Veterinary Anaesthesia and Analgesia, 2015, 42,

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1 Veterinary Anaesthesia and Analgesia, 2015, 42, doi: /vaa RESEARCH PAPER A comparison of cardiopulmonary function, recovery quality, and total dosages required for induction and total intravenous anesthesia with propofol versus a propofol-ketamine combination in healthy Beagle dogs Martin J Kennedy & Lesley J Smith Section of Anesthesia and Pain Management, Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA Correspondence: Lesley J Smith, Section of Anesthesia and Pain Management, Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706, USA. smithl@svm.vetmed.wisc.edu Abstract Objective To compare cardiopulmonary function, recovery quality, and total dosages required for induction and 60 minutes of total intravenous anesthesia (TIVA) with propofol (P) or a 1:1 mg ml 1 combination of propofol and ketamine (KP). Study design Randomized crossover study. Animals Ten female Beagles weighing kg. Methods Dogs were randomized for administration of P or KP in a 1:1 mg ml 1 ratio for induction and maintenance of TIVA. Baseline temperature, pulse, respiratory rate (f R ), noninvasive mean blood pressure (MAP), and hemoglobin oxygen saturation (SpO 2 ) were recorded. Dogs were intubated and spontaneously breathed room air. Heart rate (HR), f R, MAP, SpO 2, end tidal carbon dioxide tension (PE CO 2 ), temperature, and salivation score were recorded every 5 minutes. Arterial blood gas analysis was performed at 10, 30, and 60 minutes, and after recovery. At 60 minutes the infusion was discontinued and total drug administered, time to extubation, and recovery score were recorded. The other treatment was performed 1 week later. Results KP required significantly less propofol for induction ( mg kg 1 KP versus mg kg 1 P, p = ) and maintenance ( mg kg 1 minute 1 KP versus mg kg 1 minute 1 P, p = ). Significantly higher HR occurred with KP. Both P and KP caused significantly lower MAP compared to baseline. MAP was significantly higher with KP at several time points. P had minimal effects on respiratory variables, while KP resulted in significant respiratory depression. There were no significant differences in salivation scores, time to extubation, or recovery scores. Conclusions and clinical relevance Total intravenous anesthesia in healthy dogs with ketamine and propofol in a 1:1 mg ml 1 combination resulted in significant propofol dose reduction, higher HR, improved MAP, no difference in recovery quality, but more significant respiratory depression compared to propofol alone. Keywords anesthesia, cardiopulmonary, constant rate infusion, dogs, ketofol, propofol. Introduction Dogs frequently undergo general anesthesia for a variety of minimally invasive procedures and inha- 350

2 lation anesthesia is the most commonly used method of general anesthesia for these procedures. Inhalation anesthesia requires specialized equipment for the delivery of oxygen and anesthetic agent as well as a means to eliminate exhaled CO 2 and anesthetic. Injectable anesthetic agents, such as propofol or ketamine, offer an alternative option for procedures of short duration or when inhalation anesthesia may not be possible or practical, such as bronchoscopy, tracheoscopy, laryngeal examination, or magnetic resonance imaging. Propofol will provide rapid and smooth induction and maintenance of anesthesia, however, it causes dose dependent respiratory depression and hypotension (Pagel & Warltier 1993; Nagashima et al. 1999, 2000; Aguiar et al. 2001). Ketamine can also be used for the induction and maintenance of anesthesia. Ketamine is unique among anesthetics in that it maintains or increases cardiac output (CO) as a result of increased sympathetic efferent activity (Wong & Jenkins 1974), except under conditions of catecholamine depletion where ketamine may act as a direct myocardial depressant (Pagel et al. 1992). Ketamine can also be associated with muscle rigidity, convulsions, and violent recoveries (Haskins et al. 1985), thus it is often used in conjunction with a benzodiazepine. A study investigating the combination of propofol with ketamine on the cardiopulmonary changes in dogs during induction of anesthesia, ketamine combined with propofol allowed a dose reduction of propofol and resulted in better maintenance of mean arterial pressure (MAP) with increased CO and oxygen delivery compared to propofol alone (Henao-Guerrero & Ricco 2014). Administration of a ketamine infusion to dogs during isoflurane anesthesia permitted a reduction in isoflurane concentration, resulting in improved hemodynamics, ventilation, and oxygenation (Boscan et al. 2005). The addition of ketamine to propofol for induction and maintenance of injectable anesthesia may partly offset the cardiovascular depression induced by administration of propofol. In addition, any propofol dose reduction afforded by the co-administration of ketamine may have the potential to reduce the dose dependent respiratory depression observed with a continuous infusion of propofol alone in dogs. The purpose of this investigation was to compare a ketamine-propofol combination to propofol alone for induction and constant rate infusion (CRI) maintenance for total intravenous anesthesia (TIVA) in unpremedicated healthy dogs. The hypotheses were that ketamine added to propofol in a 1:1 mg ml 1 mixture used as TIVA would 1) provide improved hemodynamic and respiratory function during a 60 minute anesthetic period compared to TIVA with propofol alone, 2) would not result in adverse recovery quality, and 3) would reduce the dose of propofol needed for both induction and maintenance of anesthesia. Materials and methods Animals The study was approved by the Institutional Animal Care and Use Committee. Ten healthy adult female Beagle dogs were used in this study (Ridgelan Laboratories, WI, USA). A week prior to the study all dogs were confirmed healthy based on physical examination and evaluation of a complete blood count and serum biochemistry profile. All dogs were withheld from food for 12 hours before anesthesia but had free access to water. All dogs were in anestrus at the time of both treatments. Experimental design The study was a randomized, blinded, placebocontrolled crossover trial. A pharmacist used a randomization table to assign each dog to receive one of two anesthetic treatments: P, induction and maintenance of anesthesia with propofol (PropoFlo; Abbott Animal Health, IL, USA) alone; or KP, induction and maintenance of anesthesia with propofol and ketamine (Ketaset; Fort Dodge Animal Health, IA, USA) in a 1:1 mg ml 1 ratio. Each dog underwent a second anesthesia 1 week later with the other treatment. The investigators were unaware of which treatment was being administered until the completion of the study when all dogs had received both treatments. Procedure A baseline temperature, pulse (HR, beats minute 1 ), respiratory rate (f R, breaths minute 1 ), noninvasive mean arterial blood pressure (MAP, mmhg) (Cardell 9402; Sharn Vet Inc., FL, USA), and hemoglobin oxygen saturation (SpO 2 ) (Nonin Life Sense; Nonin Medical, MN, USA) were obtained and recorded prior to the administration of any treatment. A 20 gauge intravenous (IV) catheter (Abbott Animal Health) was aseptically placed percutaneously in a cephalic vein of each dog for drug administration. Each dog Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

3 was assigned three syringes, with each syringe containing 20 ml of propofol mixed with either 2 ml of saline (P) or 2 ml of ketamine (KP). The final concentration of drug administered was either 9.1 mg ml 1 propofol (P) or 9.1 mg ml 1 propofol and 9.1 mg ml 1 ketamine (KP). In this study, unmarked syringes (ketamine or saline) were mixed with propofol immediately prior to administration, such that no dog was administered any drug combination that had been mixed for more than 1 hour. All the components of anesthesia (i.e. intubation, assessment of depth, adjustment of drug administration rate, determination of extubation time, and scoring recovery) were done by the same anesthetist (MK) who was unaware of the treatment. Anesthesia was induced by IV administration of the treatment drug(s) to effect at a rate of approximately 1 ml per 15 seconds until endotracheal intubation could be accomplished. The dogs were allowed to spontaneously breathe room air. Anesthesia was maintained by administration of the treatment drug by CRI using a syringe pump (Medfusion 2010; Medex Inc., GA, USA). One syringe pump was used for all treatments and was programmed to deliver the treatment drug on a mg kg 1 minute 1 rate based on a propofol concentration of 9.1 mg ml 1. Each dog was positioned in left lateral recumbency on a heated surgery table (VSSI Inc., MO, USA) and monitored using noninvasive blood pressure, pulse oximeter, and capnometer (Nonin Life Sense; Nonin Medical). The pulse oximeter probe was placed on the tongue. A blood pressure cuff width of approximately 40% the limb circumference was placed just proximal to the tarsus on the right pelvic limb. A 22 gauge catheter was aseptically placed percutaneously in a dorsal pedal artery, or the coccygeal artery if attempts in the dorsal pedal arteries were unsuccessful. SpO 2, MAP, HR, f R, and end tidal carbon dioxide tension (PE CO 2, mmhg) were monitored continuously and recorded every 5 minutes. Rectal temperature (Jorgensen Labs, CO, USA) and salivation (using a three point scale: 1) minimum; 2) moderate; 3) extreme) were recorded every 5 minutes. Apnea was defined as no spontaneous breathing for 30 seconds. In the event that apnea occurred, the adverse respiratory event was recorded and the patient received one manual breath with a resuscitator bag every 30 seconds until spontaneous breathing resumed. Blood was collected from the arterial catheter into a 1 ml heparinized syringe (Smiths Medical Inc., NH, USA) for blood gas analyses at 10, 30, and 60 minutes after induction, and once the animal was considered fully recovered from anesthesia. The 10 minute arterial blood was collected directly into the heparinized syringe upon catheter placement and the catheter was then flushed with 0.5 ml of heparinized saline (PreFill IV Flush; Covidien, MA, USA). For subsequent arterial sample collections, 1.0 ml of blood was first aspirated and discarded, then 0.5 ml was collected for analysis, and then the catheter was then flushed with 0.5 ml of heparinized saline. The final arterial blood gas sample taken at the time of full recovery was used as each animal s baseline due to the inability to place an arterial catheter prior to anesthesia under the conditions of this study. Arterial blood was analyzed immediately for ph, partial pressures of oxygen (PaO 2 ) and carbon dioxide (PaCO 2 ), and base excess with an istat point of care analyzer (Vetscan; Heska Corp., CO, USA). Arterial blood gas results were corrected for temperature using the rectal temperature measured at the time of sample collection. The objective was to maintain the lightest plane of anesthesia that prevented purposeful movement. Assessment of anesthetic depth was based on ocular reflexes, jaw tone, presence or absence of swallowing, presence or absence of limb withdrawal in response to toe pinching, and presence or absence of anal tone in response to obtaining a rectal temperature. Immediately after endotracheal intubation, the CRI was administered at a starting rate of 0.4 mg kg 1 minute 1 of propofol. Anesthetic depth was monitored at least once every minute and the CRI rate was adjusted up or down in mg kg 1 minute 1 increments based on assessment of clinical signs of anesthetic depth. If a given dog s plane of anesthesia was deemed too light for the patient to remain intubated, then a bolus of 0.5 mg kg 1 was administered using the syringe pump. The CRI was discontinued after 60 minutes and the total volume of treatment drug administered for both induction and maintenance of anesthesia was recorded. Dogs were extubated when there was an adequate swallow reflex to protect the airway and the time to extubation was recorded. The quality of recovery was scored using a 5 point scale: 1) smooth, quiet, nonvocal without paddling or flailing; 1.5) some minor paddling of short duration but no vocalization or uncoordinated movement; 2) some vocalization, paddling or uncoordinated movement but of short duration and easily calmed; 2.5) some vocalization with paddling or uncoordinated 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

4 movement of moderate duration and severity; 3) emergence delirium with excessive vocalizing and uncoordinated movement. A dog was considered to be fully recovered from anesthesia when it assumed sternal or standing position and was observed to respond to auditory, visual and tactile stimulation with mental alertness similar to before anesthesia. After arterial blood was collected for analysis, both IV and arterial catheters were removed and the dogs were returned to their normal housing. Statistical methods Data were analyzed for normality with a Shapiro- Wilk test. Normally distributed data are reported as mean (SD) and nonparametric data are reported as median (range). The amount of treatment drug required and time to extubation were analyzed with paired t-tests. Recovery and salivation scores were nonparametric and thus were analyzed with a Wilcoxon matched pairs signed rank test. HR, MAP, SpO 2,PE CO 2, f R, and blood gas results were analyzed with a two way ANOVA for repeated measures with a Sidak s multiple comparisons test for significance. Statistical significance was determined by p < All statistical analyses were performed with commercially available software (Prism 6; Graphpad, CA, USA). Results The dogs were a median age of 2.3 ( ) years and weighed kg. The dose rate of propofol required for induction of anesthesia was significantly lower with KP versus P(p = ), as well as for maintenance of anesthesia (p = ) (Table 1). All of the dogs were intubated without difficulty. None of the dogs experienced excessive salivation during treatment with KP and there was no significant difference in salivation scores between treatments (Table 1). Both anesthetic protocols resulted in a slight decrease in body temperature during the 60 minutes of anesthesia; F ( C) for P versus F ( C) for KP (p = 0.062). All dogs had an acceptable recovery from anesthesia. Recoveries were either smooth or there was minor paddling of short duration with no significant difference in recovery score or time to extubation between treatments (Table 1). There was no significant difference between treatments with respect to baseline (time 0) cardiopulmonary values (Figs 1 & 2, Tables 2 & 3). Treatment with P did not significantly affect HR; treatment with KP resulted in significantly higher HR with the maximum value reaching beats minute 1 at 10 minutes and then gradually decreasing to beats minute 1 at 60 minutes (Fig. 1). Treatment with P resulted in MAP significantly lower than baseline at all time points (Fig. 2). Beyond the first 5 minutes of the anesthetic period treatment with KP, MAP was significantly lower compared to baseline values, however, MAP was significantly higher with KP compared to P at 10, 25, 30, 35, 40, 50, and 55 minutes (Fig. 2). The highest MAP was observed at 5 minutes for both P and KP, mmhg and mmhg, respectively. For P the lowest MAP (78 7 mmhg) occurred at 40 minutes, while for KP the lowest MAP was at 45 minutes (91 20 mmhg). There were three apneic episodes, one with P and two with KP, with no significant difference between treatments. SpO 2 measured via pulse oximetry did not significantly differ from baseline during treatment with P, whereas treatment with KP resulted in significantly lower SpO 2 at several time points compared to P (Table 2), reaching the lowest value of 78 10% at 10 minutes. Five dogs in P and all Table 1 Drug requirements, extubation times, and scoring of induction, maintenance, salivation, and recovery of total intravenous anesthesia for 60 minutes with propofol only (P) or propofol and ketamine (KP) in 10 female Beagle dogs. See text for explanation of salivation and recovery scoring Treatment Induction dose (mg kg 1 ) CRI dose (mg kg 1 minute 1 ) Salivation score (0 3) Time to extubation (minutes) Recovery score (1 3) P (0 1) (1 2) KP *, *, 0(0 1) (1 2) CRI, Constant rate infusion. Normally distributed data are mean SD and nonparametric data are median (range). *Dose rates are the same for propofol and ketamine. Significantly different between treatment groups (p < 0.05) Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

5 Figure 1 Heart rate (HR) before (time 0) and during total intravenous anesthesia for 60 minutes with propofol (P, propofol mg kg 1 followed by mg kg 1 minute 1 ) or propofol and ketamine (KP, mg kg 1 each of propofol and ketamine followed by mg kg 1 minute 1 of each drug) in 10 female Beagle dogs. *Statistical significance between treatment groups (p < 0.05). Statistical significance compared to time 0 (p < 0.05). Figure 2 Mean arterial pressure (MAP) before (time 0) and during total intravenous anesthesia for 60 minutes with propofol (P, propofol mg kg 1 followed by mg kg 1 minute 1 ) or propofol and ketamine (KP, mg kg 1 each of propofol and ketamine followed by mg kg 1 minute 1 of each drug) in 10 female Beagle dogs. *Statistical significance between treatment groups (p < 0.05). Statistical significance compared to time 0 (p < 0.05). dogs in KP developed hypoxemia (SpO 2 < 92%) (p = 0.032). The duration of hypoxemia in P was minutes and in KP was minutes (p < 0.001). PE CO 2 was significantly higher at several time points in KP compared to P, reaching a maximum of 44 3 mmhg ( kpa) at 60 minutes (Table 2). Treatment with P and with KP both resulted in a significant reduction in f R compared to baseline, and treatment with KP Table 2 Noninvasive respiratory variables recorded before anesthesia (time 0) and during total intravenous anesthesia for 60 minutes with propofol (P) or propofol and ketamine (KP) in 10 female Beagle dogs. The treatment was administered IV for induction of anesthesia (P: mg kg 1 propofol; KP: mg kg 1 propofol and mg kg 1 ketamine) and as a constant rate infusion for maintenance (P: mg kg 1 minute 1 propofol; KP: mg kg 1 minute 1 propofol and mg kg 1 minute 1 ketamine) while the dogs spontaneously breathed room air Time (minutes) Variable Treatment SpO2 (%) P KP *, 78 10*, 79 11*, 83 8*, * PE CO2 (mmhg) P KP * 44 3* * * 43 2* 44 3* f R (breaths minute 1 ) P KP *, *, 10 3*, 12 6 SpO 2, hemoglobin oxygen saturation; PE CO 2, end tidal carbon dioxide partial pressure; f R, respiratory rate. *Significant difference between treatments at that time point (p < 0.05). Significantly different from time 0 (p < 0.05) Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

6 resulted in significantly lower f R than treatment with P at 15, 50, and 55 minutes (Table 2). Due to technical difficulty in placing arterial catheters in 3 of the dogs (three dogs during P and one dog during KP), only seven paired sets of arterial blood gas measurements were obtained for both treatments and used for statistical analysis. Treatment with KP or P did not result in any significant change in arterial blood ph or base excess compared to baseline (Table 3). PaO 2 did not significantly change from baseline during treatment with P and was significantly higher compared to KP at 10 minutes. Treatment with KP resulted in significantly lower PaO 2 at 10 and 30 minutes when compared to baseline (Table 3), with the lowest value mmhg ( kpa) occurring at 10 minutes. KP resulted in a significantly higher PaCO 2 compared to P at 10 minutes (Table 3). PaCO 2 was significantly increased at 30 minutes compared to baseline with P, and significantly increased at 10, 30, and 60 minutes with KP, with the maximum value of 43 2 mmhg ( kpa) at 30 minutes (Table 3). Discussion In the current study, addition of ketamine to propofol on a 1:1 mg ml 1 basis resulted in a 25% reduction ( mg kg 1 versus mg kg 1 ) in the dose rate of propofol required for orotracheal intubation and a 50% reduction ( mg kg 1 minute 1 versus mg kg 1 minute 1 ) in the dose rate of propofol required for maintenance of TIVA in nonpremedicated healthy dogs. Previous studies in premedicated dogs have demonstrated similar reductions in the amount of propofol required for induction and maintenance of anesthesia when ketamine was co-administered (Lerche et al. 2000; Seliskar et al. 2007; Mannarino et al. 2012; Henao-Guerrero & Ricco 2014), while some investigators reported that the addition of ketamine had no influence on the dose rate of propofol required for orotracheal intubation in premedicated dogs (Mair et al. 2009). The lack of propofol reduction observed by Mair et al. (2009) is likely due to the smaller doses of ketamine that were used in that study in comparison to the doses used in the present study and in other studies. The propofol dose reductions observed in the study reported here suggest a 30% reduction in overall drug cost with KP compared to P used alone, based on current pricing at our pharmacy. Monitoring arterial blood pressure in anesthetized patients reveals trends in their cardiovascular status. Maintaining MAP is important because it represents the mean driving pressure for vital organ perfusion (Haskins 2007), and thus it has been recommended that MAP in an anesthetized patient should be maintained within 20% of the awake value (White & Eng 2009). It is also critical that MAP not be maintained at the cost of tissue perfusion, so that MAP should be maintained by supporting CO rather Table 3 Arterial ph, partial pressures of oxygen (PaO 2 ) and carbon dioxide (PaCO 2 ), and Base excess measured during 60 minutes of total intravenous anesthesia with propofol (P) or propofol and ketamine (KP) in 10 female Beagle dogs spontaneously breathing air. See Table 2 for drug dose rates. Baseline (BL) values were measured after the dogs recovered from anesthesia Time (minutes) Variable Treatment BL ph P KP PaO 2 (mmhg) (kpa) PaCO 2 (mmhg) (kpa) Base excess (mmol L 1 ) P (12 1) (11 3) 76 7 (10 1) (11 2) KP 87 9 (12 1) 55 12*, (7 2) (9 2) (10 2) P ( ) ( ) ( ) ( ) KP ( ) *, ( ) ( ) ( ) P KP *Significantly different between treatments at that time point (p < 0.05). Significantly different from BL (p < 0.05) Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

7 than the result of excessive vasoconstriction. In the present study, MAP in KP was within 20% of the baseline value for 7 of the 12 time points and within 25% of the baseline value for all 12 time points. In contrast, MAP in P was within 20% of the baseline value for only 1 of the 12 time points and within 25% of the baseline value for only 2 of the 12 time points. Based on these recommendations, in this study TIVA with KP supported MAP better compared to TIVA with P alone. Henao-Guerrero & Ricco (2014) made similar observations when comparing propofol to propofol and ketamine for induction of anesthesia. In their study, dogs induced with propofol alone experienced significant decreases in MAP, while dogs induced with ketamine and propofol were able to maintain their MAP at pre-induction values. Seliskar et al. (2007) also observed higher MAP with ketamine-propofol TIVA compared to propofol alone in dogs premedicated with medetomidine. Propofol TIVA in dogs is associated with dose dependent hypotension due to reductions in both myocardial contractility and systemic vascular resistance (SVR) (Pagel & Warltier 1993; Nagashima et al. 1999, 2000). In this study, treatment with KP also resulted in significantly lower MAP when compared to baseline, however, the addition of ketamine attenuated some of the decrease in MAP observed with P alone. The improved MAP observed with KP can be explained in part by the dose reduction of propofol required for both induction and maintenance. The administration of ketamine also indirectly stimulates the cardiovascular system, via catecholamine release, resulting in increased HR and MAP (Tweed et al. 1972; Wong & Jenkins 1974), however, with catecholamine depletion or lack of an intact autonomic nervous system ketamine can be a myocardial depressant (Traber & Wilson 1969; Pagel et al. 1992). Previous studies in dogs using similar induction doses of ketamine (5 mg kg 1 ) have demonstrated increased MAP as a result of increased HR and CO with no change in SVR (Traber et al. 1970a,b, 1971; Priano et al. 1973). In those studies the increase in HR was comparable to that observed in the study reported here following ketamine administration, with the duration of effect lasting 30 minutes. The longer duration of increased HR observed in our study was likely due to the KP CRI prolonging the initial effects of the induction dose of ketamine. During treatment with KP the HR was elevated above the normal upper limit for healthy dogs for the first 25 minutes (Haskins et al. 2005), however, a similar range of HR has been shown to provide optimum MAP and CO without compromising coronary blood flow in instrumented dogs with normal hearts (Pitt & Gregg 1968). Henao-Guerrero & Ricco (2014) also observed that dogs induced with ketamine and propofol had improved MAP due to significantly increased HR, increased CO, and a decrease in SVR. The smaller increase in HR observed in that study was likely an attenuated response to the ketamine due to premedication (Haskins et al. 1986; Jacobson et al. 1994). Other investigators have found ketamine administration to significantly increase MAP in hypovolemic dogs by increasing the HR without affecting SVR (Haskins & Patz 1990). In contrast, Mannarino et al. (2012) failed to observe any difference in MAP comparing ketamine-propofol-lidocaine to propofol alone for TIVA in dogs despite achieving a significant dose reduction in propofol. In that study there was no significant difference in HR or cardiac index between treatments, although one possible explanation could be that the dose of ketamine (1 mg kg 1 ) may have been insufficient to produce the higher HR and improved MAP observed in other studies. Based on the results of the study reported here and the other studies referenced above, the increase in HR appears crucial to any increase in MAP that may result from administration of ketamine. One of the proposed advantages of a ketaminepropofol combination compared to propofol alone is that any reduction in propofol dose could result in less respiratory depression (Andolfatto & Willman 2010; Singh et al. 2010; Henao-Guerrero & Ricco 2014). In the present study, however, treatment with KP resulted in more severe respiratory depression than treatment with P as indicated by the significantly lower PaO 2, lower SpO 2, higher PE CO 2, and higher PaCO 2 observed at various time points. The magnitude of increase in PaCO 2 observed here with KP was comparable to that observed by Aguiar et al. (2001) when administering propofol TIVA to premedicated dogs at similar infusion rates. Seliskar et al. (2007) compared ketamine and propofol to propofol alone for TIVA in dogs premedicated with medetomidine and found that treatment with ketamine and propofol resulted in significantly higher PaCO 2 and lower minute ventilation despite the 50% reduction in propofol dose, and concluded that the negative respiratory effects of ketamine and propofol were additive. In the current study, the lower PaO 2 observed with KP was possibly the result of hypoventilation with increased ventilation-perfusion mis Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

8 match compared to treatment with P, though neither minute ventilation nor alveolar-arterial oxygen gradients were measured making such conclusions speculative. A study comparing a 1:1 mg ml 1 mixture of ketamine and propofol to propofol alone for induction of anesthesia in premedicated dogs found that apnea was more common in the dogs receiving propofol and ketamine (Lerche et al. 2000). The authors concluded that ketamine exacerbated the respiratory depressant effects of propofol and that the dose of ketamine was likely higher than needed. Other investigators have found a similar incidence of apnea when comparing ketamine and propofol to propofol alone for induction of premedicated dogs (Mair et al. 2009). In the present study there was no significant difference in the prevalence of apnea between anesthetic protocols, then again only 10 dogs were studied. PaO 2 was significantly lower and PaCO 2 significantly higher during the time period immediately following induction with KP which supports a finding of more severe respiratory depression immediately after induction with KP compared to P. Henao-Guerrero & Ricco (2014) also found no difference in the occurrence of apnea between treatments when comparing induction with propofol versus propofol and ketamine. In addition, they found both treatments resulted in similar prevalence of hypoxemia although PaCO 2 was significantly elevated only with ketamine and propofol. The respiratory depression observed in KP may be due to additive respiratory depressant effects of ketamine and propofol and/or a relative overdose of ketamine (Lerche et al. 2000; Seliskar et al. 2007). Propofol decreases the ventilatory response to CO 2 and arterial hypoxemia due to its effects on the central chemoreceptors, with the magnitude of respiratory depression being directly related to the concentration of propofol in the central nervous system (CNS) (Blouin et al. 1993). Ketamine also alters the ventilatory response to CO 2, but the effects differ depending on dosage and rate of administration. Bolus doses of ketamine cause a significant decrease in the slope of the CO 2 response curve in dogs (Hirshman et al. 1975), while an infusion results in a shift of the CO 2 response curve to the right without a change in slope (Hamza et al. 1989). These differing effects of ketamine on the slope of the CO 2 response curve appear to be related to the difference in CNS concentrations of ketamine following an IV bolus versus a CRI (Idvall et al. 1979; Hamza et al. 1989). Given that ketamine has been reported to act on l opioid receptors and that its effects on ventilation are qualitatively similar to that of l opioids, and that administration of l opioids enhances the respiratory depression caused by propofol administration (Hamza et al. 1989; Lamont & Mathews 2007), it is reasonable to propose that ketamine similarly enhanced the respiratory depressant effects of propofol under the conditions of this study. Treatment with KP leading to greater respiratory depression with less cardiovascular depression may be advantageous in certain circumstances, such as long term ventilation in the intensive care unit, nevertheless our study period was only 60 minutes and further investigations of longer duration of anesthesia are needed before such recommendations can be made. The dosing strategy used in this study may have contributed to the more severe respiratory depression observed in the KP dogs. The decision to use ketamine and propofol in a 1:1 mg ml 1 combination was based on the use of this particular ratio for procedural sedation in humans (Willman & Andolfatto 2007; Rapeport et al. 2009; Andolfatto & Willman 2010; Weatherall & Venclovas 2010). In addition, mixing ketamine and propofol could potentially result in destabilization of propofol s lipid emulsion and produce emboli; ketamine and propofol in a 1:1 mg ml 1 combination mixed in the same syringe has been shown to be physically compatible for at least 3 hours (Donnelly et al. 2008). Since ketamine s respiratory depressant effects are dose dependent, it is possible that a reduced ratio of ketamine to propofol may have resulted in less respiratory depression. Further studies would be required to optimize the ketamine to propofol ratio. There are several limitations to this study. Only 10 dogs were used, yet the blinded crossover design would allow a smaller sample size to demonstrate an effect of treatment. The major cardiovascular variable measured in this study was blood pressure and the measurements were obtained with a noninvasive oscillometric device. Although direct blood pressure measurement is the gold standard, oscillometric MAP measurements made on the pelvic limb with the cuff proximal to the tarsus and the dog in lateral recumbency have demonstrated reasonable bias and precision compared to direct blood pressure monitoring for the range of MAP reported in this study (Bosiack et al. 2010). In addition, any bias introduced by this method of blood pressure measurement was the same for both treatments. It would Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

9 have been ideal to also measure stroke volume and SVR for a more thorough evaluation of the effects of these treatments on the cardiovascular system, though this type of invasive monitoring requires specialized equipment and prior anesthesia for instrumentation of the dogs and that was not possible under the conditions of the study. Conclusions made about the effects of KP and P on alveolar ventilation were inferred based on only a few significant differences in f R, while the addition of spirometry would have allowed actual measurement of tidal volumes for comparison. Collecting blood gas samples at more time points may have also demonstrated differences between treatments at more than just the four time points assessed. The lack of an objective protocol for assessing anesthetic depth may also be criticized. The same investigator, an experienced veterinary anesthetist, unaware of treatment, performed all the inductions and assessed all dogs for anesthetic depth and adjusted the CRI rate accordingly, thus any bias should be relatively uniform across treatments. Despite the shortcomings of this study, it was designed to assess the use of P and KP under clinical conditions and was able to demonstrate differences using the monitoring and anesthetic equipment commonly available to most veterinary clinicians. In summary, this study documented a significant dose reduction of propofol when ketamine was coadministered with propofol for TIVA. Administration of propofol alone for TIVA resulted in decreased MAP, no change in HR, and fewer dogs were hypoxemic. Induction and maintenance of TIVA with a 1:1 mg ml 1 combination of ketamine and propofol resulted in significantly higher HR and attenuated some of the decline in MAP, but with respiratory depression resulting in hypoxemia and hypercapnia at some time points when dogs breathed room air. Both TIVA methods resulted in acceptable recovery quality. Oxygen supplementation and/or assisted ventilation should be provided when anesthetizing dogs with ketamine-propofol. Acknowledgements The authors would like to thank Abbott Animal Health for their financial support and Ridgelan Labs for their generous hospitality in the use of their facilities. We would also like to thank Janet Sosnicki, Sushant Rana, and Bryan Schumacher for their voluntary assistance. The authors declare no conflict of interest. References Aguiar AJA, Luna SPL, Oliva VNLS et al. (2001) Continuous infusion of propofol in dogs premedicated with methotrimeprazine. Vet Anaesth Analg 28, Andolfatto G, Willman E (2010) A prospective case series of pediatric procedural sedation and analgesia in the emergency department using single-syringe ketaminepropofol combination (ketofol). Acad Emerg Med 17, Blouin RT, Seifert HA, Babenco HD et al. (1993) Propofol decreases the hypoxic ventilatory response during conscious sedation and isohypercapnia. Anesthesiology 79, 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, Bosiack AP, Mann FA, Dodam JR et al. (2010) Comparison of ultrasonic Doppler flow monitor, oscillometric, and direct arterial blood pressure measurements in ill dogs. J Vet Emerg Crit Care 20, Donnelly RF, Willman E, Andolfatto G (2008) Stability of ketamine-propofol mixtures for procedural sedation and analgesia in the emergency department. Can J Hosp Pharm 61, Hamza J, Ecoffey C, Gross JB (1989) Ventilatory response to CO 2 following intravenous ketamine in children. Anesthesiology 70, Haskins SC (2007) Monitoring anesthetized patients. In: Lumb & Jones Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell, Ames, IA, USA. pp Haskins SC, Patz JD (1990) Ketamine in hypovolemic dogs. Crit Care Med 18, Haskins SC, Farver TB, Patz JD (1985) Ketamine in dogs. Am J Vet Res 46, Haskins SC, Farver TB, Patz JD (1986) Cardiovascular changes in dogs given diazepam and diazepam-ketamine. Am J Vet Res 47, Haskins S, Pascoe PJ, Ilkiw JE et al. (2005) Reference cardiopulmonary values in normal dogs. Comp Med 55, Henao-Guerrero N, Ricco CH (2014) Comparison of the cardiorespiratory effects of a combination of ketamine and propofol, propofol alone, or a combination of ketamine and diazepam before and after induction of anesthesia in dogs sedated with acepromazine and oxymorphone. Am J Vet Res 75, Hirshman CA, McCullough RE, Cohen PJ et al. (1975) Hypoxic ventilatory drive in dogs during thiopental, ketamine, or pentobarbital anesthesia. Anesthesiology 43, Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42,

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