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Effect of dexmedetomidine, morphine-lidocaine-ketamine, and dexmedetomidine-morphine-lidocaine-ketamine constant rate infusions on the minimum alveolar concentration of isoflurane and bispectral index in dogs

Lisa Sams Ebner DVM, MS1, Phillip Lerche BVSc, PhD2, Richard M. Bednarski DVM, MS3, and John A. E. Hubbell DVM, MS4
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  • 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 3 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.
  • | 4 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

Abstract

Objective—To determine the effect of dexmedetomidine, morphine-lidocaine-ketamine (MLK), and dexmedetomidine-morphine-lidocaine-ketamine (DMLK) constant rate infusions on the minimum alveolar concentration (MAC) of isoflurane and bispectral index (BIS) in dogs.

Animals—6 healthy adult dogs.

Procedures—Each dog was anesthetized 4 times with a 7-day washout period between anesthetic episodes. During the first anesthetic episode, the MAC of isoflurane (baseline) was established. During the 3 subsequent anesthetic episodes, the MAC of isoflurane was determined following constant rate infusion of dexmedetomidine (0.5 μg/kg/h), MLK (morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine, 0.6 mg/kg/h), or DMLK (dexmedetomidine, 0.5 μg/kg/h; morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine 0.6 mg/kg/h). Among treatments, MAC of isoflurane was compared by means of a Friedman test with Conover posttest comparisons, and heart rate, direct arterial pressures, cardiac output, body temperature, inspired and expired gas concentrations, arterial blood gas values, and BIS were compared with repeated-measures ANOVA and a Dunn test for multiple comparisons.

Results—Infusion of dexmedetomidine, MLK, and DMLK decreased the MAC of isoflurane from baseline by 30%, 55%, and 90%, respectively. Mean heart rates during dexmedetomidine and DMLK treatments was lower than that during MLK treatment. Compared with baseline values, mean heart rate decreased for all treatments, arterial pressure increased for the DMLK treatment, cardiac output decreased for the dexmedetomidine treatment, and BIS increased for the MLK and DMLK treatments. Time to extubation and sternal recumbency did not differ among treatments.

Conclusions and Clinical Relevance—Infusion of dexmedetomidine, MLK, or DMLK reduced the MAC of isoflurane in dogs. (Am J Vet Res 2013;74:963–970)

Abstract

Objective—To determine the effect of dexmedetomidine, morphine-lidocaine-ketamine (MLK), and dexmedetomidine-morphine-lidocaine-ketamine (DMLK) constant rate infusions on the minimum alveolar concentration (MAC) of isoflurane and bispectral index (BIS) in dogs.

Animals—6 healthy adult dogs.

Procedures—Each dog was anesthetized 4 times with a 7-day washout period between anesthetic episodes. During the first anesthetic episode, the MAC of isoflurane (baseline) was established. During the 3 subsequent anesthetic episodes, the MAC of isoflurane was determined following constant rate infusion of dexmedetomidine (0.5 μg/kg/h), MLK (morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine, 0.6 mg/kg/h), or DMLK (dexmedetomidine, 0.5 μg/kg/h; morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine 0.6 mg/kg/h). Among treatments, MAC of isoflurane was compared by means of a Friedman test with Conover posttest comparisons, and heart rate, direct arterial pressures, cardiac output, body temperature, inspired and expired gas concentrations, arterial blood gas values, and BIS were compared with repeated-measures ANOVA and a Dunn test for multiple comparisons.

Results—Infusion of dexmedetomidine, MLK, and DMLK decreased the MAC of isoflurane from baseline by 30%, 55%, and 90%, respectively. Mean heart rates during dexmedetomidine and DMLK treatments was lower than that during MLK treatment. Compared with baseline values, mean heart rate decreased for all treatments, arterial pressure increased for the DMLK treatment, cardiac output decreased for the dexmedetomidine treatment, and BIS increased for the MLK and DMLK treatments. Time to extubation and sternal recumbency did not differ among treatments.

Conclusions and Clinical Relevance—Infusion of dexmedetomidine, MLK, or DMLK reduced the MAC of isoflurane in dogs. (Am J Vet Res 2013;74:963–970)

Isoflurane is an inhalation agent commonly used for anesthetizing dogs. The amount of isoflurane required to achieve a surgical plane of anesthesia is frequently associated with myocardial depression and substantial vasodilation that can result in hypotension.1 In a study2 that described anesthetic complications in dogs, hypotension (485/1,281 [37.9%]) was the second most frequent complication reported following hypoventilation (812/1,281 [63.4%]). For anesthetized dogs, hypotension is defined as an MAP < 60 mm Hg and an SAP < 80 mm Hg.3 Arterial blood pressure is the primary determinant for cerebral and coronary perfusion4; an MAP < 60 mm Hg is associated with loss of autoregulation and reduced blood flow to the kidneys and brain, which can cause short- or long-term renal or CNS dysfunction.5 Balanced or multimodal anesthesia, in which concurrent administration of analgesic agents allows the amount of inhalant anesthetic administered to be decreased while still maintaining an adequate surgical plane of anesthesia, can decrease the severity of cardiovascular depression in anesthetized dogs, compared with the administration of the inhalant anesthetic alone.6 The MAC is the lowest alveolar concentration of an inhalant anesthetic that prevents gross purposeful movement in response to a noxious stimulus in 50% of animals, and the MAC of isoflurane has been established for dogs and cats.7 Results of multiple studies8–12 indicate that administration of 1 or more analgesics, including opioids, α2-adrenoceptor agonists, N-methyl-d-aspartate receptor antagonists, and lidocaine, can reduce the MAC of various inhalant anesthetics required for a surgical plane of anesthesia and thereby reduce cardiorespiratory depression and the risk of anesthetic complications. In dogs, administration of MLK reduces the MAC of isoflurane and is not associated with adverse hemodynamic effects12; the components of MLK (morphine [opioid receptor agonist], lidocaine [sodium channel blocker], and ketamine [N-methyl-d-aspartate receptor antagonist]) each provide analgesia by a different mechanism of action. Results of 1 study13 suggest that dexmedetomidine, an α2-adrenoceptor agonist, is a reliable and effective adjunct to anesthesia in healthy dogs when administered as a CRI concurrently with the administration of isoflurane, and investigators of another study14 reported that in anesthetized dogs, a CRI of 0.5 μg of dexmedetomidine/kg/h reduced the MAC of isoflurane by 18%, compared with the MAC of isoflurane when the inhalant was administered alone. The addition of dexmedetomidine to an MLK CRI may further reduce the MAC of isoflurane for anesthetized dogs.

Bispectral index is a measure of consciousness in humans and animals and is determined by measuring the bicoherence between various leads of an EEG.15 The BIS is inversely related to anesthetic depth. Values for BIS are unitless and range from 0 to 100, with 100 indicative of full consciousness and 0 indicative of no cortical activity (ie, an isoelectric EEG).16 In anesthetized human patients, a BIS < 60 is an indication that a surgical plane of anesthesia has been achieved, whereas a BIS ≥ 60 is suggestive of deep sedation (BIS, 60) to total consciousness (BIS, 100).15 In human patients, monitoring BIS during anesthesia is useful because it can differentiate whether a sedative or analgesic plane of anesthesia has been achieved.17 In anesthetized veterinary patients, monitoring changes in BIS in response to surgical stimulation might be useful for the maintenance of an adequate plane of anesthesia without the need for excessive administration of drugs during the procedure, thereby reducing costs and minimizing conscious arousal.18

The purpose of the study reported here was to determine the effect of a CRI of dexmedetomidine, MLK, or DMLK on the MAC of isoflurane and BIS in healthy anesthetized dogs. We used MAC determination to evaluate the extent of analgesia and BIS monitoring to assess the depth or quality of anesthesia.

Materials and Methods

Animals—The study was approved by the Animal Care and Use Committee of The Ohio State University and was performed in accordance with the International Association for the Study of Pain's Guidelines for the Use of Animals in Research.19 Six conditioned, mixed-breed, sexually intact (3 males and 3 females) dogs were used in the study. Each dog was determined to be healthy on the basis of results of a physical examination, CBC, serum biochemical analysis, ECG, and fecal analysis for parasites. The mean ± SD age and weight of the dogs were 11 ± 0.9 months (range, 10 to 12 months) and 14.4 ± 5.8 kg (range, 6.5 to 21.2 kg), respectively. After completion of the study, all dogs were adopted by private owners.

Study design—Each dog underwent 4 anesthetic episodes with at least a 7-day washout between episodes. For each dog, the MAC of isoflurane was determined during the first anesthetic episode when isoflurane was administered alone (baseline treatment). During the subsequent anesthetic episodes, each dog was anesthetized with isoflurane and concurrently administered a CRI of lactated Ringer's solutiona (5 mL/kg/h) and dexmedetomidine hydrochlorideb (0.5 μg/kg/h), MLK (morphine sulfatec [0.2 mg/kg/h], lidocaine hydrochlorided [3 mg/kg/h], and ketamine hydrochloridee [0.6 mg/kg/h]), or DMLK (dexmedetomidine [0.5 μg/kg/h], morphine [0.2 mg/kg/h], lidocaine [3 mg/kg/h], and ketamine [0.6 mg/kg/h]) in a randomized crossover study design. To determine the isoflurane-sparing effect of each treatment (dexmedetomidine, MLK, or DMLK), the MAC of isoflurane was determined beginning 120 minutes after initiation of the treatment infusion and compared with the MAC of isoflurane for the baseline treatment.

Anesthetic induction and instrumentation—For each dog, food but not water was withheld for approximately 12 hours prior to each anesthetic episode. A 20-gauge catheterf was aseptically inserted into a cephalic vein. Anesthesia was induced with propofolg (6 mg/kg, IV to effect). Each dog was intubated with a cuffed endotracheal tube.h A gas-sampling line was attached to the end of the endotracheal tube, which was then connected to the Y-piece of a circle anesthetic breathing system. Each dog was positioned in left lateral recumbency. Anesthesia was maintained with isofluranei delivered in 100% oxygen by an out-of-circle precision vaporizerj that was set to achieve an estimated ETISO of 1.6%. Each dog was mechanically ventilated with an estimated tidal volume of 10 to 15 mL/kg at a rate of 6 breaths/min. A warm-water circulating padk and forced warm-air blanketl were used to maintain the dog's body temperature between 37.5° and 38°C. Inspired and expired gas samples were continuously monitored with an infrared gas analyzer,m which was calibrated in accordance with the manufacturer's instructions daily. Heart rate and rhythm and Spo2 were continuously monitored with a lead II ECG and pulse oximeter.n A 20-gauge catheterf was percutaneously inserted into a dorsal metatarsal artery, and a direct arterial pressure monitoro was used to measure SAP, diastolic arterial pressure, and MAP. Cardiac output was monitored by means of the LiDCO method; briefly, the catheter used to monitor direct arterial pressure was coupled to a single-point LiDCO calibration system that was connected to a hemodynamic monitor,p which was used to derive CO, stroke volume, SVR, and Do2. The LiDCO calibration system was calibrated in accordance with the manufacturer's instructions prior to each anesthetic episode.

Determination of the MAC of isoflurane—Following induction of anesthesia, each dog was allowed to equilibrate at an ETISO of 1.6% for at least 60 minutes. To determine the MAC of isoflurane, an iterative bracketing technique was used in which a noxious supramaximal electrical stimulus is delivered to the buccal mucosa. Briefly, two 24-gauge, 10-mm platinum subdermal needle electrodesq were placed approximately 1 cm apart in the maxillary buccal mucosa caudal and dorsal to the incisors. The electrodes were connected to an electrical stimulatorr that delivered a predetermined stimulus (50 V and 5 Hz for 10 milliseconds) for a period of 1 minute. If the dog had gross purposeful movement (lifting of the head or repeated movement of the limbs), the stimulus was discontinued. Movements not considered gross purposeful movements (ie, a negative response to the electrical stimulus) included slight paw movement, an arched back, blinking of the eyes, nystagmus, chewing, and swallowing. If the electrical stimulus resulted in no gross purposeful movement, the isoflurane concentration was decreased by 20% and the dog was allowed to equilibrate at that concentration for 15 minutes before the electrical stimulus was applied. This process was repeated until gross purposeful movement was observed. Following the observation of gross purposeful movement, the isoflurane concentration was increased by 10%, the dog was allowed to equilibrate at that concentration for 15 minutes, and the electrical stimulus was applied. This process was repeated until the electrical stimulus no longer resulted in gross purposeful movement. The MAC was the median value between the ETISO at which gross purposeful movement occurred and the ETISO at which gross purposeful movement did not occur. During each anesthetic episode, the MAC of isoflurane was determined twice. If the MAC calculations differed by > 10%, the MAC was determined a third time. The mean MAC for that anesthetic episode was calculated and used for subsequent analyses.

Determination of BIS—For each dog, a 2-channel referential montage that was arranged in a bifrontal configuration was used to record an EEG as described.20 Electroencephalogram activity was continuously monitored throughout each anesthetic episode, and BIS values were calculated and recorded by use of a BIS monitors with the high-frequency filter set at 70 Hz and the low-frequency filter set at 2 Hz. The BIS value was calculated and displayed every 5 seconds and represented the EEG activity during the previous minute. Bispectral index values were rejected if the signal quality index was < 50. Starting 1 minute before the electrical stimulation, a BIS value was recorded every 15 seconds. During the electrical stimulation, no BIS values were recorded. For 1 minute after electrical stimulation, a BIS value was recorded every 15 seconds. This resulted in a total of 8 BIS values from which the mean BIS value at the time of MAC determination was calculated.

Treatment administration—For each dog following anesthetic induction and instrumentation during each of the 3 subsequent anesthetic episodes, anesthesia was maintained with isoflurane delivered at the mean MAC determined for that dog during the initial anesthetic episode. A volume of lactated Ringer's solution equivalent to the volume of treatment (dexmedetomidine, MLK, or DMLK) that was to be administered was removed from the fluid bag before the drugs were added into the lactated Ringer's solution. Treatment doses and rate of fluid administration were chosen on the basis of results of other studies12,14 and a pilot study conducted by our laboratory group, in which a CRI of DMLK for 3 hours did not induce loss of consciousness or anesthesia in either of 2 healthy dogs. The CRIs were delivered by means of an appropriately calibrated volumetric infusion pumpt and were administered for 120 minutes prior to initiation of the determination of the MAC of isoflurane as described.

Data collection—After the MAC of isoflurane had been determined for each anesthetic episode, the ETISO was adjusted to the mean MAC, and the dog was allowed to equilibrate at that concentration for 20 minutes before CO, HR, heart rhythm, SAP, diastolic arterial pressure, MAP, Spo2, end-tidal gas concentrations, and BIS values were recorded and an arterial blood sample was anaerobically collected for determination of pH and blood gas values. Immediately after that data had been obtained, all instrumentation was removed from the dog except for the BIS monitor and gas analyzer, which were left in place for continued monitoring of the dog during recovery from anesthesia. Following discontinuation of isoflurane delivery, the dog remained connected to the circle anesthetic breathing system and was administered 100% oxygen at the same rate as that used to deliver isoflurane without the circuit being flushed. When the dog began to swallow, the ETISO and 4 BIS values were recorded; the dog was then extubated, and another 4 BIS values were recorded. Any adverse reactions during recovery were recorded. Dogs that appeared dysphoric during recovery from anesthesia were administered a single dose of acepromazine maleateu (0.02 mg/kg, IV).

Statistical analysis—Statistical software for the analysis of parametricv and nonparametricw data was used, and values of P < 0.05 were considered significant. Distributions of data were analyzed for normality with the Kolmogorov-Smirnov test. The median and range were reported for data that were not normally distributed (ie, the MAC of isoflurane), and the mean ± SD was reported for data that were normally distributed. The MAC of isoflurane was compared among treatments by means of the Friedman test with Conover posttest comparisons. Repeated-measures ANOVA was used to assess the effect of treatment on cardiorespiratory and metabolic outcome variables. End-tidal isoflurane concentration and mean BIS value (mean for 8 BIS values obtained before and after extubation) at extubation were compared among treatments with ANOVA. When the fixed effect of treatment was significant, comparisons within and among treatments were performed with Dunnett and Tukey posttests, respectively.

Results

Duration of anesthesia and adverse events—The mean duration for each anesthetic episode was 7.5 hours, and the times to extubation and sternal recumbency did not vary significantly among the treatments (Table 1). For all dogs, Spo2 remained > 97% and body temperature ranged from 37.5° to 38.0°C throughout all anesthetic episodes. Four dogs became dysphoric after extubation and were sedated with acepromazine, and 1 dog regurgitated during recovery from anesthesia with isoflurane alone (baseline treatment). When anesthetized with the dexmedetomidine, MLK, and DMLK treatments, none of the dogs became dysphoric during recovery. Two dogs vomited during recovery from the dexmedetomidine treatment, and 1 dog regurgitated during recovery from the MLK treatment. Adverse events were not observed in any of the dogs following the DMLK treatment.

Table 1—

Mean ± SD values of outcome variables for 6 healthy adult dogs when anesthesia was maintained with isoflurane only (baseline) or isoflurane and concurrent administration of a CRI of lactated Ringer's solution (5 mL/kg/h) and dexmedetomidine (0.5 μg/kg/h), MLK (morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine, 0.6 mg/kg/h), or DMLK (dexmedetomidine, 0.5 μg/kg/h; morphine, 0.2 mg/kg/h; lidocaine, 3 mg/kg/h; and ketamine, 0.6 mg/kg/h); values were obtained 20 minutes after equilibration at the MAC of isoflurane or during recovery from anesthesia.

 Treatment
VariableIsoflurane onlyIsoflurane and dexmedetomidineIsoflurane and MLKIsoflurane and DMLK
SAP (mm Hg)91 ± 10a115 ± 8b119 ± 14b117 ± 11b
MAP (mm Hg)64 ± 7a70 ± 7a,b73 ± 4a,b76 ± 8b
HR (beats/min)99 ± 11a53 ± 10b78 ± 17c49 ± 6b
CO (L/min)2.3 ± 0.7a1.3 ± 0.5b1.8 ± 0.4a,b1.5 ± 0.9a,b
CI (L/min/m2)3.9 ± 0.92.2 ± 0.33.1 ± 0.62.4 ± 1.0
SVR (dyn/s/cm−5)1,983 ± 1,023a4,367 ± 1,494b3,200 ± 692a,b4,642 ± 2,012b
Do2 (mL of O2/min)665 ± 464a269 ± 89b344 ± 37a,b300 ± 132a,b
BIS at MAC determination74 ± 7.3a71 ± 7.6a80 ± 5.5b82 ± 6b
BIS at extubation82 ± 8a85 ± 8a89 ± 5b91 ± 6b
ETISO just prior to extubation (%)0.53 ± 0.15a0.40 ± 0.09a,b0.28 ± 0.23b0.03 ± 0.08c
Time from discontinuation of treatment to extubation (min)13.6 ± 8.813.8 ± 8.27.5 ± 6.26.8 ± 5.4
Time from discontinuation of treatment to sternal recumbency (min)15 ± 11.415.2 ± 7.916.7 ± 5.920.2 ± 11.4
pH7.41 ± 0.027.44 ± 0.027.43 ± 0.087.39 ± 0.02
Pao2 (mm Hg)568 ± 31.4578 ± 20.5556 ± 33.3556 ± 35.7
Paco2 (mm Hg)31.5 ± 2.332.3 ± 2.6933.3 ± 5.4135.8 ± 1.95
Bicarbonate (mmol/L)20.2 ± 122.4 ± 1.822.3 ± 1.721.8 ± 1.4
Base excess (mmol/L)–4.6 ± 1–2 ± 1.9–2.3 ± 2.5–3.4 ± 1.6
Sao2 (%)99.4 ± 0.299.8 ± 0.4299.7 ± 0.2299.6 ± 0.25

CI = Cardiac index. Sao2 = Arterial oxygen saturation.

Within a variable, values with different superscript letters differ significantly (P < 0.05).

Each dog underwent 4 anesthetic episodes with at least a 7-day washout period between episodes. For each dog, the MAC of isoflurane was determined during the first anesthetic episode; then, during the subsequent 3 anesthetic episodes, anesthesia was maintained with isoflurane and a CRI of dexmedetomidine, MLK, or DMLK in a randomized crossover study design.

Treatment effects—The median MAC of isoflurane was 1.30% (range, 1.13% to 1.50%) for the baseline treatment and decreased to 0.90% (range, 0.75% to 1.15%), 0.58% (range, 0.35% to 0.80%), and 0.08% (range, 0% to 0.35%) for the dexmedetomidine, MLK, and DMLK treatments, respectively. The mean SAP for the dexmedetomidine, MLK, and DMLK treatments was increased, compared with the mean SAP for the baseline treatment (Table 1). The mean MAP was increased for the DMLK treatment, compared with the mean MAP for the baseline treatment. The dexmedetomidine, MLK, and DMLK treatments resulted in a lower mean HR, compared with the mean HR for the baseline treatment. The mean HR for the MLK treatment was higher than that for the dexmedetomidine or DMLK treatments. No arrhythmias were detected in any of the dogs during the baseline treatment, whereas all dogs developed a sinus arrhythmias during the dexmedetomidine and DMLK treatments. Compared with values for the baseline treatment, CO and Do2 were decreased for the dexmedetomidine treatment and SVR was increased for the dexmedetomidine and DMLK treatments. Stroke volume and arterial blood gas variables did not vary significantly among treatments. During the MLK and DMLK treatments, the mean BIS values at the time of MAC equilibration and extubation were significantly greater than those for the baseline and dexmedetomidine treatments.

Discussion

Results of the present study indicated that IV administration of morphine, lidocaine, ketamine, and dexmedetomidine concurrently with inhaled administration of isoflurane caused a significant reduction in the MAC of isoflurane. In the present study, the baseline (ie, administration of isoflurane alone) MAC of isoflurane was similar to the MAC of isoflurane reported by investigators of other studies.7,12 The MAC of isoflurane when dogs were anesthetized with isoflurane and dexmedetomidine or MLK in the present study was lower, compared with the MAC of isoflurane determined in other studies in which dogs were anesthetized with isoflurane and a CRI of dexmedetomidine14 or MLK12,21 equivalent to that used in the present study. The reason the MAC of isoflurane varied among studies is likely because of variation in study subjects or protocols. The MAC of an inhalant is specific for each dog and is dependent on the dog's age and physical status and the magnitude and duration of the noxious stimulus applied.22,23

In the present study, the extent of analgesia induced by each treatment was assessed by the determination of the MAC of isoflurane, whereas the depth or quality of anesthesia induced by each treatment was assessed by measurement of the BIS. The BIS value at MAC equilibration for the baseline treatment of the present study was similar to that found in another study20 in which BIS was used to monitor the depth of anesthesia in isoflurane-anesthetized dogs. In the present study, the mean BIS value for the DMLK and MLK treatments increased approximately 11% and 8%, respectively, compared with the mean BIS value for the baseline treatment. Administration of the MLK treatment resulted in a decreased MAC of isoflurane, compared with that for the baseline treatment, and this decrease in MAC, in conjunction with the increase in the mean BIS value, may suggest that the dogs were at a greater state of consciousness when anesthetized with the MLK treatment than when they were anesthetized with the baseline treatment. In another study12 that involved dogs anesthetized with isoflurane, the mean BIS value increased approximately 10% when a concurrent CRI of MLK was administered, compared with the mean BIS value when dogs were not administered MLK; however, this difference in mean BIS value was not statistically significant. The increased mean BIS value when dogs were anesthetized with the MLK and DMLK treatments in the present study suggested that those treatments resulted in a lighter plane of anesthesia (ie, dogs were at an increased state of consciousness); however, the dogs likely did not respond to the noxious stimuli because of the antinociceptive effects of the drugs used in the CRIs. When dogs were anesthetized with the dexmedetomidine treatment, the mean BIS value was not significantly different from that for the baseline treatment despite a 30% decrease in the MAC of isoflurane; this was most likely the result of the sedative effects of dexmedetomidine. Interestingly, the addition of dexmedetomidine to the MLK CRI (ie, DMLK) resulted in a mean BIS value that did not differ significantly from the mean BIS value when dexmedetomidine was not administered (ie, MLK); this finding was most likely a reflection of a light plane of anesthesia achieved for the DMLK treatment, as evidenced by the 93% reduction in the MAC of isoflurane for the DMLK treatment, compared with that for the baseline treatment.

During the present study, the hemodynamic variables monitored remained within clinically acceptable limits regardless of treatment. Administration of an α2-adrenoceptor agonist, such as dexmedetomidine, typically induces vasoconstriction with a subsequent baroreflex-mediated decrease in HR and CO, which are perpetuated by reduced sympathetic tone.24 In the present study, CRI of dexmedetomidine or DMLK resulted in hemodynamic changes that were expected on the basis of results of other studies25–28 and included decreased HR and increased MAP and SVR, compared with baseline values. The lowest HR recorded during the present study was 42 beats/min when a dog was administered the DMLK treatment; however, the corresponding direct MAP (83 mm Hg; reference limits, 80 to 120 mm Hg) for that dog was within reference limits.2 The increase in MAP and SVR when dogs were administered the DMLK treatment was expected because dexmedetomidine causes a dose-dependent increase in SVR,29 and MAP is dependent on SVR. However, MAP is also dependent on CO, and there is a dynamic relationship between SVR and CO, as evidenced by the fact that when dogs were administered a CRI of dexmedetomidine, MAP did not increase significantly from the baseline MAP because the SVR increase was accompanied by a concurrent decrease in CO.

A possible explanation for the difference in MAP response between the dexmedetomidine and DMLK treatments is that the MAC of isoflurane when dogs were administered dexmedetomidine was significantly greater (ie, the volume of isoflurane delivered was greater) than that when dogs were administered DMLK. The mean SVR did not differ between the dexmedetomidine and DMLK treatments; therefore, it is unlikely that isoflurane-induced vasodilation was responsible for the differences in MAP between the 2 treatments. When dogs were administered the dexmedetomidine treatment, the decrease in CO from baseline CO was consistent with results of another study.28 To our knowledge, the use of LiDCO has not been validated for the measurement of CO in dogs with SVR increased from reference limits. Ideally, we would have measured CO with the LiDCO method in conjunction with the gold-standard thermodilution technique using a Swan-Ganz catheter to determine whether the CO measurements obtained with the LiDCO method were valid; therefore, the CO findings for the present study should be interpreted with caution. Administration of dexmedetomidine generally suppresses hemodynamic variables associated with myocardial oxygen consumption such as HR.30 When hemodynamic variables were compared between the dexmedetomidine and DMLK treatments, CO did not differ significantly despite the fact that the CO for the dexmedetomidine treatment did differ significantly from the baseline CO. This finding may have been caused by nonsignificant differences in stroke volume among treatments or the inclusion of ketamine in the DMLK treatment. Administration of ketamine induces myocardial depression, which can be obscured by stimulation of sympathetic nerves to the heart.31 Stimulation of the sympathetic nervous system increases HR, which generally results in an increased CO. Results of another study32 indicate that administration of ketamine (10 mg/kg, IM) to dogs increased plasma epinephrine, norepinephrine, cortisol, and glucose concentrations from those preadministration; however, concurrent administration of medetomidine and ketamine prevented or attenuated the increase in those concentrations. To our knowledge, no studies have been conducted to determine the effect that administration of a subanesthetic dose of ketamine, such as those used in the MLK and DMLK treatments of the present study, has on serum or plasma concentrations of catecholamines. Another explanation for the lack of a significant difference in the CO between the dexmedetomidine and DMLK treatments was that the present study was underpowered.

In the present study, the mean Do2 for the dexmedetomidine treatment was decreased, compared with the Do2 for the baseline treatment. This finding was similar to that of another study25; however, in that study,25 oxygen delivery was maintained at a rate above the critical Do2 for a 24-hour CRI of dexmedetomidine during and after anesthetic induction and maintenance with propofol or isoflurane. For dogs in which anesthesia is maintained with isoflurane, the critical Do2 is 11.5 mL•min−1•kg−1.33 In the present study, the dexmedetomidine treatment had the lowest mean Do2 (on a per kg basis; 18.6 mL•min−1•kg−1), which was greater than the critical Do2 for dogs and suggested that oxygen delivery was sufficient, despite the fact that this Do2 was 60% less than the Do2 for the baseline treatment.

The mean times from discontinuation of anesthetic administration until extubation and sternal recumbency did not vary significantly among the treatments of the present study and were similar to those reported by investigators of another study34 that involved dogs in which anesthesia was maintained with isoflurane. In the present study, the development of adverse events occurred only during the recovery period after treatment administration had been discontinued. Following the baseline treatment, 4 dogs developed dysphoria and were sedated with acepromazine. We attributed the dysphoria in those dogs to the lack of sedative administration during anesthesia. Following the dexmedetomidine treatment, 2 dogs vomited, which, along with intestinal hypomotility, is a common adverse effect associated with administration of an α2-adrenoceptor agonist.24 During recovery from the MLK treatment, 1 dog regurgitated, which was attributed to administration of morphine; in dogs, CRI of morphine (0.12 mg/kg/h) is associated with panting, vomiting, defecation, and dysphoria.35 In contrast, no adverse events were observed during recovery from the DMLK treatment, which we attributed to the combined sedative effects of dexmedetomidine, morphine, lidocaine, and ketamine.

Following the DMLK treatment in the present study, ETISO just prior to extubation was significantly decreased and the BIS value at extubation was increased, compared with those values following the baseline treatment. This finding suggested that following the DMLK treatment, dogs were at a greater level of consciousness than they were following the baseline treatment, which likely accounted for the lack of dysphoria observed during the recovery period. The ETISO just prior to extubation was decreased after the MLK treatment, compared with that after the baseline treatment, and was likewise decreased after the DMLK treatment, compared with that after the dexmedetomidine or MLK treatments. This finding suggested that the sedative effects of the various drug combinations used in the CRIs were sustained long enough after their discontinuation for the dogs to expire a substantial proportion of residual isoflurane prior to extubation, which generally allowed for an uneventful recovery from anesthesia.

The present study had a few inherent limitations, one of which was the limited number of dogs that were available for the study. Results of a calculation prior to study initiation indicated that evaluation of 6 dogs would provide sufficient power (ie, 80%) to detect a 20% reduction in the MAC of isoflurane with a type I error rate of 0.05. Also, the study dogs were healthy and did not have clinical signs of pain, whereas dogs that undergo anesthesia are frequently diseased or injured and may respond to the treatment protocols evaluated in the present study differently than did the study population. Typically, ketamine and lidocaine are used as adjunct anesthetics for patients with signs of severe acute or chronic pain36,37; it is possible that the isoflurane-sparing effects of these 2 drugs were not completely elicited during the present study. Another limitation of the present study was that the 3 components of the MLK infusion (morphine, lidocaine, and ketamine) were not assessed separately. We chose to not assess the drugs that comprised the MLK treatment individually in the present study because those assessments had already been performed at our laboratory for dogs anesthetized with isoflurane12 and other investigators38 for dogs anesthetized with sevoflurane. Nevertheless, we concede that determination of the MAC of isoflurane following a CRI of each drug separately would have provided a more accurate evaluation of the isoflurane-sparing effect of each drug in the present study. Additionally, it was unlikely that steady-state plasma concentrations for the drugs administered by means of CRI were achieved by 120 minutes after initiation of infusion, the time at which the bracketing technique used to determine the MAC of isoflurane was begun. Serial measurement of the plasma concentration of the individual drugs used in the CRIs would have allowed us to determine the time at which the respective steady-state concentrations were achieved; however, that was beyond the scope of the present study. Moreover, because the MAC of isoflurane was generally not determined until 4 to 6 hours after the bracketing technique was begun, regardless of treatment, we believe it was likely that the steady-state plasma concentration for most, if not all, drugs had been achieved at the time the MAC was actually determined.

Findings of the present study indicated that for dogs in which anesthesia is maintained with isoflurane, concurrent administration of a CRI of dexmedetomidine, MLK, or DMLK resulted in an MAC of isoflurane that was significantly reduced, compared with that when isoflurane was administered alone (baseline treatment). The BIS values for the MLK and DMLK treatments were significantly higher, compared with the BIS value for the baseline treatment, which suggested that dogs were at a greater state of consciousness during the MLK and DMLK treatments than they were during the baseline treatment. Given the design of the present study, we were unable to use BIS values to differentiate between the sedative and analgesic effects of the drugs used in the various treatments. Among the treatments evaluated, the DMLK treatment caused the largest reduction in the MAC of isoflurane relative to that of the baseline treatment, induced cardiovascular changes that were well-tolerated by healthy dogs, and resulted in uneventful recovery from anesthesia with no adverse events observed in any of the study dogs.

ABBREVIATIONS

BIS

Bispectral index

CO

Cardiac output

CRI

Constant rate infusion

DMLK

Dexmedetomidine-morphine-lidocaine-ketamine

Do2

Oxygen delivery to tissue

EEG

Electroencephalogram

ETISO

End-tidal concentration of isoflurane

HR

Heart rate

LiDCO

Lithium dilution cardiac output

MAC

Minimum alveolar concentration

MAP

Mean arterial pressure

MLK

Morphine-lidocaine-ketamine

SAP

Systolic arterial pressure

Spo2

Oxygen saturation of hemoglobin

SVR

Systemic vascular resistance

a.

Lactated Ringer's injection USP, Baxter Healthcare Corp, Deerfield, Ill.

b.

Dexdomitor, Pfizer Animal Health, New York, NY.

c.

Morphine sulfate, Baxter Healthcare Corp, Deerfield, Ill.

d.

Lidocaine injectable, Sparhawk Laboratories Inc, Lenexa, Kan.

e.

KetaVed, VEDCO Inc, St Joseph, Mo.

f.

Surflo IV catheter, Terumo Medical Corp, Elkton, Md.

g.

PropoFlo, Abbott Laboratories, North Chicago, Ill.

h.

Murphy cuffed endotracheal tube, Tyco Healthcare Group LP, Pleasanton, Calif.

i.

Isothesia, Butler Animal Health Supply, Dublin, Ohio.

j.

Ohmeda Isotec 3, GE Healthcare, Pataskala, Ohio.

k.

Gaymar t pump, Gaymar Industries Inc, Orchard Park, NY.

l.

Gaymar Thermacare, Gaymar Industries Inc, Orchard Park, NY.

m.

Datascope gas module SE, Datascope Corp, Mahwah, NJ.

n.

Datascope Passport 2, Datascope Corp, Mahwah, NJ.

o.

SpaceLabs Medical Inc, Redmond, Wash.

p.

LiDCOplus hemodynamic monitor, LiDCO Ltd, London, England.

q.

Genuine grass platinum subdermal needle electrodes, Astro-Med Inc, West Warwick, RI.

r.

Grass SD9 stimulator, Grass Medical Instruments, Quincy, Mass.

s.

BIS VISTA monitoring system, Aspect Medical Systems Inc, Norwood, Mass.

t.

Heska Vet/IV 2.2, Heska Corp, Loveland, Colo.

u.

Acepromazine maleate injection, VEDCO Inc, St Joseph, Mo.

v.

GraphPad Prism, GraphPad Software Inc, La Jolla, Calif.

w.

Brightstat.com, BrightStat Software, Bern, Switzerland.

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Contributor Notes

This manuscript represents a portion of a thesis submitted by Dr. Ebner to the Graduate Program in Comparative and Veterinary Medicine, College of Veterinary Medicine of The Ohio State University as partial fulfillment of the requirements for a Master of Science degree.

Supported by Canine Research Funds, an intramural grant from the College of Veterinary Medicine of The Ohio State University.

Address correspondence to Dr. Ebner (lisasamsdvm@yahoo.com).