (g dl 1 ) CO-Hb (%) Met Hb (%) CaO 2 (ml dl 1 ) Hb-O 2 (%) RHb (%) O 2 -cap (%) Control data points represent data collected 78 minutes after dexmedetomidine 5 lg kg 1 IM, propofol induction and 30 minutes of isoflurane maintenance. f R, Respiratory rate; PaCO 2, arterial pressure of CO 2, PaO 2, arterial pressure of oxygen; HCO 3, Bicarbonate; SBE, standard base excess; SaO 2, arterial oxygen saturation; Tot Hb, total hemoglobin; CO-Hb, carboxyhemoglobin; Met Hb, methemoglobin; CaO 2, oxygen content; Hb-O 2, oxygenated hemoglobin; RHb, reduced hemoglobin; O 2 -cap, oxygen capacity. The reported p-value was calculated to indicate the overall significance of the association between the independent variable and the outcome for each measured variable Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

5 Time (minutes) Baseline p-value Na + (meq L 1 ) K + (meq L 1 ) Cl (meq L 1 ) ica ++ (meq L 1 ) Glucose (mg dl 1 ) Lactate (mmol L 1 ) PCV (%) TP (g dl 1 ) Table 3 Electrolyte variables before and during dexmedetomidine infusion Control data points represent data collected 78 minutes after dexmedetomidine 10 lg kg 1 IM, propofol induction and 30 minutes of isoflurane maintenance. The reported p-value was calculated to indicate the overall significance of the association between the independent variable and the outcome for each measured variable. Co-oximetry, PCV/TP measurements Baseline PCV was 44 2% and during infusion was 44 2%, p = 0.11 (Table 2). Baseline total protein was g dl 1 and during infusion was g dl 1 (p = 0.77). Baseline total hemoglobin was g dl 1 and during infusion was g dl 1 (p = 012). Baseline carboxyhemoglobin was % and during infusion was % (p = 0.41). Baseline methemoglobin was % and during infusion was % (p = 0.73). Baseline oxygen content was ml dl 1 and during infusion was ml dl 1 (p = 0.87). Baseline oxyhemoglobin was % and during infusion was % (p = 0.42). Baseline reduced hemoglobin was % and during infusion was % (p = 0.19). Discussion This study describes the cardiovascular, respiratory, PaO 2, PaCO 2, hemoglobin, carboxyhemoglobin, methemoglobin, ph, acid base, electrolytes, plasma glucose and lactate changes seen when dogs receive a loading dose of dexmedetomidine at 0.5 lg kg 1 IV administered over 5 minutes followed by an infusion of dexmedetomidine at 0.5 lg kg 1 hour 1. Our major finding was that no significant changes were observed when comparing pre-infusion baseline values to those measured during the continuous infusion of dexmedetomidine over 1 hour. These findings agree with results from a study in which dogs receiving dexmedetomidine at 0.5 lg kg 1 hour 1 during isoflurane anesthesia showed no response in any measured variable aside from a significant decrease in heart rate over a 3 hour infusion (Pascoe 2005). Significant cardiovascular side effects are to be expected from the initial intramuscular dose of dexmedetomidine and these have been described previously (Congdon et al. 2011). Elimination halflife of 10 lg kg 1 intravenous dexmedetomidine is reported to be hours (Kuusela et al. 2000), therefore some effect of this dose should be expected to be present at the onset of infusion dosing as this occurred minutes after initial dexmedetomidine IM bolus. Though cardiovascular effects of IM dexmedetomidine at 10 lg kg 1 have not been reported in the literature, effects of IM medetomidine at 20 lg kg 1 have been reported (Hayashi et al. 1995). That report found that cardiac index was significantly decreased from baseline at 120 minutes, therefore the current study data must be interpreted in light of the effect of IM dexmedetomidine. To evaluate any effect on measured variables from the 10 lg kg 1 IM dexmedetomidine in the current study, data are presented in Table 4 that show the pre-infusion baseline variables from the current study and the control values before the IM dexmedetomidine from the previous study (Congdon et al. 2011). These values suggest that cardiovascular side effects of IM dexmedetomidine were still present at the onset of the current study. As can be seen in Table 4, CO decreased from values before IM dexmedetomidine ( L minute 1 ) when compared to values immediately before dexmedetomidine infusion ( L minute 1 ). A number of variables could have contributed to the difference in CO at these time points including the negative inotropic Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

6 Table 4 Data collected before intramuscular dexmedetomidine, 10 lg kg 1, (reported in Congdon et al. 2011) and values obtained after induction of anesthesia with propofol and 30 minutes of isoflurane anesthesia but before dexmedetomidine infusion bolus. Time between these data points is minutes. Variable Pre-IM Dm time = 0 minutes Pre-Infusion bolus time = minutes CO (L minute 1 ) HR (beats minute 1 ) ph PaCO 2 (mmhg) PaO 2 (mmhg) SaO 2 (%) ica ++ (meq L 1 ) Total protein (g dl 1 ) HbO 2 (%) RHb (%) effects of propofol and isoflurane, however given the half-life of dexmedetomidine mentioned previously, this is likely to be due to a persistent effect of the IM dexmedetomidine. Both propofol (Quandt et al. 1998) and isoflurane (Steffey & Howland 1977; Jones & Snowdon 1986) are recognized respiratory depressants and induction and maintenance of anesthesia with these agents account for the increase in PaCO 2 ( mmhg before IM dexmedetomidine and mmhg preinfusion) and the subsequent decrease in ph ( pre-im dexmedetomidine and pre-infusion) seen during infusion measurements. Previous studies evaluating the respiratory changes from dexmedetomidine failed to show an increase in PaCO 2 despite a reduction in respiratory rate (Alvaides et al. 2008; Congdon et al. 2011). Comparing pre-im dexmedetomidine to preinfusion values, PaO 2, S a O 2 and HbO 2 increased because the F i O 2 increased from 0.21 to Ionized calcium measurements have been shown to decrease with increases in ph (Wang et al. 2002) so it is likely that the increase in ionized calcium could be due to the decrease in ph as a result of the respiratory acidosis. Total protein may have decreased due to intravenous fluid therapy during general anesthesia. In summary, the previously reported changes in the described cardiovascular parameters are to be expected from the intramuscular dexmedetomidine. However, in the described clinical scenario of dexmedetomidine microdose (0.5 lg kg 1 ) followed by infusion (0.5 lg kg 1 hour 1 ) after IM dexmedetomidine, we have shown that there are no further depressant effects on cardiovascular function during dexmedetomidine infusion. To the authors knowledge this appears to be only the second paper to evaluate cardiac output during dexmedetomidine infusion under general anesthesia in the veterinary literature. Recent studies have evaluated dexmedetomidine infusions of lg kg 1 minute 1 after small bolus doses in the range of lg kg 1 IV (Pascoe et al. 2006; Uilenreef et al. 2008). A previous study evaluated a 25 lg m 2 (~1 lg kg 1 ) IV bolus followed by 25 lg m 2 minute 1 (~1 lg kg 1 minute 1 ) infusion during propofol or isoflurane maintained general anesthesia (Lin et al. 2008). Cardiac output decreased significantly during the initial 5 minutes of infusion and remained below baseline for the duration of general anesthesia. These results conflict with the current study but we had already administered dexmedetomidine prior to our baseline measurements. Significant bias and drawbacks exist in this study. Clearly the inclusion of intramuscular dexmedetomidine very likely continued to have an effect during dexmedetomidine infusion as a variety of parameters had not returned to pre-intramuscular values as compared to infusion baseline data. Results and conclusions of this study must be considered relative to this effect. However, the observation that no additional decrease in cardiovascular parameters, blood gas changes, respiratory parameters and electrolytes after the onset of infusion is a valid and clinically relevant observation. During the execution of the study concern arose regarding the function of the LiDCO cardiac output monitoring system, and the accuracy of the results during measurement. HR averaged beats minute 1 during the study and was often irregular due to a sinus arrhythmia. The LiDCO sensor requires that blood be drawn at 4 ml minute 1 over the lithium sensor to create the curve for measurement of CO. There were data points where repeat lithium dilution CO analysis was necessary to generate a smooth curve because initial measurement failed to generate a CO value. It was thought that one source of error might be the low and irregular heart rate, but further study would be required to investigate this hypothesis Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

7 LiDCO compared to thermodilution cardiac output (TDCO) had a very high correlation coefficient of with thermodilution (Mason et al. 2001). Lithium dilution cardiac output via the LiDCO system has been used successfully for measurement of CO for studies evaluating medetomidine infusions (Carter et al. 2010; Kaartinen et al. 2010) with no complications reported. LiD- CO has also been employed to measure CO in horses after alpha-2 premedication with no measurement complications reported (Ringer et al. 2007; Kalchofner et al. 2009). LiDCO has been compared to TDCO in horses and LiDCO measurements differed only by 4% (r = 0.94) from TDCO values (Linton et al. 2000). Given the studies comparing traditional TDCO measurement and the correlation of the LiDCO method to TDCO we thought that employing LiDCO in this study was relevant and appropriate and would allow valid interpretation of data while employing a less invasive technique for CO measurement in our study population. All data reported in this study were taken from ideal curves produced from the LiDCO computer and repeat measurements during the study period were performed to ensure proper measurements. Lithium accumulation was not a concern in this study as total lithium injections averaged doses over minutes. The LiDCO manufacturer has set a serum lithium concentration of 0.2 mmol L 1 beyond which the CO measurement in this system is unreliable due to interference at the lithium sensor from background concentrations of lithium. Previous work has shown that to reach a serum lithium concentration of 0.1 mmol L 1 would require 16 injections of the manufacturer recommended dose of lithium over a 3 7 hour period (Mason et al. 2002). Summary This study evaluated the cardiorespiratory, acidbase, electrolyte and blood gas alterations in response to a 0.5 lg kg 1 IV dexmedtomidine bolus followed by a 0.5 lg kg 1 hour 1 IV dexmedetomidine infusion in propofol-isoflurane anesthetized dogs that had received a 10 lg kg 1 IM premedication before induction of anesthesia. Expected changes in CO, HR, temperature, ph, PaCO 2, PaO 2, SaO 2, total protein and reduced hemoglobin were seen after the intramuscular dexmedetomidine before the onset of the current study. However, no additional changes of significance were seen in any study variable in response to dexmedtomidine bolus or infusion over 1 hour. To the author s knowledge, this is the first study to have evaluated a dexmedetomidine infusion in dogs after an intramuscular dose of 10 ug kg 1, and showed that there were no further cardiovascular and respiratory changes with an IV loading dose of 0.5 lg kg 1 and a 0.5 lg kg 1 minute 1 CRI for 1 hour. Acknowledgements The authors would like to thank Dr. Sangeeta Rao and Dr. Francisco Olea-Popelka and Colorado State University s Research and Statistical Support Services program for their assistance in the statistical analysis of this data. References Alvaides RK, Neto FJ, Aguiar AJ et al. (2008) Sedative and cardiorespiratory effects of acepromazine or atropine given before dexmedetomidine in dogs. Vet Rec 162, Bloor BC, Frankland M, Alper G et al. (1992) Hemodynamic and sedative effects of dexmedetomidine in dog. J Pharmacol Exp Ther 263, Braz LG, Braz JR, Castiglia Y et al. (2008) Dexmedetomidine alters the cardiovascular response during infra-renal aortic cross-clamping in sevofluraneanesthetized dogs. J Invest Surg 21, Carter JE, Campbell NB, Posner LP et al. (2010) The hemodynamic effects of medetomidine continuous rate infusions in the dog. Vet Anaesth Analg 37, Congdon JM, Niyom S, Marquez M et al. (2011) Evaluation of the sedative and cardiovascular effects of intramuscular administration of dexmedetomidine with and without concurrent atropine administration in dogs. J Am Vet Med Assoc 239, Gomez-Villamandos RJ, Palacios C, Benitez A et al. (2008) Effect of medetomidine infusion on the anaesthetic requirements of desflurane in dogs. Res Vet Sci 84, Grimm KA, Tranquilli WJ, Gross DR et al. (2005) Cardiopulmonary effects of fentanyl in conscious dogs and dogs sedated with a continuous rate infusion of medetomidine. Am J Vet Res 66, Hayashi K, Nishimura R, Yamaki A et al. (1995) Cardiopulmonary effects of medetomidine, medetomi dine-midazolam and medetomidine-midazolam-atipamez ole in dogs. J Vet Med Sci 57, Jones RS, Snowdon SL (1986) Experimental investigation of the cardiovascular and respiratory effects of increasing concentrations of isoflurane in the dog. Res Vet Sci 40, Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 40,

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