• View in gallery

    Mean ± SEM algometric pressure tolerance in 6 healthy dogs at predetermined time points before (baseline [time 0]) and after a single IM injection of DBTZ (dexmedetomidine [7.5 μg/kg]–butorphanol [0.15 mg/kg]–tiletamine-zolazepam [3.0 mg/kg]; white circles) or DTrK (dexmedetomidine [15.0 μg/kg]-tramadol [3.0 mg/kg]-ketamine [3.0 mg/kg]; black triangles). Each dog received each treatment in a crossover-design study with a 5-day washout period between treatments; the algometer probes were applied to a hind paw digit. *Within a treatment, value differs significantly (P < 0.05) from baseline values. †Within a time point, values differ significantly (P < 0.05) between DBTZ and DTrK treatment groups.

  • View in gallery

    Mean ± SEM tolerance to transcutaneous electrical nerve stimulation in the same 6 dogs in Figure 1. The nerve stimulator was attached via two 25-gauge needles inserted in the skin over the lateral aspect of a femur. The device was set in tetanus mode to deliver a 0.22-millisecond square wave pulse stimulus of 400 V at incremental values of 0 to 100 pulses/s (Hz), where 1 = 0 Hz, and 9 = 100 Hz; the test was not performed at baseline in unanesthetized dogs. *Within a treatment, value differs significantly (P < 0.05) from 0. See Figure 1 for remainder of key.

  • View in gallery

    Mean ± SEM heart rate determined via auscultation in the same 6 dogs in Figure 1. See Figure 1 for remainder of key.

  • View in gallery

    Mean ± SEM indirect MAP determined via oscillometry in the same 6 dogs as in Figure 1. See Figure 1 for remainder of key.

  • View in gallery

    Mean ± SEM values for ETco2 determined via capnography for the same dogs as in Figure 1. See Figure 1 for remainder of key.

  • 1. Ko JC, Payton M & Weil AB et alComparison of anesthetic and cardiorespiratory effects of tiletamine-zolazepam-butorphanol and tiletamine-zolazepam-butorphanol-medetomidine in dogs. Vet Ther 2007; 8: 113126.

    • Search Google Scholar
    • Export Citation
  • 2. Barletta M, Austin BR & Ko JC et alEvaluation of dexmedetomidine and ketamine in combination with opioids as injectable anesthesia for castration in dogs. J Am Vet Med Assoc 2011; 238: 11591167.

    • Search Google Scholar
    • Export Citation
  • 3. Krimins RA, Ko JC & Weil AB et alHemodynamic effects in dogs after intramuscular administration of a combination of dexmedetomidine-butorphanol-tiletamine-zolazepam or dexmedetomidine-butorphanol-ketamine. Am J Vet Res 2012; 73: 13631370.

    • Search Google Scholar
    • Export Citation
  • 4. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879923.

  • 5. Seddighi MR, Egger CM & Rohrbach BW et alEffects of tramadol on the minimum alveolar concentration of sevoflurane in dogs. Vet Anaesth Analg 2009; 36: 334340.

    • Search Google Scholar
    • Export Citation
  • 6. Mastrocinque S, Fantoni DT. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg 2003; 30: 220228.

    • Search Google Scholar
    • Export Citation
  • 7. Monteiro ER, Junior AR & Assis HM et alComparative study on the sedative effects of morphine, methadone, butorphanol or tramadol, in combination with acepromazine, in dogs. Vet Anaesth Analg 2009; 36: 2533.

    • Search Google Scholar
    • Export Citation
  • 8. Tas O, De Rooster H & Baert E et alThe accuracy of the Lactate Pro hand-held analyser to determine blood lactate in healthy dogs. J Small Anim Pract 2008; 49: 504508.

    • Search Google Scholar
    • Export Citation
  • 9. Bernhardt O, Schiffman EL, Look JO. Reliability and validity of a new fingertip-shaped pressure algometer for assessing pressure pain thresholds in the temporomandibular joint and masticatory muscles. J Orofac Pain 2007; 21: 2938.

    • Search Google Scholar
    • Export Citation
  • 10. Varcoe-Cocks K, Sagar KN & Jeffcott LB et alPressure algometry to quantify muscle pain in racehorses with suspected sacroiliac dysfunction. Equine Vet J 2006; 38: 558562.

    • Search Google Scholar
    • Export Citation
  • 11. McMillan CJ, Livingston A & Clark CR et alPharmacokinetics of intravenous tramadol in dogs. Can J Vet Res 2008; 72: 325331.

  • 12. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001; 53: 597652.

  • 13. Beck CC. Chemical restraint of exotic species. J Zoo Wildl Med 1972; 3: 366.

  • 14. Gray CW, Bush M, Beck CC. Clinical experience using CI-744 in chemical restraint and anesthesia of exotic animals. J Zoo Wildl Med 1974; 5: 1221.

    • Search Google Scholar
    • Export Citation
  • 15. Ko JC, Knesl O & Weil AB et alFAQs—analgesia, sedation, and anesthesia: making the switch from medetomidine to dexmedetomidine. Compend Contin Educ Pract Vet 2009; 31(suppl 1A): 124.

    • Search Google Scholar
    • Export Citation
  • 16. Ko JC, Berman AG. Anesthesia in shelter medicine. Top Companion Anim Med 2010; 25: 9297.

  • 17. Itami T, Tamaru N & Kawase K et alCardiovascular effects of tramadol in dogs anesthetized with sevoflurane. J Vet Med Sci 2011; 73: 16031609.

    • Search Google Scholar
    • Export Citation
  • 18. Pang D, Boysen S. Lactate in veterinary critical care: pathophysiology and management. J Am Anim Hosp Assoc 2007; 43: 270279.

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Evaluation of anesthetic, analgesic, and cardiorespiratory effects in dogs after intramuscular administration of dexmedetomidine–butorphanol–tiletamine-zolazepam or dexmedetomidine-tramadol-ketamine drug combinations

Rebecca A. Krimins DVM, MS1, Jeff C. Ko DVM, MS2, Ann B. Weil MS, DVM3, and Mark E. Payton PhD4
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  • 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
  • | 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
  • | 3 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
  • | 4 Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078.

Abstract

Objective—To compare anesthetic, analgesic, and cardiorespiratory effects in dogs after IM administration of dexmedetomidine (7.5 μg/kg)–butorphanol (0.15 mg/kg)–tiletamine-zolazepam (3.0 mg/kg; DBTZ) or dexmedetomidine (15.0 μg/kg)-tramadol (3.0 mg/kg)-ketamine (3.0 mg/kg; DTrK) combinations.

Animals—6 healthy adult mixed-breed dogs.

Procedures—Each dog received DBTZ and DTrK in a randomized, crossover-design study with a 5-day interval between treatments. Cardiorespiratory variables and duration and quality of sedation-anesthesia (assessed via auditory stimulation and sedation-anesthesia scoring) and analgesia (assessed via algometry and electrical nerve stimulation) were evaluated at predetermined intervals.

Results—DBTZ or DTrK induced general anesthesia sufficient for endotracheal intubation ≤ 7 minutes after injection. Anesthetic quality and time from drug administration to standing recovery (131.5 vs 109.5 minutes after injection of DBTZ and DTrK, respectively) were similar between treatments. Duration of analgesia was significantly longer with DBTZ treatment, compared with DTrK treatment. Analgesic effects were significantly greater with DBTZ treatment than with DTrK treatment at several time points. Transient hypertension (mean arterial blood pressure > 135 mm Hg), bradycardia (heart rate < 60 beats/min), and hypoxemia (oxygen saturation < 90% via pulse oximetry) were detected during both treatments. Tidal volume decreased significantly from baseline with both treatments and was significantly lower after DBTZ administration, compared with DTrK, at several time points.

Conclusions and Clinical Relevance—DBTZ or DTrK rapidly induced short-term anesthesia and analgesia in healthy dogs. Further research is needed to assess efficacy of these drug combinations for surgical anesthesia. Supplemental 100% oxygen should be provided when DBTZ or DTrK are used.

Abstract

Objective—To compare anesthetic, analgesic, and cardiorespiratory effects in dogs after IM administration of dexmedetomidine (7.5 μg/kg)–butorphanol (0.15 mg/kg)–tiletamine-zolazepam (3.0 mg/kg; DBTZ) or dexmedetomidine (15.0 μg/kg)-tramadol (3.0 mg/kg)-ketamine (3.0 mg/kg; DTrK) combinations.

Animals—6 healthy adult mixed-breed dogs.

Procedures—Each dog received DBTZ and DTrK in a randomized, crossover-design study with a 5-day interval between treatments. Cardiorespiratory variables and duration and quality of sedation-anesthesia (assessed via auditory stimulation and sedation-anesthesia scoring) and analgesia (assessed via algometry and electrical nerve stimulation) were evaluated at predetermined intervals.

Results—DBTZ or DTrK induced general anesthesia sufficient for endotracheal intubation ≤ 7 minutes after injection. Anesthetic quality and time from drug administration to standing recovery (131.5 vs 109.5 minutes after injection of DBTZ and DTrK, respectively) were similar between treatments. Duration of analgesia was significantly longer with DBTZ treatment, compared with DTrK treatment. Analgesic effects were significantly greater with DBTZ treatment than with DTrK treatment at several time points. Transient hypertension (mean arterial blood pressure > 135 mm Hg), bradycardia (heart rate < 60 beats/min), and hypoxemia (oxygen saturation < 90% via pulse oximetry) were detected during both treatments. Tidal volume decreased significantly from baseline with both treatments and was significantly lower after DBTZ administration, compared with DTrK, at several time points.

Conclusions and Clinical Relevance—DBTZ or DTrK rapidly induced short-term anesthesia and analgesia in healthy dogs. Further research is needed to assess efficacy of these drug combinations for surgical anesthesia. Supplemental 100% oxygen should be provided when DBTZ or DTrK are used.

Injectable anesthetic combinations can provide an alternative to inhalation anesthesia for surgical procedures in dogs. Agents that can be administered IM may be particularly useful when the anesthetist encounters an excited, nervous, or aggressive dog that does not allow restraint for placement of an IV catheter for anesthetic administration or placement of a face mask for inhalation anesthesia induction. The IM administration of injectable anesthetic combinations at various dosages as premedication in dogs is a common practice in modern veterinary anesthesia that can smooth the transition to IV anesthetic induction and maintenance with inhalation anesthesia. Results of a previous study1 comparing the effects of butorphanol–tiletamine-zolazepam combinations with and without medetomidine in dogs indicated that adding medetomidine (15 μg/kg) to a lower dose of butorphanol–tiletamine-zolazepam (0.15 mg of butorphanol/kg and 3 mg of tiletamine-zolazepam/kg) induced better sedative and analgesic effects with a smoother recovery, compared with administration of a higher dose of butorphanol–tiletamine-zolazepam (0.2 mg of butorphanol/kg and 5 mg of tiletamine-zolazepam/kg) alone. In that study,1 the addition of an α2–adrenoceptor agonist, medetomidine, to the protocol enhanced the sedative effects of butorphanol–tiletamine-zolazepam, allowing smaller doses of these drugs to be used and significantly improving the quality of muscle relaxation and analgesia. Results of another study2 evaluating dexmedetomidine (15 μg/kg)-ketamine (3.0 mg/kg) in combination with various opioids (hydromorphone [0.05 mg/kg], buprenorphine [40 μg/kg], and butorphanol [0.2 mg/kg]) in dogs undergoing castration showed that all 3 anesthetic combinations provided suitable anesthesia for completion of the surgical procedure in most patients. A hemodynamic study3 comparing dexmedetomidine-butorphanol-ketamine with DBTZ in dogs found that DBTZ and dexmedetomidine-butorphanol-ketamine had similar hemodynamic profiles characterized by increased MAP, increased systemic vascular resistance, and reflex bradycardia. That study3 also revealed that the oxygen extraction ratio was significantly higher in dogs that received dexmedetomidine-butorphanol-ketamine than in DBTZ-treated dogs.

Tramadol is a centrally acting, synthetic opioid with a molecular structure similar to that of codeine.4 Tramadol induces analgesia through 2 mechanisms; tramadol and its metabolite O-desmethyl-tramadol (M1) act on μ-opioid receptors, and tramadol also inhibits serotonin and norepinephrine reuptake, enhancing inhibition of pain transmission in the spinal cord.4 Tramadol has been shown to significantly reduce the minimum alveolar concentration of sevoflurane in dogs.5 The IV administration of 2.0 mg of tramadol/kg shortly after anesthetic induction but before surgery produced comparable postoperative analgesia with less respiratory depression in dogs undergoing ovariohysterectomy, compared with morphine (0.2 mg/kg, IV) administered in the same manner.6 In a comparative study7 in dogs, when various opioids were given after administration of acepromazine (0.05 mg/kg, IV), the sedative effects of tramadol (2.0 mg/kg, IV) were similar to those of morphine (0.5 mg/kg, IV) or butorphanol (0.15 mg/kg, IV) but were less intense than those of methadone (0.5 mg/kg, IV).

In many countries, an injectable formulation of tramadol is readily available and is not considered a controlled substance; this makes it attractive as part of an anesthetic-analgesic combination. The use of this formulation of tramadol (not currently commercially available in the United States) as a component of an injectable anesthetic protocol is novel. The sedative and analgesic properties of tramadol in combination with sedatives such as dexmedetomidine and dissociatives such as ketamine or tiletamine have not been explored. Furthermore, the cardiorespiratory effects of tramadol may be less profound than that of other opioids, providing an advantage when used as part of an anesthetic combination.

The purpose of the study reported here was to compare anesthetic, analgesic, and cardiorespiratory effects in dogs after IM administration of DBTZ or DTrK. The DBTZ protocol has been previously described3; the doses of dexmedetomidine and ketamine for use with tramadol were selected on the basis of doses used to induce a surgical plane of anesthesia in combination with various opioids in a previous study,2 and the tramadol dose was chosen on the basis of results of a pilot study. Furthermore, results from a pilot study in our laboratory indicated that a dose of dexmedetomidine < 15 μg/kg in combination with ketamine (3.0 mg/kg) would not produce a surgical plane of anesthesia in dogs and resulted in a poorer overall quality of anesthesia, compared with DBTZ.

Materials and Methods

Animals—Six healthy mixed-breed dogs (2 female and 4 male) were used in the study. Dogs were 2 years old with a mean ± SD weight of 19.4 ± 2.4 kg. Each dog was considered healthy on the basis of history and results of a complete physical examination, CBC, and serum biochemical analysis. Food, but not water, was withheld for 12 hours prior to induction of general anesthesia. The study was approved by the Purdue University Animal Care and Use Committee.

Study design—Each dog received 2 injectable anesthetic combinations (DBTZ and DTrK) in a randomized crossover study with a 5-day washout period between treatments. The DBTZ treatment contained dexmedetomidinea (7.5 μg/kg), butorphanol tartrateb (0.15 mg/kg), and tiletamine-zolazepamc (3.0 mg/kg). The DTrK treatment consisted of dexmedetomidinea (15.0 μg/kg), tramadol hydrochlorided (3.0 mg/kg), and ketamine hydrochloridee (3.0 mg/kg).

Cardiorespiratory variables and response to auditory stimulation were assessed at baseline (immediately prior to drug administration) and at 5, 10, 15, 20, 30, 40, 50, 60, 70, and 80 minutes after anesthetic injection. Analgesia was assessed via response to noxious stimulus; this was determined with algometryf only at baseline and was subsequently evaluated with algometry and electrical nerve stimulationg at 5, 10, 15, 20, 30, 40, 50, 60, 70, and 80 minutes after anesthetic injection. Blood samples (0.1 mL) were collected for measurement of lactate concentrations at 0 (baseline), 10, 20, 40, 60, and 80 minutes; samples were obtained via venipuncture of a cephalic vein with an insulin syringe, and lactate concentrations were measured with a commercially available unith validated for use in dogs.8 Cardiorespiratory data were collected prior to all other assessments at each time point. Investigators performing the evaluations were blinded to the treatment administered.

Induction of anesthesia—Drugs were drawn up in separate syringes immediately prior to injection and then mixed in 1 syringe for IM administration in the right or left quadriceps femoris muscle. After a dog became recumbent, it was placed on a warm water circulating blanketi in right lateral recumbency and covered with a forced hot-air warmer blanketj to maintain body temperature. Rectal temperature was measured during anesthesia with a thermometer. Each dog was intubated shortly after injection with an appropriately sized endotracheal tube and was monitored throughout anesthesia and recovery.

Measurement of cardiorespiratory variables—Heart rate was determined via auscultation with a stethoscope. Indirect MAP, Spo2 (measured with a probe placed on a toe web [in awake dogs] or on the tongue [in anesthetized dogs]) and ETco2 (measured via a tightly fitted face mask, or an endotracheal tube when dogs were intubated) were determined by use of an electronic monitork that included an oscillometric device, pulse oximeter, and capnograph. The same monitork included a lead II ECG used to continuously monitor dogs for cardiac arrhythmias. Respiratory rate and minute volume were measured with a respirometerl attached to the tightly fitted face mask (prior to anesthesia) or endotracheal tube (during anesthesia). Tidal volume was derived from the following equation: minute volume = respiratory rate × tidal volume. Dogs were allowed to spontaneously breathe room air throughout the study.

Assessment of sedation-anesthesia—Response to auditory stimulus was evaluated with a clickerm held close to the dog's ear. The clicking noise was made 3 times in rapid succession, and sedation was graded according to predetermined response criteria (Appendix 1).1,2 Times from injection to onset of sedation (ie, reduced activity) and lateral recumbency, duration of lateral recumbency, duration of endotracheal intubation, time from injection to extubation, time from injection to sternal recumbency during recovery, and time from injection to standing recovery were recorded. Scores were assessed for overall quality of endotracheal intubation, sedation-anesthesia, and recovery as previously described (Appendices 2–4).1,2

Evaluation of analgesia—Analgesia was assessed via 2 methods previously found to be reproducible in dogs.1 Response to a noxious stimulus was assessed by use of an algometerf with sensors applied to a hind paw digit; determination of pain thresholds for pressure application in soft tissues, muscles, and joints in humans9 and horses10 has been described elsewhere. The algometerf used in the present study (calibrated before each use according to the manufacturer's recommended procedure) was equipped with a squeeze handle; when squeezed, 2 nontraumatizing probes exerted a noxious pressure (device range, 0 to 2,000 kPa/s) on the tissue. Pressure was gradually increased from 0 kPa/s until the dog responded to the stimulus. When a response (eg, withdrawal of the limb, head lifting, or other purposeful movement such as ear twitching, swallowing, or eye blinking) was detected, the pressure was released and the digital pressure reading was recorded.

Transcutaneous electrical nerve stimulation was performed in anesthetized dogs with a nerve stimulatorg attached via two 25-gauge needles inserted in the skin over the lateral aspect of the left femur. The needles were placed 5 cm apart and attached to the nerve stimulator electrode. The device was used in tetanus mode to provide a 0.22-millisecond square wave pulse stimulus of 400 V at intensity settings of 0 to 100 pulses/s (Hz), where 1 indicated the lowest intensity setting (0 Hz) and 9 indicated the highest intensity setting (100 Hz). At each time point, stimulation was performed for 2 seconds beginning with the lowest setting. The setting at which there was no response (ie, no gross purposeful movement, including lack of limb withdrawal, head or neck moving, tail twitching, swallowing, or blinking) was determined and recorded. If a test result was negative, intensity was increased by 1 setting until a response was detected or the maximum stimulation was reached; if a test result was positive, intensity was reduced by 1 setting and the test was repeated.

Statistical analysis—Statistical analyses were conducted with commercially available statistical software.n,o Data for response to auditory stimulus were analyzed with nonparametric ANOVA,n and results are reported as median and range. All parametric data are reported as mean ± SEM. A mixed model ANOVA procedureo was used to determine significance of the differences attributable to treatments. Pairwise t tests were performed when results of ANOVA were significant. Values of P < 0.05 were considered significant.

Results

No vomiting, retching, or profuse salivation was observed in any of the treated dogs during the study. All dogs completed the study and recovered uneventfully.

Sedation-anesthesia—Intramuscular administration of DBTZ or DTrK rapidly induced lateral recumbency with a smooth transition to general anesthesia in all dogs; endotracheal intubation was completed ≤ 7 minutes after injection in all dogs. There were no significant differences in time from injection to onset of sedation (2.3 ± 0.2 minutes vs 2.7 ± 0.2 minutes) or time from injection to lateral recumbency (5.1 ± 0.8 minutes vs 6.2 ± 1.0 minutes) between the DBTZ and DTrK treatments, respectively. Quality scores for endotracheal intubation (3.0 ± 0.0) and sedation-anesthesia (4.0 ± 0.0) were identical for the 2 treatments. Duration of intubation was significantly longer after DBTZ administration (82.3 ± 4.4 minutes) than after DTrK administration (66.2 ± 7.1 minutes). The degree of sedation as assessed via auditory stimulation response scores was significantly greater, compared with baseline values, from 5 to 80 minutes after injection of DBTZ or DTrK (Table 1).

Table 1—

Median (range) scores for sedation evaluated via response to auditory stimulation (noise made with a clicker held close to the ear; range of possible scores, 1 to 5) in 6 healthy dogs before (baseline [time 0]) and after a single IM injection of DBTZ (dexmedetomidine [7.5 μg/kg]-butorphanol [0.15 mg/kg]-tiletamine-zolazepam [3.0 mg/kg]) or DTrK (dexmedetomidine [15.0 μg/kg]-tramadol [3.0 mg/kg]-ketamine [3.0 mg/kg]).

Time (min)Score
DBTZDTrK
01.0 (1.0–1.0)1.0 (1.0–1.0)
55.0* (5.0–5.0)5.0* (4.0–5.0)
105.0* (5.0–5.0)5.0* (5.0–5.0)
155.0* (5.0–5.0)5.0* (5.0–5.0)
205.0* (5.0–5.0)5.0* (4.0–5.0)
305.0* (5.0–5.0)5.0* (4.0–5.0)
405.0* (5.0–5.0)5.0* (4.0–5.0)
505.0* (5.0–5.0)4.0* (3.0–5.0)
605.0* (2.0–5.0)4.0* (3.0–5.0)
704.5* (1.0–5.0)4.0* (3.0–5.0)
804.0* (1.0–5.0)4.0* (3.0–5.0)

Each dog received each treatment in a crossover-design study with a 5-day washout period between treatments.

Within a treatment, value differs significantly (P < 0.05) from the baseline value.

Within a time point, values differ significantly (P < 0.05) between DBTZ and DTrK treatment groups.

Time from injection to sternal recumbency during recovery was significantly longer with DBTZ treatment (118.3 ± 10.6 minutes) than with DTrK treatment (76.3 ± 5.2 minutes). However, the time from injection to standing recovery was similar between treatments (131.5 ± 15.5 minutes vs 109.5 ± 21.5 minutes for DBTZ and DTrK, respectively). During recovery, the time from sternal recumbency to standing was significantly longer with DTrK treatment (33.2 ± 19.7 minutes) than with DBTZ treatment (13.2 ± 7.2 minutes). Recovery quality scores were similar between treatments (3.8 ± 0.5 and 3.9 ± 0.2 for DBTZ and DTrK, respectively), and recovery after both treatments was considered smooth in all dogs.

Analgesia—Duration of analgesia measured via algometry and electrical nerve stimulation was significantly longer with DBTZ treatment (70 and 60 minutes, respectively), compared with that of DTrK treatment (50 and 40 minutes, respectively; Figures 1 and 2). Intensity of analgesia was significantly greater with DBTZ treatment than with DTrK treatment from 30 to 70 minutes after injection as measured via algometry and from 20 to 60 minutes after injection as measured via electrical nerve stimulation.

Figure 1—
Figure 1—

Mean ± SEM algometric pressure tolerance in 6 healthy dogs at predetermined time points before (baseline [time 0]) and after a single IM injection of DBTZ (dexmedetomidine [7.5 μg/kg]–butorphanol [0.15 mg/kg]–tiletamine-zolazepam [3.0 mg/kg]; white circles) or DTrK (dexmedetomidine [15.0 μg/kg]-tramadol [3.0 mg/kg]-ketamine [3.0 mg/kg]; black triangles). Each dog received each treatment in a crossover-design study with a 5-day washout period between treatments; the algometer probes were applied to a hind paw digit. *Within a treatment, value differs significantly (P < 0.05) from baseline values. †Within a time point, values differ significantly (P < 0.05) between DBTZ and DTrK treatment groups.

Citation: American Journal of Veterinary Research 73, 11; 10.2460/ajvr.73.11.1707

Figure 2—
Figure 2—

Mean ± SEM tolerance to transcutaneous electrical nerve stimulation in the same 6 dogs in Figure 1. The nerve stimulator was attached via two 25-gauge needles inserted in the skin over the lateral aspect of a femur. The device was set in tetanus mode to deliver a 0.22-millisecond square wave pulse stimulus of 400 V at incremental values of 0 to 100 pulses/s (Hz), where 1 = 0 Hz, and 9 = 100 Hz; the test was not performed at baseline in unanesthetized dogs. *Within a treatment, value differs significantly (P < 0.05) from 0. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 73, 11; 10.2460/ajvr.73.11.1707

Cardiorespiratory variables—Heart rate response was biphasic after administration of DBTZ or DTrK, with a significant decrease from baseline values 5 minutes after injection, a return to values similar to baseline from 10 to 15 (DTrK) or 20 (DBTZ) minutes after injection, and a significant decrease from baseline values at all remaining time points (Figure 3). Bradycardia (heart rate < 60 beats/min) occurred with both treatments; this was detected from 40 to 80 minutes after injection of DTrK and 50 and 80 minutes after injection of DBTZ. The lowest mean heart rate detected was 41.3 ± 3.2 beats/min after DTrK administration and 57.0 ± 9.0 beats/min after DBTZ administration, both at 80 minutes after injection. Differences in heart rate were not significantly different between the 2 treatments. Other than bradycardia and sinus arrhythmias, no cardiac arrhythmias were detected during the study.

Figure 3—
Figure 3—

Mean ± SEM heart rate determined via auscultation in the same 6 dogs in Figure 1. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 73, 11; 10.2460/ajvr.73.11.1707

The MAP was significantly increased, compared with baseline values, from 5 to 20 minutes after DBTZ administration and from 5 to 30 minutes after DTrK administration (Figure 4). Thereafter, MAP was similar to baseline at all time points evaluated for both treatments. The MAP was significantly higher with DTrK treatment (170.0 ± 18.3 mm Hg) than with DBTZ treatment (141.5 ± 9.9 mm Hg) at 5 minutes after injection. Compared with baseline values, respiratory rates were significantly decreased from 5 to 80 minutes after injection and ETco2 was significantly increased from 5 to 80 minutes after injection for both treatments (Table 2; Figure 5). The ETco2 was significantly higher with DBTZ treatment than with DTrK treatment from 40 to 70 minutes after injection. In addition, respiratory depression was more profound with DBTZ treatment than with DTrK treatment; tidal volume was significantly lower at 5, 10, 60, 70, and 80 minutes after injection of DBTZ. Hypoxemia (Spo2 < 90%) was detected at 10 to 20 minutes after injection during both treatments. The lowest mean Spo2 reading was 79 ± 3% with DBTZ treatment and 85 ± 1% with DTrK treatment; both occurred 10 minutes after injection, and the Spo2 remained between 91 ± 1% and 94 ± 4% thereafter for both treatments. Body temperatures were maintained between 37.2° and 38.6°C throughout anesthesia. Blood lactate concentrations were within the laboratory reference interval and < 1.5 mmol/L at all time points for both treatments.

Table 2—

Mean ± SEM respiratory rate and tidal volume at predetermined time points in the same 6 dogs as in Table 1.

Time (min)Respiratory rate (breaths/min)Tidal volume (mL/breath)
DBTZDTrKDBTZDTrK
025 ± 226 ± 3251 ± 40248 ± 48
513 ± 3*†7 ± 1*†180 ± 28*†230 ± 72*†
1010 ± 1*9 ± 2*146 ± 13*†221 ± 10*†
1510 ± 1*10 ± 1*150 ± 13*182 ± 14
209 ± 1*12 ± 1*160 ± 11*178 ± 12
309 ± 1*11 ± 1*173 ± 9197 ± 12
4010 ± 1*12 ± 1*185 ± 12245 ± 25
5012 ± 1*12 ± 1*190 ± 13247 ± 18
6016 ± 2*†10 ± 1*†192 ± 16*†276 ± 29*†
7015 ± 1*†9 ± 1*†211 ± 16*†330 ± 74*†
8017 ± 2*†8 ± 1*†205 ± 18*†349 ± 63*†

Respiratory rate and minute volume were measured with a respirometer attached to a tightly fitted face mask (prior to anesthesia) or endotracheal tube (during anesthesia). Tidal volume was derived from the following equation: minute volume = respiratory rate × tidal volume.

See Table 1 for key.

Figure 4—
Figure 4—

Mean ± SEM indirect MAP determined via oscillometry in the same 6 dogs as in Figure 1. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 73, 11; 10.2460/ajvr.73.11.1707

Figure 5—
Figure 5—

Mean ± SEM values for ETco2 determined via capnography for the same dogs as in Figure 1. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 73, 11; 10.2460/ajvr.73.11.1707

Discussion

In a previous study11 evaluating the sedative effects of tramadol at 1, 2, and 4 mg/kg administered IV in dogs, it was found that the sedative effects of tramadol increased in a dose-dependent manner. In the study reported here, DTrK was as effective as DBTZ in inducing a rapid onset of sedation and transition to general anesthesia following a single IM injection. Both injectable anesthetic combinations were considered to provide a rapid and smooth anesthetic induction, with the dogs assuming lateral recumbency < 6 minutes and intubation achieved ≤ 7 minutes after injection. These results were similar to those of a previous study2 in which dogs were anesthetized for castration via IM injection of dexmedetomidine (15 μg/kg) and ketamine (3 mg/kg) in combination with various opioids (butorphanol [0.2 mg/kg], hydromorphone [0.05 mg/kg], or buprenorphine [40 μg/kg]). In that study,2 all 3 dexmedetomidine-ketamine-opioid combinations rapidly induced general anesthesia and allowed endotracheal intubation to be performed. Results of the present study suggest that injectable tramadol may be as effective as those opioids in combination with dexmedetomidine and ketamine for inducing general anesthesia; however, whether this drug combination is suitable for surgery such as castration or ovariohysterectomy remains to be tested. Results of DBTZ administration in the present study were also similar to results in a previous study1 in which medetomidine (15 μg/kg) rather than dexmedetomidine (7.5 μg/kg) was administered in combination with tiletamine-zolazepam (3.0 mg/kg) and butorphanol (0.15 mg/kg) IM; in that study, general anesthesia was achieved ≤ 5 minutes after a single injection of the drug combination.

The use of noxious electrical stimuli for assessing the efficacy of centrally acting analgesics has been well accepted.1,5,12 In the present study, use of an algometer and a nerve stimulator allowed us to evaluate the duration and intensity of analgesia provided by the 2 treatments. Intensity of analgesia evaluated with both methods significantly increased from baseline values (via algometry) and from 0 (via electrical nerve stimulation) and reached maximal values ≤ 5 minutes after administration of DBTZ or DTrK, indicating that both drug combinations rapidly induced analgesia after IM injection. However, a disparity in analgesic intensity was detected between the 2 drug treatments 20 to 30 minutes after injection. Analgesic intensity measured via algometry after DBTZ injection remained at the maximum value (2,000 kPa/s) for 40 minutes, whereas analgesic intensity after DTrK injection was decreased at 30 minutes after injection and was significantly lower than values for DBTZ treatment at most remaining time points. Duration of analgesia (ie, values significantly greater than baseline) determined with this method was 70 minutes after injection of DBTZ and 50 minutes after injection of DTrK. Results for electrical nerve stimulation were similar. These results indicate that the DTrK treatment resulted in a shorter duration of analgesia with a weaker analgesic intensity than as did the DBTZ treatment. It is interesting to note that this difference was detected despite the fact that the dexmedetomidine dose in the DTrK treatment was twice that in DBTZ treatment (15 vs 7.5 μg/kg, respectively). This suggests that the ketamine-tramadol combination at the dose used did not provide as much analgesia as did tiletamine-zolazepam–butorphanol at the dose used. Tiletamine has 2 to 3 times the potency of ketamine.13,14 Therefore, it is logical to assume that tiletamine-zolazepam may have provided a better analgesic effect than ketamine in these drug combinations. However, exactly how much analgesia was contributed by the dissociatives in this study is unknown and warrants further investigation. The duration of anesthesia and analgesia after DBTZ administration in the present study was similar to clinical observations reported when the same dose of DBTZ was used as injectable anesthesia for ovariohysterectomy in dogs.15,16

The duration from injection to sternal recumbency during recovery was significantly longer with DBTZ treatment than with DTrK treatment (118.3 ± 10.6 minutes vs 76.3 ± 5.2 minutes, respectively), as was duration of intubation (82.3 ± 4.4 minutes vs 66.2 ± 7.1 minutes, respectively). However, the total duration of anesthesia (from injection to standing recovery) was not significantly different between the 2 treatments, indicating that the total recovery time was comparable.

In our opinion, the biphasic heart rate response detected in the present study (a decrease from baseline at 5 minutes after injection, briefly returning to values similar to baseline from 10 to 15 [DTrK] or 20 [DBTZ] minutes, then decreasing below baseline at all remaining time points) was likely attributable to the pharmacokinetic properties of individual drugs. During the first 5 minutes, the decreased heart rate is believed to be related to a decrease in sympathetic tone, reflex response from peripheral hypertension, activation of parasympathetic tone, or some combination of these induced by dexmedetomidine-butorphanol or dexmedetomidine-tramadol combinations in the treatments. The subsequent transient increase in heart rate is thought to be related to sympathetic stimulation by the dissociative drug (ketamine in DTrK or tiletamine in DBTZ combinations). After 15 or 20 minutes, sympathetic stimulation from the dissociative anesthetic was diminishing, while parasympathetic effects predominated, as evidenced by sinus arrhythmia. A similar biphasic heart rate pattern was detected in a previous hemodynamic study3 in dogs with a dose of DBTZ identical to that used in the present study and comparable dosing of dexmedetomidine-butorphanol-ketamine.

Hypertension (MAP > 135 mm Hg) was detected after administration of DBTZ or DTrK in the present study, with MAP increasing significantly from baseline values from 5 to 20 (DBTZ) or 30 (DTrK) minutes. A similar result was reported in dogs that received dexmedetomidine-ketamine-opioid2 or tiletamine-zolazepam–butorphanol–medetomidine1 treatments. The MAP in dogs of the present study was apparently higher with DTrK treatment than with DBTZ treatment at all time points after injection, and this difference was significant 5 minutes after injection. We speculate that the higher MAP detected following DTrK administration was attributable to the higher dose (15.0 vs 7.5 μg/kg) of dexmedetomidine included in this drug combination or to an additional hypertensive effect of tramadol. We further speculate that the higher dose of dexmedetomidine induced a greater pressor effect. However, IV administration of 4 mg of tramadol/kg has been shown to cause an increase in blood pressure as well as a prolonged increase in systemic vascular resistance in sevoflurane-anesthetized dogs.17 Therefore, it is also possible that a vasopressor effect of tramadol was enhanced when it was used in combination with dexmedetomidine and ketamine in the present study.

The DBTZ treatment resulted in more profound respiratory depression than did the DTrK treatment. This was supported by the significantly higher ETco2 and significantly lower tidal volume at several time points after DBTZ injection, compared with values after DTrK injection. Increased respiratory depression, in conjunction with longer duration and increased intensity of analgesia, suggests that the DBTZ treatment induced a deeper plane of anesthesia than did the DTrK treatment during this time period.

Hypoxemia (Spo2 < 90%) was detected during both treatments and appeared to be more severe with DBTZ treatment than with DTrK treatment. The hypoxemia may have been mainly due to hypoventilation, given that ETco2 was significantly higher with DBTZ treatment than with DTrK treatment at several time points. In a previous study, dogs treated with dexmedetomidine-ketamine-opioid combinations also had hypoxemic episodes and responded well to supplemental 100% oxygen treatment.2 It is therefore strongly advised that supplemental oxygen be provided when these 2 anesthetic combinations are used. Although hypoxemia was detected during this study, venous blood lactate concentrations were all within the laboratory reference range and < 1.5 mmol/L, which reflects an acceptable overall perfusion status averaged over time and over different areas of the body.18

ABBREVIATIONS

DBTZ

Dexmedetomidine–butorphanol–tiletamine-zolazepam

DTrK

Dexmedetomidine-tramadol-ketamine

ETco2

End-tidal carbon dioxide concentration

MAP

Mean arterial blood pressure

Spo2

Oxygen saturation as measured by pulse oximetry

a.

Dexdomitor, Pfizer Animal Health, New York, NY.

b.

Torbugesic, Pfizer Animal Health, New York, NY.

c.

Telazol, Pfizer Animal Health, New York, NY.

d.

Tramadol Hcl injection, Huons Co Ltd, Hwaseong City, Kyunggi-do, Korea.

e.

Ketaset, Pfizer Animal Health, New York, NY.

f.

Somedic algometer type II, Somedic Production AB, Stockholm, Sweden.

g.

Life-Tech Inc, Staffor, Tex.

h.

Lactate Pro Meter, Quesnel, BC, Canada.

i.

Gaymar TP Professional, Gaymar Industries Inc, Orchard Park, NY.

j.

Gaymar Hot Air Hugger, Gaymar Industries Inc, Orchard Park, NY.

k.

PC-VetGard+, Mill Creek, Wash.

l.

Wright/Haloscale respirometer, Ferraris Respiratory, Louisville, Colo.

m.

Blank clicker, The Clicker Co, Payson, Ariz.

n.

SAS, version 9.1, SAS Institute Inc, Cary, NC.

o.

Proc Mixed, SAS, version 9.1, SAS Institute Inc, Cary, NC.

References

  • 1. Ko JC, Payton M & Weil AB et alComparison of anesthetic and cardiorespiratory effects of tiletamine-zolazepam-butorphanol and tiletamine-zolazepam-butorphanol-medetomidine in dogs. Vet Ther 2007; 8: 113126.

    • Search Google Scholar
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  • 2. Barletta M, Austin BR & Ko JC et alEvaluation of dexmedetomidine and ketamine in combination with opioids as injectable anesthesia for castration in dogs. J Am Vet Med Assoc 2011; 238: 11591167.

    • Search Google Scholar
    • Export Citation
  • 3. Krimins RA, Ko JC & Weil AB et alHemodynamic effects in dogs after intramuscular administration of a combination of dexmedetomidine-butorphanol-tiletamine-zolazepam or dexmedetomidine-butorphanol-ketamine. Am J Vet Res 2012; 73: 13631370.

    • Search Google Scholar
    • Export Citation
  • 4. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879923.

  • 5. Seddighi MR, Egger CM & Rohrbach BW et alEffects of tramadol on the minimum alveolar concentration of sevoflurane in dogs. Vet Anaesth Analg 2009; 36: 334340.

    • Search Google Scholar
    • Export Citation
  • 6. Mastrocinque S, Fantoni DT. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg 2003; 30: 220228.

    • Search Google Scholar
    • Export Citation
  • 7. Monteiro ER, Junior AR & Assis HM et alComparative study on the sedative effects of morphine, methadone, butorphanol or tramadol, in combination with acepromazine, in dogs. Vet Anaesth Analg 2009; 36: 2533.

    • Search Google Scholar
    • Export Citation
  • 8. Tas O, De Rooster H & Baert E et alThe accuracy of the Lactate Pro hand-held analyser to determine blood lactate in healthy dogs. J Small Anim Pract 2008; 49: 504508.

    • Search Google Scholar
    • Export Citation
  • 9. Bernhardt O, Schiffman EL, Look JO. Reliability and validity of a new fingertip-shaped pressure algometer for assessing pressure pain thresholds in the temporomandibular joint and masticatory muscles. J Orofac Pain 2007; 21: 2938.

    • Search Google Scholar
    • Export Citation
  • 10. Varcoe-Cocks K, Sagar KN & Jeffcott LB et alPressure algometry to quantify muscle pain in racehorses with suspected sacroiliac dysfunction. Equine Vet J 2006; 38: 558562.

    • Search Google Scholar
    • Export Citation
  • 11. McMillan CJ, Livingston A & Clark CR et alPharmacokinetics of intravenous tramadol in dogs. Can J Vet Res 2008; 72: 325331.

  • 12. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001; 53: 597652.

  • 13. Beck CC. Chemical restraint of exotic species. J Zoo Wildl Med 1972; 3: 366.

  • 14. Gray CW, Bush M, Beck CC. Clinical experience using CI-744 in chemical restraint and anesthesia of exotic animals. J Zoo Wildl Med 1974; 5: 1221.

    • Search Google Scholar
    • Export Citation
  • 15. Ko JC, Knesl O & Weil AB et alFAQs—analgesia, sedation, and anesthesia: making the switch from medetomidine to dexmedetomidine. Compend Contin Educ Pract Vet 2009; 31(suppl 1A): 124.

    • Search Google Scholar
    • Export Citation
  • 16. Ko JC, Berman AG. Anesthesia in shelter medicine. Top Companion Anim Med 2010; 25: 9297.

  • 17. Itami T, Tamaru N & Kawase K et alCardiovascular effects of tramadol in dogs anesthetized with sevoflurane. J Vet Med Sci 2011; 73: 16031609.

    • Search Google Scholar
    • Export Citation
  • 18. Pang D, Boysen S. Lactate in veterinary critical care: pathophysiology and management. J Am Anim Hosp Assoc 2007; 43: 270279.

Appendix 1

Scoring system1,2 used to evaluate sedation via response to auditory stimulation (noise made with a clicker held close to the dog's ear) in 6 healthy dogs at predetermined time points before and after a single IM injection of DBTZ or DTrK.

ScoreDescription
1Total response to the clicker noise with head turning, ear twitchings, and looking toward direction of clicker; aware of surroundings; minimal sedation
2Moderate response to the clicker noise; head and neck move slightly and ears twitch in response to the noise; dog is unsure where noise is originating; moderate sedation
3No head movement in response to the clicker noise; minimal eye movement or blinking, with or without ear twitching; moderately heavy sedation
4Blinking response only to the clicker noise (no other body movement); profound sedation
5No response to the clicker noise; no purposeful movements; no blinking reponse; all clinical signs consistent with general anesthesia

Appendix 2

Criteria1 used to score quality of intubation in dogs.

Intubation scoreCriteria
1Difficult intubation; tube cannot be retained; tight jaw tone accompanied by chewing motion; strong tongue withdrawal
2Easy intubation with slight coughing or swallowing reflex following intubation but no gagging reflex; relaxed jaw tone; no chewing motions; slight tongue withdrawal
3Intubation easily achieved; animal becomes rapidly unconscious; good muscle relaxation

Appendix 3

Criteria1,2 used to score quality of anesthesia in dogs.

Sedation-anesthesia scoreCriteria
0Active; aware of the surrounding environment; minimal sedation
1Mild to moderate sedation with reduced activity; does not assume sternal or lateral recumbency
2Moderate sedation; mildly aware of the surrounding environment; sternal recumbency only
3Profound sedation; eyes droopy; head down; inactive; assumes sternal or lateral recumbency; tight jaw tone; unable to be intubated
4Rapid smooth induction of anesthesia; no movement; rapidly assumes lateral recumbency with excellent muscle relaxation; loose jaw tone and easy intubation

Appendix 4

Criteria2 used to score quality of recovery in dogs.

Recovery scoreCriteria
1Prolonged struggling; unable to stand without assistance; hyperkinesia in response to manual assistance
2Some struggling; repeated attempts to stand and requires assistance to stand; very unstable while walking and unable to maintain balance; some signs of residual anesthetic effects
3Some struggling; requires some assistance to stand; able to maintain balance once standing; minimal signs of residual anesthetic effects
4Dog assumes sternal recumbency with little or minimal struggling; stands and walks with minimal effort; no signs of anesthetic effects

Contributor Notes

Dr. Krimms current address is Veterinary Imaging of the Chesapeake, Annapolis, MD 20401.

Address correspondence to Dr. Ko (jcko@purdue.edu).