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Evaluation of the isoflurane‐sparing effects of fentanyl, lidocaine, ketamine, dexmedetomidine, or the combination lidocaine‐ketamine‐dexmedetomidine during ovariohysterectomy in dogs

      Abstract

      Objective

      To evaluate the isoflurane‐sparing effects of an intravenous (IV) constant rate infusion (CRI) of fentanyl, lidocaine, ketamine, dexmedetomidine, or lidocaine‐ketamine‐dexmedetomidine (LKD) in dogs undergoing ovariohysterectomy.

      Study design

      Randomized, prospective, blinded, clinical study.

      Animals

      Fifty four dogs.

      Methods

      Anesthesia was induced with propofol and maintained with isoflurane with one of the following IV treatments: butorphanol/saline (butorphanol 0.4 mg kg−1, saline 0.9% CRI, CONTROL/BUT); fentanyl (5 μg kg−1, 10 μg kg−1 hour−1, FENT); ketamine (1 mg kg−1, 40 μg kg−1 minute−1, KET), lidocaine (2 mg kg−1, 100 μg kg−1 minute−1, LIDO); dexmedetomidine (1 μg kg−1, 3 μg kg−1 hour−1, DEX); or a LKD combination. Positive pressure ventilation maintained eucapnia. An anesthetist unaware of treatment and end‐tidal isoflurane concentration (Fe′Iso) adjusted vaporizer settings to maintain surgical anesthetic depth. Cardiopulmonary variables and Fe′Iso concentrations were monitored. Data were analyzed using anova (p < 0.05).

      Results

      At most time points, heart rate (HR) was lower in FENT than in other groups, except for DEX and LKD. Mean arterial blood pressure (MAP) was lower in FENT and CONTROL/BUT than in DEX. Overall mean ± SD Fe′Iso and % reduced isoflurane requirements were 1.01 ± 0.31/41.6% (range, 0.75 ± 0.31/56.6% to 1.12 ± 0.80/35.3%, FENT), 1.37 ± 0.19/20.8% (1.23 ± 0.14/28.9% to 1.51 ± 0.22/12.7%, KET), 1.34 ± 0.19/22.5% (1.24 ± 0.19/28.3% to 1.44 ± 0.21/16.8%, LIDO), 1.30 ± 0.28/24.8% (1.16 ± 0.18/32.9% to 1.43 ± 0.32/17.3%, DEX), 0.95 ± 0.19/54.9% (0.7 ± 0.16/59.5% to 1.12 ± 0.16/35.3%, LKD) and 1.73 ± 0.18/0.0% (1.64 ± 0.21 to 1.82 ± 0.14, CONTROL/BUT) during surgery. FENT and LKD significantly reduced Fe′Iso.

      Conclusions and clinical relevance

      At the doses administered, FENT and LKD had greater isoflurane‐sparing effect than LIDO, KET or CONTROL/BUT, but not at all times. Low HR during FENT may limit improvement in MAP expected with reduced Fe′Iso.

      Keywords

      Introduction

      Inhalation anesthetics have been widely used for anesthetic maintenance in veterinary medicine. Main advantages include rapid control of the anesthetic depth by adjustments of the vaporizer dial and fresh oxygen flow, and favorable pharmacokinetic profile, allowing relatively rapid induction and recovery from anesthesia because anesthetic gas uptake and elimination occurs mainly via the lungs (Steffey & Howland
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      Isoflurane potency in the dog and cat.
      ). However, one of the main concerns is the progressive cardiopulmonary depression observed with high doses of inhalation agents such as isoflurane (ISO). High risk patients or animals with systemic disease may develop severe cardiovascular depression if anesthesia is maintained with an inhalation anesthetic alone. Consequently, anesthetic agents such as fentanyl, lidocaine, ketamine and/or dexmedetomidine have been used in an attempt to reduce inhalation agent requirements resulting in less cardiovascular depression (Wagner et al.
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      Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs.
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      Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
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      Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs.
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      Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs.
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      ). Combinations of drugs with different pharmacologic mechanisms may provide greater analgesia than each drug given alone, with further inhalant‐sparing effect (Muir et al.
      • Muir WW
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      Effects of morphine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.
      ; Doherty et al.
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      Effects of intravenous lidocaine, ketamine, and the combination on the minimum alveolar concentration of sevoflurane in dogs.
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      Reduction of the minimum alveolar concentration of isoflurane in dogs using a constant rate of infusion of lidocaine–ketamine in combination with either morphine or fentanyl.
      ).
      The aim of this study was to evaluate the ISO‐sparing effects of a continuous rate infusion (CRI) of fentanyl (FENT), lidocaine (LIDO), ketamine (KET), dexmedetomidine (DEX) on separate occasions, or the combination lidocaine‐ketamine‐dexmedetomidine (LKD) in dogs undergoing ovariohysterectomy. The authors hypothesized that all drug treatments would reduce the ISO requirements in comparison to a control group administered a single dose of butorphanol (CONTROL/BUT). This ISO‐sparing effect would lead to less hypotension during anesthesia and surgery in the treated groups.

      Materials and methods

      The study protocol was approved by the Animal Research Ethics Committee of the Faculty of Veterinary Medicine, Mexico State Autonomous University, Mexico (protocol number FE44/2009‐ 103.5/09/4195).

      Animals

      Fifty four client‐owned mixed‐breed intact non pregnant female dogs (1–6 years old) were enrolled in a randomized, prospective, blinded clinical study after the owner's written consent was obtained. The dogs were considered to be healthy based on medical history, physical examination, complete blood count (CBC) and serum biochemical analyses. Dogs with abnormal laboratory data or any clinical signs of systemic disease were not included in the study.

      Anesthetic procedure and treatments

      Food but not water was withheld for 10 hours before anesthesia. Approximately 5 minutes before induction of anesthesia, an arterial blood sample was collected percutaneously from the femoral artery in heparinized syringes (Pro‐vent Plus 1 mL; Smiths Medical, MN, USA), and immediately analyzed for arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), arterial pH (pHa), bicarbonate (HCO3), lactate and glucose concentrations (IL GEM Premier 3000, Instrumentation Laboratory, MA, USA). Blood‐gas measurements were corrected to body temperature.
      A 20‐gauge catheter was aseptically placed into a cephalic vein and connected to a resealable male luer injection port (BD‐luer loK; Becton Dickinson and Company, NJ, USA). Saline 0.9% (Solucion DX‐CS; Pisa Farmaceutica, Mexico) was administered at 3 mL kg−1 hour−1 throughout anesthesia by the use of a syringe infusion device (Graseby 3400; Graseby Medical, UK). Anesthesia was induced by administration of propofol (6 mg kg−1; Diprivan; Zeneca Pharma, Mexico) IV over 1 minute. The dogs were intubated with appropriately sized cuffed endotracheal tubes and connected to a rebreathing system (Multiplus MEVD; Royal Medical Co. Ltd., South Korea). ISO (Isoflurane USP, Piramal Health Care, India) in 100% oxygen was administered for maintenance of anesthesia, with an initial oxygen flow rate of approximately 100 mL kg−1 minute−1 that was reduced to approximately 50 mL kg−1 minute−1 after 15 minutes. Intermittent positive pressure ventilation (IPPV) was started at the beginning of anesthesia (Vent V; Royal Medical Co. Ltd) and adjusted to maintain eucapnia (end‐tidal carbon dioxide tension (Pe′CO2) 33–45 mmHg, 4.4–5.9 kPa). Dogs were then placed in lateral recumbency and a 22‐gauge catheter (Introcan; B‐Braun, Brazil) was introduced into a dorsal pedal artery for blood pressure monitoring and sampling of arterial blood. A thermal warming blanket (HoMedics HP300‐A; HoMedics, China) was used to maintain rectal temperature at 37–38ºC. All surgeries were performed through a ventral midline incision by the same surgeons (FDE/CSA).
      Five minutes after induction of anesthesia the dogs were randomly assigned to one of the following treatments:
      • Group FENT: A loading dose (5 μg kg−1) of fentanyl (Fentanest; Janssen, Mexico) followed by a CRI of 10 μg kg−1 hour−1;
      • Group KET: A loading dose (1 mg kg−1) of ketamine (Inoketan; Virbac, Mexico) followed by a CRI of 40 μg kg−1 minute−1;
      • Group LIDO: A loading dose (2 mg kg−1) of lidocaine (Pisacaina 2%; Pisa Farmaceutica, Mexico) followed by a CRI of 100 μg kg−1 minute−1;
      • Group DEX: A loading dose (1 μg kg−1) of dexmedetomidine (Dexdormitor; Pfizer Animal Health, Mexico) followed by a CRI of 3 μg kg−1 hour−1;
      • Group LKD: A loading dose (2 mg kg−1) of lidocaine followed by a CRI of 100 μg kg−1 minute−1, a loading dose (1 mg kg−1) of ketamine followed by a CRI of 40 μg kg−1 minute−1 and a loading dose (1 μg kg−1) of dexmedetomidine followed by a CRI of 3 μg kg−1 hour−1;
      • Group CONTROL/BUT: A loading dose (0.4 mg kg−1) of IV butorphanol (Torbugesic; Fort Dodge, IA, USA) followed by a CRI of saline 0.9%.
      Loading doses were diluted to a final volume of 0.2 mL kg−1 with sterile water and administered IV over 2 minutes. In all groups, drugs for CRI were diluted to 60 mL with saline 0.9% and delivered at 2 ml kg−1 hour−1. All CRIs were started immediately after the loading dose and infused (Colleague 3; Baxter, IN, USA) throughout anesthesia. Surgery commenced 45 minutes after the beginning of CRIs and instrumentation. As part of a different study, at the end of surgery, treatments were not discontinued but instead, doses were decreased and administered for another 4 hours as follows:
      • Group FENT: a CRI of 2.5 μg kg−1 hour−1;
      • Group KET: a CRI of 10 μg kg−1 minute−1;
      • Group LIDO: a CRI of 25 μg kg−1 minute−1;
      • Group DEX: a CRI of 1 μg kg−1 hour−1;
      • Group LKD: a CRI of 25 μg kg−1 minute−1 (LIDO), a CRI of 10 μg kg−1 minute−1 (KET) and a CRI of 1 μg kg−1 hour−1 (DEX) in combination;
      • Group CONTROL/BUT: a CRI of saline 0.9% at 2 ml kg−1 hour−1.
      Postoperative pain scores were evaluated using four different pain scoring systems and rescue analgesia was provided with IM and subcutaneous administration of morphine (0.5 mg kg−1; Graten; Pisa Farmaceutica, Mexico) and carprofen (4 mg kg−1; Rimadyl; Pfizer Animal Health, NY, USA), respectively. The latter data will be reported elsewhere.

      Monitoring, time points and adjustment of vaporizer settings

      Inspired ISO (FiIso) and end‐tidal ISO (Fe′Iso) concentrations, Pe′CO2 and respiratory rate (fR) were continuously monitored by sampling from the proximal end of the endotracheal tube (V9400 Capnograph Agent monitor; Surgivet, MA, USA). The gas analyzer was calibrated before starting each experiment with a standard gas mixture provided by the manufacturer (Agent Calibration kit, Surgivet).
      Heart rate (HR) and rhythm were obtained from a continuous lead II ECG recording. Systolic, mean and diastolic arterial blood pressures (SAP, MAP and DAP, respectively) were continuously monitored (Advisor; Surgivet) from the dorsal pedal artery via saline‐filled tubing connected to a pressure transducer (BD DTX Plus; Becton Dickinson and Company). The zero reference point for the pressure transducer was the level of the thoracic inlet while in dorsal recumbency. Hemoglobin oxygen saturation (SpO2) was monitored with a pulse oximeter (Advisor; Surgivet) with an infrared sensor attached to the dog's tongue. Rectal temperature (RT) was recorded with a digital thermometer. Arterial blood samples were collected for blood‐gas analysis at 10, 20, and 30 minutes during surgery and 10 minutes after extubation (POST).
      Data were recorded immediately at the beginning of the skin incision (T0, baseline), and then immediately after celiotomy (T1), during traction and ligation (just before excision) of the left (T2) and right ovary (T3), at the time that the uterus was clamped for performing the hysterectomy (T4), at the midpoint of closure of the abdominal wall (T5), at the midpoint of subcutaneous closure (T6), and at the midpoint of skin closure (T7).
      Surgical depth of anesthesia was assessed using the absence of palpebral reflex, lack of jaw tone, and MAP between 60 and 90 mmHg. Higher MAP was accepted if palpebral reflex and jaw tone were absent and no response to surgical stimulation was observed. Decreases in jaw tone were assessed by attempting to open the jaws wide and estimating the amount of passive resistance. Palpebral reflexes were tested by gently tapping the medial canthus of the eye. Based on clinical signs and autonomic responses to surgical stimulation, the vaporizer was adjusted by an anesthetist (EGB) who was blinded to the treatments. If MAP or HR increased by 20% from previously recorded values in response to surgical stimulation at the specified time points, surgery was stopped and isoflurane administration was increased. Surgery continued when MAP or HR values decreased below the initial 20% increment. Conversely, if MAP or HR values decreased by 20%, isoflurane administration was decreased. When MAP decreased to 60 mmHg, 0.9% saline, 5 mL kg−1, was infused over 15 minutes.
      Surgery time (time from the first incision until placement of the last suture), anesthesia time (time from injection of propofol to turning off the vaporizer), and time to extubation (time elapsed from turning off the vaporizer dial until extubation) were recorded for each dog. Dogs were disconnected from the rebreathing circuit at extubation. Time to first head lift, time to accomplish sternal recumbency (time elapsed from turning off the vaporizer until sternal recumbency), and time to standing (time elapsed from turning off the vaporizer until standing and defined as ability to stay standing at least 10 seconds without assistance) were recorded for each dog. Extubation was performed once the dogs’ cough reflex or swallowing was evident.

      Statistical analysis

      A Shapiro‐Wilk test was used to analyze data and normality. Data are reported as mean ± standard deviation (SD) values, except where indicated. To study temporal changes during anesthesia, a one‐way anova for repeated measures was performed for each group followed by Dunnett′s test when appropriate. For comparisons between groups, one‐way anova was performed at each time point followed by post‐hoc Tukey test when appropriate (Graphpad Software 5.0, CA, USA). Differences were considered significant at p < 0.05.

      Results

      Surgery was without complications in all cases and all dogs were discharged from the hospital 24 hours later. There were no significant differences among groups for body weight, anesthetic and surgery times (Table 1). Time to extubation was shorter in LIDO, and KET and CONTROL/BUT when compared with FENT, DEX or LKD, and DEX and LKD, respectively (p < 0.05) (Table 1). Time to first head lift was longer in LKD when compared with all other groups (p < 0.05). Time to sternal recumbency was shorter in LIDO when compared with FENT, and longer in LKD when compared with all groups, with the exception of FENT (p < 0.05). Time to standing was significantly shorter in LIDO when compared with FENT and KET, and longer in LKD when compared with all other groups.
      Table 1Body weight, surgery time, anesthetic time and specific recovery times (mean ± SD) in isoflurane‐anesthetized dogs undergoing ovariohysterectomy receiving a CRI of fentanyl (loading dose of 5 μg kg−1 followed by 10 μg kg−1 hour−1; FENT), ketamine (loading dose of 1 mg kg−1 followed by 40 μg kg−1 minute−1; KET), lidocaine (loading dose of 2 mg kg−1 followed by 100 μg kg−1 minute−1; LIDO), dexmedetomidine (loading dose of 1 μg kg−1 followed by 3 μg kg−1 hour−1; DEX), a combination of lidocaine‐ketamine‐dexmedetomidine (LKD) or saline 0.9%/butorphanol (loading dose of 0.4 mg kg−1 of IV butorphanol followed by a CRI of saline 0.9%; CONTROL/BUT)
      GroupBody weight (kg)Surgery time (minutes)Anesthetic time (minutes)Time to extubation (minutes)Time to first head lift (minutes)Time to sternal recumbency (minutes)Time to standing (minutes)
      FENT (n = 10)15.4 ± 5.938.7 ± 8.785.8 ± 11.512.0 ± 4.9ad16.1 ± 8bcd23.9 ± 10.1 cd36.5 ± 10.2b
      KET (n = 8)15.7 ± 4.740.9 ± 7.187.5 ± 9.47.3 ± 2.7bcd11.4 ± 4.4c21 ± 8.3bcd40.3 ± 13.6bd
      LIDO (n = 9)14.4 ± 5.939.3 ± 5.285.7 ± 10.86.3 ± 1.9bc9 ± 2.1bc11.3 ± 2.8b22.1 ± 5.9c
      DEX (n = 8)17 ± 6.441.5 ± 7.688.6 ± 12.314 ± 4.6a16.1 ± 5.6bcd21.3 ± 6.3bcd28.6 ± 9.3bc
      LKD (n = 10)16 ± 4.640 ± 8.390.1 ± 12.116.5 ± 4.9a29.6 ± 8.4a37.5 ± 10.2a59.9 ± 11.8a
      CONTROL/BUT (n = 9)15.2 ± 6.138.9 ± 8.986.9 ± 9.77.3 ± 2.8bcd9.7 ± 3.3bc14.4 ± 3.9bc26 ± 5.4bc
      a,b,c,d significantly different among groups (p < 0.05).

      Blood‐gas and biochemical variables

      Baseline measurements were not significantly different among groups for pH, PaCO2, PaO2, HCO3, glucose and lactate concentrations (Table 2). Some differences were found at different time points but all values were close to baseline values and unlikely to be of clinical relevance with the exception of glucose concentrations (Table 2).
      Table 2Arterial blood variables (mean ± SD) recorded in isoflurane‐anesthetized dogs undergoing ovariohysterectomy receiving either a CRI of fentanyl (FENT), ketamine (KET), lidocaine (LIDO), dexmedetomidine (DEX), lidocaine‐ketamine‐dexmedetomidine (LKD) or saline 0.9% (CONTROL/BUT). See Table 1 for dosage regimens
      VariablesGroupBaseline10 minutes20 minutes30 minutesPost
      pHFENT7.33 ± 0.067.34 ± 0.047.31 ± 0.037.31 ± 0.037.29 ± 0.04a
      KET7.38 ± 0.037.32 ± 0.05
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      7.29 ± 0.06a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      7.33 ± 0.03
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      7.33 ± 0.03
      LIDO7.38 ± 0.027.40 ± 0.077.38 ± 0.04b7.37 ± 0.037.39 ± 0.04b
      DEX7.39 ± 0.037.36 ± 0.047.34 ± 0.037.34 ± 0.037.37 ± 0.02b
      LKD7.40 ± 0.037.35 ± 0.057.33 ± 0.04
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      7.32 ± 0.04
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      7.38 ± 0.05b
      CONTROL/BUT7.32 ± 0.057.32 ± 0.087.30 ± 0.067.31 ± 0.087.32 ± 0.05
      PaCO2 (mmHg and kPa)FENT37 ± 4.437 ± 2.435 ± 3.634 ± 4.439 ± 4.7abd
      5.0 ± 0.64.9 ± 0.34.7 ± 0.54.6 ± 0.65.2 ± 0.6
      KET38 ± 2.536 ± 2.638 ± 1.135 ± 2.337 ± 3.8bc
      5.0 ± 0.34.7 ± 0.35.0 ± 0.24.7 ± 0.34.9 ± 0.5
      LIDO37 ± 4.236 ± 4.937 ± 1.834 ± 1.546 ± 5.5a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      5.0 ± 0.64.8 ± 0.64.9 ± 0.24.6 ± 0.26.1 ± 0.7
      DEX35 ± 2.635 ± 3.233 ± 1.9b34 ± 2.430 ± 0.9c
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      4.6 ± 0.34.7 ± 0.44.4 ± 0.34.5 ± 0.33.9 ± 0.1
      LKD36 ± 4.138 ± 5.937 ± 3.237 ± 2.136 ± 4.5bc
      4.8 ± 0.65.1 ± 0.85.0 ± 0.44.9 ± 0.34.7 ± 0.6
      CONTROL/BUT37 ± 3.139 ± 4.939 ± 1.8a38 ± 3.537 ± 4.1bc
      5.0 ± 0.45.1 ± 0.75.3 ± 0.25.0 ± 0.54.9 ± 0.5
      PaO2 (mmHg and kPa)FENT98 ± 6.5496 ± 73518 ± 69516 ± 78105 ± 12b
      13.1 ± 0.966.2 ± 9.769.1 ± 9.268.8 ± 10.414.0 ± 1.6
      KET97 ± 2569 ± 58567 ± 72587 ± 6799 ± 4
      12.9 ± 0.375.8 ± 7.875.6 ± 9.678.2 ± 9.013.2 ± 0.6
      LIDO98 ± 4558 ± 43593 ± 35547 ± 5689 ± 2a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      13.1 ± 0.574.3 ± 5.779.1 ± 4.773.0 ± 7.511.9 ± 0.2
      DEX96 ± 9557 ± 65532 ± 66561 ± 61111 ± 12b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      12.7 ± 1.274.3 ± 8.770.9 ± 8.874.8 ± 8.114.9 ± 1.7
      LKD98 ± 5532 ± 52577 ± 27557 ± 4399 ± 9
      13.1 ± 0.771.0 ± 6.976.9 ± 3.774.2 ± 5.713.2 ± 1.2
      CONTROL/BUT101 ± 4.7581 ± 69559 ± 73543 ± 68108 ± 9b
      13.4 ± 0.677.4 ± 9.274.5 ± 9.872.4 ± 9.114.4 ± 1.2
      HCO3 (mmol L−1)FENT21.1 ± 2.019.2 ± 2.5
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      18.7 ± 2.0
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      18.7 ± 2.0
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.1 ± 2.1
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      KET21.7 ± 2.119.5 ± 2.3
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      18.6 ± 2.2
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.1 ± 1.6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.6 ± 1.3
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LID21.0 ± 1.821.4 ± 2.421.1 ± 2.120.5 ± 1.522.1 ± 3.2
      DEX22.0 ± 1.419.9 ± 1.7
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.1 ± 1.3
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.5 ± 1.0
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.9 ± 1.1
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LKD21.4 ± 1.720.3 ± 2.620.0 ± 1.420.0 ± 1.620.4 ± 1.7
      CONTROL/BUT20.6 ± 2.620.8 ± 1.819.6 ± 2.218.6 ± 2.7
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      19.4 ± 1.7
      Glucose (mg dL−1)FENT106 ± 1791 ± 15b98 ± 22 cd113 ± 22bc119 ± 23bc
      KET105 ± 14112 ± 10122 ± 10abc132 ± 20abc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      136 ± 29
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LIDO97 ± 11100 ± 9b103 ± 10bc94 ± 7c100 ± 10c
      DEX93 ± 12137 ± 18a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      155 ± 34a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      167 ± 22a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      166 ± 25a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LKD93 ± 5112 ± 15131 ± 22ab
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      141 ± 27ab
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      149 ± 38ab
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      CONTROL/BUT100 ± 697 ± 22b111 ± 5bc108 ± 16bc119 ± 16
      Lactate (mmol L−1)FENT1.3 ± 0.41.4 ± 0.51.7 ± 0.7
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.9 ± 0.9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.9 ± 1.1
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      KET1.2 ± 0.22.0 ± 0.7
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.9 ± 0.4
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.9 ± 0.41.8 ± 0.4
      LIDO1.0 ± 0.41.5 ± 0.71.8 ± 0.71.7 ± 0.41.2 ± 0.4b
      DEX1.1 ± 0.31.6 ± 0.5
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.9 ± 0.4
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      2.2 ± 0.5
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.9 ± 0.5
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LKD1.2 ± 0.41.4 ± 0.51.6 ± 0.6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.7 ± 0.6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      1.4 ± 0.6b
      CONTROL/BUT1.5 ± 0.61.9 ± 0.82.3 ± 1.02.3 ± 1.12.8 ± 1.2a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      * Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      At 10 and 30 minutes, and at 20 minutes and POST, glucose concentrations were higher in DEX when compared with FENT, LIDO, CONTROL/BUT, and FENT and LIDO, respectively. At 30 minutes and POST, glucose was higher in LKD than in LIDO. Compared with baseline, glucose was significantly higher in DEX (10, 20, 30 minutes and POST), KET (30 minutes and POST) and LKD (20, 30 minutes and POST).

      Cardiopulmonary variables

      HR was significantly higher at T2 in FENT, LIDO and DEX, at T3 and T4 in DEX, and at T2 and T3 in CONTROL/BUT (Table 3). SAP, MAP and DAP were higher at T2, T3 and T4 when compared with baseline in CONTROL/BUT. SAP, MAP and DAP were higher from T2 to T7 when compared with baseline in all other groups. Two dogs in the DEX group developed a second degree atrioventricular (A‐V) block 3−5 minutes after the loading dose.
      Table 3Variables (mean ± SD) recorded in isoflurane‐anesthetized dogs undergoing ovariohysterectomy receiving either a CRI of fentanyl (FENT), ketamine (KET), lidocaine (LIDO), dexmedetomidine (DEX), lidocaine‐ketamine‐dexmedetomidine (LKD) or saline 0.9%/butorphanol (CONTROL/BUT). See Table 1 for dosage regimens
      VariablesGroupTime points
      T0T1T2T3T4T5T6T7
      HR (beats minute−1)FENT56 ± 10c56 ± 10bc73 ± 24cd
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      65 ± 23b61 ± 21b55 ± 16c55 ± 16de57 ± 16c
      KET105 ± 20a107 ± 20a115 ± 23ae
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      108 ± 18ac109 ± 17ad100 ± 23ab102 ± 18ac
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      111 ± 15de
      LIDO106 ± 20a101 ± 13a118 ± 18ae
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      109 ± 12ac99 ± 12ac98 ± 14ab97 ± 15abc99 ± 16abd
      DEX71 ± 14bc72 ± 17bc92 ± 21bcde
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      90 ± 24bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      86 ± 19cd
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      79 ± 20bc77 ± 19bd79 ± 18abc
      LKD78 ± 17b76 ± 16b82 ± 14bc85 ± 16bc80 ± 12bc78 ± 12bc74 ± 16be72 ± 14c
      CONTROL/BUT104 ± 7a104 ± 18a129 ± 10a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      129 ± 15a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      115 ± 7a114 ± 18a109 ± 21a104 ± 19ab
      SAP (mmHg)FENT79 ± 8a81 ± 8a117 ± 13
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      123 ± 18
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      113 ± 11a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      103 ± 14b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      103 ± 17ac
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      105 ± 14ac
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      KET88 ± 692 ± 14124 ± 17
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      126 ± 15
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      125 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      112 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      114 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      116 ± 12
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LIDO102 ± 15b101 ± 11b132 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      125 ± 6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      115 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      114 ± 12
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      113 ± 13
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      116 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      DEX100 ± 10b106 ± 11b135 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      134 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      131 ± 9b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      125 ± 6a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      126 ± 9b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      127 ± 11b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LKD104 ± 11b106 ± 9b124 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      126 ± 9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      121 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      117 ± 14
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      119 ± 15bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      120 ± 17
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      CONTROL/BUT86 ± 1689 ± 21125 ± 22
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      120 ± 21
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      115 ± 22
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      100 ± 22b97 ± 20a97 ± 25a
      DAP (mmHg)FENT47 ± 7a51 ± 10a89 ± 18a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      93 ± 21
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      78 ± 10d
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      72 ± 13ad
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      73 ± 19ad
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      73 ± 13ac
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      KET65 ± 1667 ± 1496 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      95 ± 6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      95 ± 11b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      83 ± 7bcd
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      83 ± 7
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      89 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LIDO75 ± 17b75 ± 13b102 ± 9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      97 ± 9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      90 ± 13
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      86 ± 9cd
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      87 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      85 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      DEX67 ± 13c78 ± 12c
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      110 ± 9b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      107 ± 6b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      102 ± 5bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      95 ± 6bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      92 ± 4bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      94 ± 2b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LKD79 ± 11d83 ± 9d101 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      103 ± 9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      97 ± 11b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      92 ± 12b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      92 ± 13b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      91 ± 11bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      CONTROL/BUT56 ± 17abc61 ± 22abc87 ± 21
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      82 ± 16a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      74 ± 14a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      63 ± 17a62 ± 20a61 ± 18a
      MAP (mmHg)FENT62 ± 5ad64 ± 8a101 ± 14a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      106 ± 19
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      95 ± 11b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      87 ± 13ac
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      87 ± 18b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      89 ± 14
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      KET73 ± 1576 ± 14107 ± 11
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      106 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      107 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      94 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      95 ± 7
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      99 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LIDO83 ± 14b86 ± 12113 ± 8
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      109 ± 6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      100 ± 12
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      96 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      96 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      97 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      DEX79 ± 1189 ± 9b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      119 ± 8b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      116 ± 6
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      112 ± 5a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      105 ± 5b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      104 ± 4a
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      106 ± 2b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      LKD89 ± 11bc91 ± 8b109 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      111 ± 9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      105 ± 10
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      102 ± 12bc
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      102 ± 13
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      102 ± 13
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      CONTROL/BUT69 ± 18a70 ± 22100 ± 20
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      97 ± 18
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      90 ± 17b
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      78 ± 18a78 ± 21b77 ± 19a
      Pe′CO2 (mmHg and kPa)FENT34.5 ± 1.435.2 ± 2.135.9 ± 1.735.6 ± 1.935.1 ± 1.135.4 ± 1.736.3 ± 1.736.4 ± 1.7
      4.6 ± 0.24.7 ± 0.34.8 ± 0.24.7 ± 0.34.7 ± 0.34.7 ± 0.14.8 ± 0.24.9 ± 0.2
      KET35.8 ± 2.336.0 ± 2.037.0 ± 2.1ac36.1 ± 2.537.3 ± 1.336.6 ± 1.636.1 ± 2.835.5 ± 2.6
      4.8 ± 0.34.8 ± 0.34.9 ± 0.34.8 ± 0.35.0 ± 0.24.9 ± 0.24.8 ± 0.44.7 ± 0.3
      LIDO35.8 ± 2.035.1 ± 2.035.3 ± 1.5bc36.4 ± 1.936.0 ± 1.936.4 ± 2.135.4 ± 2.035.6 ± 1.8
      4.8 ± 0.34.7 ± 0.34.7 ± 0.24.9 ± 0.34.8 ± 0.34.9 ± 0.34.7 ± 0.34.7 ± 0.2
      DEX35.5 ± 2.334.8 ± 2.335.5 ± 1.135.8 ± 2.536.4 ± 2.135.9 ± 1.535.8 ± 2.536.3 ± 2.2
      4.7 ± 0.34.6 ± 0.34.7 ± 0.14.8 ± 0.34.8 ± 0.34.8 ± 0.24.8 ± 0.34.8 ± 0.3
      LKD35.0 ± 1.935.4 ± 2.034.5 ± 1.6b35.6 ± 1.436.6 ± 2.2
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      36.6 ± 2.2
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      37.0 ± 2.3
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      36.9 ± 1.9
      Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      4.7 ± 0.34.7 ± 0.34.6 ± 0.34.7 ± 0.24.9 ± 0.24.9 ± 0.34.9 ± 0.34.9 ± 0.2
      CONTROL/BUT36.6 ± 2.136.6 ± 2.537.9 ± 1.5a36.7 ± 1.137.1 ± 0.937.3 ± 1.637.9 ± 1.337.3 ± 2.6
      4.9 ± 0.34.9 ± 0.35.0 ± 0.24.9 ± 0.15.0 ± 0.15.0 ± 0.25.0 ± 0.25.0 ± 0.3
      * Significantly different from baseline values (p < 0.05). a, b, c, d, e significantly different among groups (p < 0.05).
      fR, SpO2 and RT were not significantly different from baseline with any treatment (data not shown). fR, SpO2 and RT values were not significantly different among groups (p > 0.05). Pe′CO2 was higher in KET and CONTROL/BUT at T2 when compared to LKD and LIDO, respectively (Table 3) (p < 0.05). Other significant changes for HR, SAP, MAP and DAP are reported in Table 3.

      Isoflurane requirement

      Fe′Iso concentrations were higher at T2 and T3, in DEX and lower in FENT, KET, LKD at T6 and T7, respectively, when compared with baseline (Table 4). Overall Fe′Iso, mean ± SD, and % reduction in Fe′Iso (ranges) were 1.01 ± 0.31/41.6% (0.75 ± 0.31/56.6% to 1.12 ± 0.80/35.3%, FENT), 1.37 ± 0.19/20.8% (1.23 ± 0.14/28.9% to 1.51 ± 0.22/12.7%, KET), 1.34 ± 0.19/22.5% (1.24 ± 0.19/28.3% to 1.44 ± 0.21/16.8%, LIDO), 1.30 ± 0.28/24.8% (1.16 ± 0.18/32.9% to 1.43 ± 0.32/17.3%, DEX), 0.95 ± 0.19/54.9% (0.7 ± 0.16/59.5% to 1.12 ± 0.16/35.3%, LKD) and 1.73 ± 0.18/0.0% (1.64 ± 0.21 to 1.82 ± 0.14, CONTROL/BUT). Fe′Iso was significantly reduced in FENT and LKD at different time points than other groups. Fe′Iso was significantly higher in CONTROL/BUT than in other groups throughout surgery.
      Table 4Fe′Iso (mean ± SD) recorded in isoflurane‐anesthetized dogs undergoing ovariohysterectomy receiving either a CRI of fentanyl (FENT), ketamine (KET), lidocaine (LIDO), dexmedetomidine (DEX), lidocaine‐ketamine‐dexmedetomidine (LKD) or saline 0.9% ‐ butorphanol (CONTROL/BUT)
      GroupTime points
      T0T1T2T3T4T5T6T7
      FENT1.10 ± 0.24bd1.12 ± 0.28bd1.12 ± 0.37b1.06 ± 0.36bd1.05 ± 0.33bc1.01 ± 0.34bc0.86 ± 0.28be
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      0.75 ± 0.31be
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      KET1.43 ± 0.20ac1.44 ± 0.21ac1.42 ± 0.231.51 ± 0.22ac1.37 ± 0.15ac1.32 ± 0.15ac1.23 ± 0.14cd
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      1.24 ± 0.17cd
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      LIDO1.35 ± 0.14cd1.38 ± 0.17cd1.44 ± 0.211.42 ± 0.25acd1.32 ± 0.23abc1.27 ± 0.19cd1.26 ± 0.16cd1.24 ± 0.19cd
      DEX1.16 ± 0.26cd1.16 ± 0.18cd1.43 ± 0.34
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      1.43 ± 0.32ad
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      1.38 ± 0.32ac1.35 ± 0.31ac1.25 ± 0.27c1.21 ± 0.26c
      LKD1.01 ± 0.16b1.00 ± 0.16b1.12 ± 0.16b1.02 ± 0.22b0.98 ± 0.24b0.91 ± 0.24b0.83 ± 0.22b
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      0.70 ± 0.16b
      Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).
      CONTROL/BUT1.74 ± 0.18a1.73 ± 0.19a1.80 ± 0.18a1.82 ± 0.14a1.74 ± 0.19a1.69 ± 0.19a1.64 ± 0.21a1.65 ± 0.20a
      * Significantly different from baseline values (T0) within the group (p < 0.05). a,b,c,d significantly different among groups (p < 0.05).

      Discussion

      The results of this study show that, in comparison with the control group, all treatments were associated with significant decreases in Fe′Iso, and such findings were in accordance with the authors’ hypothesis. However, this isoflurane‐sparing effect did not always provide significantly higher blood pressures during anesthesia and surgery. The opioid vagal‐mediated bradycardia (Steagall et al.
      • Steagall PVM
      • Teixeira FJ
      • Minto BW
      • et al.
      Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs.
      ) produced by FENT may have partially prevented a greater increase in MAP that would be expected with reduced inhalant anesthetic administration. For any interpretation of data, one must bear in mind that all comparisons in this study were made with a group that had been administered a single dose of butorphanol, a drug that produces reduction in the minimum alveolar concentration of isoflurane (MACISO) in dogs (Ko et al.
      • Ko JC
      • Lange DN
      • Mandsager RE
      • et al.
      Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs.
      ). However, butorphanol is a short‐acting opioid analgesic (Camargo et al.
      • Camargo JB
      • Steagall PV
      • Minto BW
      • et al.
      Post-operative analgesic effects of butorphanol or firocoxib administered to dogs undergoing elective ovariohysterectomy.
      ) and decreases in isoflurane requirements would be also short‐lived since plasma concentrations of the drug would be expected to decline over time.
      HR was lower in the FENT group compared with the other groups, with the exception of DEX and LKD, throughout the surgery. Opioids may induce an increase in vagal tone leading to bradycardia (Steagall et al.
      • Steagall PVM
      • Teixeira FJ
      • Minto BW
      • et al.
      Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs.
      ) and anticholinergic drugs have been used to prevent or treat opioid‐induced bradycardia (Ilkiw et al.
      • Ilkiw JE
      • Pascoe PJ
      • Haskins SC
      • et al.
      The cardiovascular sparing effect of fentanyl and atropine, administered to enflurane anesthetized dogs.
      ; Dyson & James‐Davies
      • Dyson DH
      • James-Davies R
      Dose effect and benefits of glycopyrrolate in the treatment of bradycardia in anesthetized dogs.
      ). In this case, an improvement in arterial blood pressure and HR would have been evident in the opioid‐treated group as it has been observed in the clinical setting (Steagall et al.
      • Steagall PVM
      • Teixeira FJ
      • Minto BW
      • et al.
      Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs.
      ). HR was rarely different among FENT, DEX and LKD since a baroreflex physiological bradycardia is commonly observed after the administration of dexmedetomidine due to increases in systemic vascular resistance resulting from an alpha2‐mediated vasoconstriction in the peripheral blood vessels (Pascoe et al.
      • Pascoe PJ
      • Raekallio M
      • Kuusela E
      • et al.
      Changes in the MAC of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs.
      ). Based on previous studies of the cardiovascular effects of dexmedetomidine (Congdon et al.
      • Congdon JM
      • Marquez M
      • Niyom S
      • et al.
      Cardiovascular, respiratory, electrolyte and acid-base balance during continuous dexmedetomidine infusion in anesthetized dogs.
      ), it is likely that its administration (DEX and LKD groups) increased systemic vascular resistance that would have countered the isoflurane‐induced vasodilation.
      Short acting opioids such as FENT, a synthetic μ (OP3) agonist, have been used to improve analgesia during general anesthesia while providing inhalant anesthetic‐sparing effects. Fentanyl has been associated with good hemodynamic stability, although bradycardia and mild respiratory depression have been reported in dogs (Sano et al.
      • Sano T
      • Nishimura R
      • Kanazawa H
      • et al.
      Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs.
      ). In a recent study in dogs, MACISO was decreased by 35% after a loading dose of fentanyl (5 μg kg−1) followed by a CRI of 9 μg kg−1 hour−1 (Ueyama et al.
      • Ueyama Y
      • Lerche P
      • Eppler M
      • et al.
      Effects of intravenous administration of perzinfotel, fentanyl, and a combination of both drugs on the minimum alveolar concentration of isoflurane in dogs.
      ). These findings are consistent with our study, where at similar doses, a 41.6% overall reduction in ISO requirements was observed. In dogs undergoing unilateral mastectomy, decreases in ISO requirements ranged from 54 to 66% after a CRI of 30 μg kg−1 hour−1 of FENT, a three‐fold dosage increase in comparison with the current study (Steagall et al.
      • Steagall PVM
      • Teixeira FJ
      • Minto BW
      • et al.
      Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs.
      ). In the authors’ experience, the doses reported here are commonly used during general anesthesia in the canine patient. ISO‐sparing effects could have been greater with higher doses of fentanyl, or if used in high‐risk patients, or when other anesthetics or analgesics are combined (Ilkiw et al.
      • Ilkiw JE
      • Pascoe PJ
      • Haskins SC
      • et al.
      The cardiovascular sparing effect of fentanyl and atropine, administered to enflurane anesthetized dogs.
      ).
      Dexmedetomidine is the most selective alpha2 agonist that is commonly used in small animal anesthesia because of its sedative, anxiolytic and analgesic effects (Khan et al.
      • Khan ZP
      • Ferguson CN
      • Jones RM
      Alpha-2 and imidazoline receptor agonist. Their pharmacology and therapeutic role.
      ; Lin et al.
      • Lin G
      • Robben JH
      • Murrell JC
      • et al.
      Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs.
      ; Uilenreef et al.
      • Uilenreef JJ
      • Murrell JC
      • McKusick B
      • et al.
      Dexmedetomidine continuous rate infusion during isoflurane anaesthesia in canine surgical patients.
      ). It is also used to reduce the dose rates of other anesthetic agents administered for induction and maintenance of general anesthesia (Khan et al.
      • Khan ZP
      • Munday IT
      • Jones RM
      • et al.
      Effects of dexmedetomidine on isoflurane requirements in healthy volunteers 1: pharmacodynamic and pharmacokinetic interactions.
      ; Uilenreef et al.
      • Uilenreef JJ
      • Murrell JC
      • McKusick B
      • et al.
      Dexmedetomidine continuous rate infusion during isoflurane anaesthesia in canine surgical patients.
      ). In the present study, DEX decreased Fe′Iso by a similar magnitude previously measured in dogs (Pascoe et al.
      • Pascoe PJ
      • Raekallio M
      • Kuusela E
      • et al.
      Changes in the MAC of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs.
      ; Campagnol et al.
      • Campagnol D
      • Teixeira FJ
      • Giordano T
      • et al.
      Effects of epidural administration of dexmedetomidine on the minimum alveolar concentration of isoflurane in dogs.
      ; Uilenreef et al.
      • Uilenreef JJ
      • Murrell JC
      • McKusick B
      • et al.
      Dexmedetomidine continuous rate infusion during isoflurane anaesthesia in canine surgical patients.
      ). However, it is clear that ISO‐sparing effects were not as great as previously demonstrated (Pascoe et al.
      • Pascoe PJ
      • Raekallio M
      • Kuusela E
      • et al.
      Changes in the MAC of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs.
      ; Campagnol et al.
      • Campagnol D
      • Teixeira FJ
      • Giordano T
      • et al.
      Effects of epidural administration of dexmedetomidine on the minimum alveolar concentration of isoflurane in dogs.
      ; Uilenreef et al.
      • Uilenreef JJ
      • Murrell JC
      • McKusick B
      • et al.
      Dexmedetomidine continuous rate infusion during isoflurane anaesthesia in canine surgical patients.
      ). This may have been related to the doses employed here, but also because comparisons were made with a control group receiving butorphanol; an agonist at k (OP1) and antagonist at μ (OP3) opioid receptors that has been shown to decrease the MACISO by 20.3 ± 12.9% (Ko et al.
      • Ko JC
      • Lange DN
      • Mandsager RE
      • et al.
      Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs.
      ).
      Alpha2 agonists have been documented to produce transient hyperglycemia resulting from alpha2‐receptor‐mediated inhibition of insulin release from beta cells (Khan et al.
      • Khan ZP
      • Ferguson CN
      • Jones RM
      Alpha-2 and imidazoline receptor agonist. Their pharmacology and therapeutic role.
      ; Pawson
      • Pawson P
      Sedatives.
      ) and, therefore, it was not surprising that glucose concentrations were higher in groups LKD and DEX.
      Lidocaine is an amide local anesthetic that has been used as an adjunct of general anesthesia in dogs (Valverde et al.
      • Valverde A
      • Doherty TJ
      • Hernández J
      • et al.
      Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
      ; Wilson et al.
      • Wilson J
      • Doherty TJ
      • Egger CM
      • et al.
      Effects of intravenous lidocaine, ketamine, and the combination on the minimum alveolar concentration of sevoflurane in dogs.
      ). It reduces the MAC of volatile anesthetics in a dose‐dependent manner, and without significant cardiovascular changes (Valverde et al.
      • Valverde A
      • Doherty TJ
      • Hernández J
      • et al.
      Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
      ; Wilson et al.
      • Wilson J
      • Doherty TJ
      • Egger CM
      • et al.
      Effects of intravenous lidocaine, ketamine, and the combination on the minimum alveolar concentration of sevoflurane in dogs.
      ). When LIDO was administered to dogs (loading dose of 2 mg kg−1 followed by a CRI of 50 μg kg−1 minute−1), it decreased MACISO by 18.7% (Valverde et al.
      • Valverde A
      • Doherty TJ
      • Hernández J
      • et al.
      Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
      ), whereas a 29% reduction was obtained at the same CRI dose even without a loading dose (Muir et al.
      • Muir WW
      • Wiese AJ
      • March PA
      Effects of morphine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.
      ). In the present study, a reduction of 22.5% (range, 16.8 to 28.3%) in ISO requirement was recorded after a loading dose of 2 mg kg−1 followed by a CRI of 100 μg kg−1 minute−1 which was quite similar to the MAC studies (Muir et al.
      • Muir WW
      • Wiese AJ
      • March PA
      Effects of morphine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.
      ; Valverde et al.
      • Valverde A
      • Doherty TJ
      • Hernández J
      • et al.
      Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
      ).
      Ketamine is a dissociative anesthetic agent with N‐methyl‐D‐aspartate (NMDA) antagonistic properties that has been used to produce ISO‐sparing effects and postoperative analgesia (Wagner et al.
      • Wagner AE
      • Walton JA
      • Hellyer PW
      • et al.
      Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs.
      ). It has been demonstrated that a KET CRI reduces the MACISO in a dose‐dependent fashion (Muir et al.
      • Muir WW
      • Wiese AJ
      • March PA
      Effects of morphine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.
      ; Solano et al.
      • Solano AM
      • Pypendop BH
      • Boscan PL
      • et al.
      Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs.
      ; Wilson et al.
      • Wilson J
      • Doherty TJ
      • Egger CM
      • et al.
      Effects of intravenous lidocaine, ketamine, and the combination on the minimum alveolar concentration of sevoflurane in dogs.
      ). In the absence of a loading dose, a 10 μg kg−1 minute−1 dose of ketamine reduced the MACISO by 25% (Muir et al.
      • Muir WW
      • Wiese AJ
      • March PA
      Effects of morphine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane.
      ). Another study using target‐controlled infusion documented MACISO reduction from 10.9 to 39.5% in dogs (Solano et al.
      • Solano AM
      • Pypendop BH
      • Boscan PL
      • et al.
      Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs.
      ), similar to the 12.7 to 28.9% reduction in Fe′Iso in this study. Since lidocaine and ketamine have been shown to produce a dose‐dependent reduction in MACISO (Valverde et al.
      • Valverde A
      • Doherty TJ
      • Hernández J
      • et al.
      Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
      ; Solano et al.
      • Solano AM
      • Pypendop BH
      • Boscan PL
      • et al.
      Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs.
      ), it is clear that higher doses of both drugs could have produced greater ISO‐sparing effects. This study could not demonstrate that a significant reduction in ISO requirements in LIDO or KET was associated with a significantly higher blood pressure during surgery when compared with CONTROL/BUT. Lidocaine and ketamine CRIs may provide other benefits like sedation, analgesia or antihyperalgesia in dogs undergoing surgery that the current study design was not able to demonstrate. In addition, recovery times were shorter in these groups when compared with FENT, DEX and/or LKD.
      To the authors’ knowledge there is no published data about the use of LKD in dogs. In the study presented here, the combination LKD resulted in greater ISO‐sparing effects than LIDO, KET and DEX, although to a lesser extent than the sum of the three treatments. An additive effect may result from this protocol due to their different mechanisms of action in the nociceptive pathway (Hendrickx et al.
      • Hendrickx JFA
      • Eger EI
      • Sonner JM
      • et al.
      Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility.
      ). LIDO is a typical sodium channel blocker that reduces the inhalant MAC by means of its sedative and analgesics effects due to unclear mechanisms (Frölich et al.
      • Frölich MA
      • McKeown JL
      • Worrell MJ
      • et al.
      Intravenous lidocaine reduces ischemic pain in healthy volunteers.
      ). Ketamine is a dissociative anesthetic and NMDA receptor antagonist that may prevent central sensitization, opioid‐induced hyperalgesia, dependence and tolerance from occurring (Pozzi et al.
      • Pozzi A
      • Muir WW
      • Traverso F
      Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonist.
      ). Dexmedetomidine is an alpha2 adrenoreceptor agonist that induces sedation and analgesia by activation of alpha2 adrenoreceptors in the central nervous system and in the dorsal horn of the spinal cord (Murrell & Hellebrekers
      • Murrell JC
      • Hellebrekers LJ
      Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog.
      ). This may explain the profound reduction in Fe′Iso (54.9% and 35.3–59.5%, mean and range, respectively) after LKD in comparison with CONTROL/BUT, KET, LIDO, and at some time points, with DEX. This combination may be useful where opioids are unavailable, however the cardiovascular effects after LKD were similar to DEX. Recovery times (time to extubation, time to first head lift, time to sternal recumbency and time to standing) were longer in DEX and LKD than in other treated groups. In the clinical setting, this may be prevented by the administration of an alpha2 adrenoreceptor antagonist to antagonize the sedative and cardiovascular effects of dexmedetomidine.
      With the exception of LKD and LIDO, there was a significant HR increase at T2 in all groups when compared with baseline. This could be due to intense surgical stimulation and autonomic nervous system activation when traction and ligation of the ovaries were performed. The CONTROL/BUT required the highest concentrations of ISO to suppress such stimulus, accompanied by decreases in arterial blood pressure most likely mediated by isoflurane‐induced vasodilation. This study confirmed that the addition of other anesthetic agents administered by CRI decreased Fe′Iso and was accompanied by varying degrees of increased arterial blood pressure.

      Conclusion and clinical relevance

      At the doses administered, FENT and LKD resulted in greater ISO‐sparing effect than did LIDO, KET or CONTROL/BUT, although this was not observed at all time points. It appeared that the low HR induced by FENT may have contributed to lower arterial pressure than expected from reduced Fe′Iso.

      Acknowledgements

      Eduardo Gutierrez‐Blanco was sponsored by a scholarship provided by SEP‐PROMEP.

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