The anesthetic combination of a low dose of ketamine mixed with propofol in the same syringe at a 1:1 ratio is frequently used to safely achieve sedation and analgesia for emergency procedures in humans, particularly for pediatric surgery.1–3 Ketamine (a dissociative agent derived from phencyclidine) is a rapid-acting general anesthetic that has been recently reevaluated as an analgesic drug in human and veterinary patients. Propofol (2,6-diisopropylphenol) is a short-acting injectable hypnotic agent for induction and maintenance of general anesthesia during minor surgical procedures. Unlike ketamine, it causes cardiopulmonary depression, particularly with rapid administration, and it has little or no analgesic activity.4
According to the concept of preemptive and multimodal analgesia, the combination of drugs with different mechanisms of action is useful to reduce doses and related adverse effects while maintaining the favorable synergistic effects of a drug combination.5,6 Combining ketamine with propofol reduces the propofol dose required to achieve sedation in humans,7 and administration of this combination results in fewer adverse effects, compared with either drug alone.8 This is partly attributable to the fact that the potential adverse effects are mainly dose dependent, and when used in combination, the dose of each drug can be reduced.1 Furthermore, the opposing hemodynamic and respiratory effects of propofol and ketamine may be considered complementary, minimizing overall adverse effects.2,3 However, evidence-based clinical data on efficacy of this drug combination are still lacking.9
Use of repeated administrations or a continuous infusion of propofol in cats is somewhat controversial. Some authors have reported adverse effects on the quality of recovery from anesthesia10 and on erythrocyte physiology when propofol is repeatedly administered,11,12 although the latter may be without clinical importance.13 Propofol is a phenolic drug that may potentially induce oxidative injury in RBCs.11 Feline hemoglobin has high concentrations of oxidable thiol groups, and the glucuronide conjugation pathway required for metabolism of some drugs (such as propofol) is inefficient in this species; therefore, administration of propofol in cats may result in increased formation of Heinz bodies.11–13 Moreover, the nonsinusoidal feline spleen is ineffective at removing Heinz body–containing RBCs from circulating blood.14 This results in higher incidence of Heinz bodies in healthy cats, compared with other species, and it is possible that increased Heinz body formation subsequent to oxidative injury could contribute to the development of hemolytic anemia.
Ketamine and propofol have been routinely used in veterinary anesthesia for many years. However, few studies investigating the combination of these 2 drugs have been published. Investigators in 1 study15 assessed the effects of different doses of ketamine administered immediately prior to induction of anesthesia via propofol infusion in healthy dogs. In another study,16 pharmacokinetics of ketamine and propofol was evaluated following simultaneous infusion in ponies that received detomidine as premedication. Recently, the effects of repeated administration of propofol on quality of recovery, clinical status, and erythrocyte physiology were evaluated in cats undergoing radiotherapy.13 The pharmacokinetics of ketamine-propofol combination was also examined in the same cats enrolled in the present study.17 However, to our knowledge, no veterinary studies investigating clinical effects of the administration of a premixed ketamine-propofol combination have been reported. Therefore, the purpose of the study reported here was to evaluate the use of a ketamine-propofol drug combination with or without dexmedetomidine for IV anesthesia in cats undergoing ovariectomy. We also sought to assess Heinz body formation following infusion of these drugs.
Materials and Methods
Cats—Fifteen client-owned female cats were enrolled in the study. Mean ± SD age was 2.18 ± 2.19 years with a range of 0.6 to 9.0 years, and mean ± SD weight was 3.1 ± 0.53 kg (6.8 ± 1.16 lb) with a range of 2.5 to 4.0 kg (5.5 to 8.8 lb). All animals were considered healthy (American Society of Anesthesiologists status I)18 on the basis of results of physical examination and routine hematologic tests (CBC and serum biochemical analysis). The study was approved by the Ethical Committee of the University of Milan, and all animals were enrolled in the study after written consent was obtained from their owners.
Anesthetic and surgical protocols—Before the study began, cats were randomly assigned to 2 groups in computer-generated order (simple randomization) for drug treatment. Food was withheld for 12 hours and water was withheld for 6 hours prior to surgery. An 18-gauge jugular catheter (for sample collection) and a 22-gauge cephalic vein catheter (for intraoperative fluid therapy and drug administration) were placed aseptically in all cats. In the ketamine-propofol group (n = 8), anesthesia was induced with a 1:1 ketaminea (2.0 mg/kg [0.91 mg/lb])-propofolb (2.0 mg/kg) combination administered IV. In the ketamine-propofol-dexmedetomidine group (n = 7), anesthesia was induced with a ketaminea (2.0 mg/kg)-propofolb (2.0 mg/kg)-dexmedetomidinec (0.003 mg/kg [0.0014 mg/lb]) combination administered IV. Drug combinations were mixed in the same syringe immediately prior to administration. Anesthesia in both groups was maintained with an IV infusion of the 1:1 ketamine-propofol combination (rate of administration for each drug, 10.0 mg/kg/h [4.55 mg/lb/h]) via syringe pump.d
Each cat was intubated with an appropriately sized endotracheal tube after induction of anesthesia and supplied with 100% oxygen; a second bolus of the ketamine-propofol combination (0.5 mg of each drug/kg [0.23 mg/lb], IV) was provided if the intubation was difficult. Cats breathed spontaneously throughout anesthesia and surgery. During surgery and until the end of the ketamine-propofol infusion, lactated Ringer's solution (5.0 mL/kg/h [2.27 mL/lb/h], IV) was administered through a cephalic catheter. All cats underwent ovariectomy according to standard surgical procedures.19 The surgeries were all performed by 1 surgeon (MB). Anesthetic depth was evaluated via a standardized method (positioning of Backhaus towel clamps). The infusion was discontinued at 25 minutes after anesthetic induction in all patients.
Cats were monitored throughout surgery, and HR, ECG (lead II), respiratory rate, Spo2, Petco2, mNIBP, and esophageal temperature were recordede every 5 minutes. The first recording was made after anesthetic induction and stabilization (baseline) but before the application of surgical stimuli. Rescue anesthesia was provided via bolus administration of the ketamine-propofol combination (0.5 mg of each drug/kg, IV) if the increase in HR or mNIBP was > 20% of the baseline value.
Blood sample analysis—Venous blood samples (1 mL) for gas analyses were collected in a heparinized syringe via jugular catheter at baseline, after removal of the last ovary, and at the end of infusion of the anesthetic drug combination. For each blood sample, pH; Hct; Pco2; Po2; percentage of oxygen saturation; bicarbonate, sodium, potassium, and calcium concentrations; and base excess were determined. The Hct was used to determine the presence and degree of anemia (defined as Hct < 37%).
Blood smears for quantification of Heinz bodies were prepared at the end of the infusion and 24 hours later. An additional sample was collected for this purpose at 1 time point 4 to 8 days after surgery. Heinz bodies were identified via examination of blood smears stained with brilliant cresyl blue, and affected cells were expressed as a percentage of 500 counted RBCs.20
Blood samples obtained from 6 randomly selected cats of the ketamine-propofol group were also used in a pharmacokinetics study reported elsewhere.17 These samples were collected at the end of IV bolus administration for anesthetic induction; at 5, 15, and 25 minutes during the infusion; and at predetermined time points during the postoperative period (up to 24 hours after the end of the infusion).
Postoperative evaluations—All cats were monitored during the postoperative period to further assess the clinical efficacy of treatment. Numeric scales were used to evaluate the degree of sedation, quality of recovery, and signs of pain after surgery.21–23 The assessments were performed by 1 trained observer (GR) who was unaware of group assignment of the cats. Postoperative sedation and muscular relaxation were assessed according to the methods of Belda et al21 at the time of extubation (time 0) and at 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 120, 180, 300, 480, 720, 1,020, and 1,440 minutes afterward, whereas alternative sedation score and degree of restlessness (according to Ansah et al22) and pain scores (according to Shaffran et al23) were evaluated at time 0 and at 30, 60, 90, 120, 180, 300, 480, 720, 1,020, and 1,440 minutes after extubation.
Evaluation of postoperative sedation21 included assessment of mandibular tone, spontaneous positioning, resistance to being placed in lateral recumbency, and responses to noise (produced by finger snapping) and noxious stimulus (produced by applying forceps to a hind paw digit). The range of possible scores was 0 to 4 for spontaneous positioning and 0 to 3 for the remaining variables; the sum of scores was calculated (maximum value, 16). The degree of sedation was considered poor if the sum of values was < 5, clinical if between 5 and 13, and deep if > 13.21 Moreover, posture, gait, and the degree of resistance to manipulation22 were monitored as alternative indicators of sedation in the postoperative period. For these assessments, posture and gait were scored on a scale of 0 (stands and walks normally) to 3 (laterally recumbent and not easily wakened by light manipulation) and degree of resistance was scored on a scale of 0 (strong resistance to manipulations) to 2 (no resistance). The sum of these values was calculated (maximum value, 5 [animal laterally recumbent, not easily wakened by light manipulations, with no resistance to manipulation]).22
Quality of recovery was determined via assessment of muscular relaxation21 and degree of restlessness.22 Muscular relaxation was scored on a scale from 0 to 3, where 0 = poor, 1 = moderate, 2 = good, and 3 = excellent.21 Degree of restlessness was assessed on a scale from 0 to 3, where 0 = resting quietly, 1 = slight restlessness, 2 = moderate restlessness, and 3 = substantial restlessness.22
To evaluate signs of pain in the postoperative period, general behavior of the cats and response to palpation of the surgical site were observed and a numeric score was assigned, where 0 = no signs of pain; 1 = signs are subtle and not easily detected in the clinical setting (cat may or may not react to palpation); 2 = lays or sits in a curled or tucked position, tries to escape or reacts to palpation; 3 = constantly vocalizing or hissing, with aggressive reaction to palpation; and 4 = prostrate and unresponsive to surroundings.23 A score ≥ 2 recorded for 3 consecutive observations led to the administration of rescue analgesia with buprenorphine (0.01 mg/kg [0.0045 mg/lb], IM). The movements of eyes and limbs and vocalizations of cats when the surgical site was palpated were also evaluated as additional indicators of pain.22 The scale for eye and limb movement ranged from 0 (no reaction) to 3 (visible reaction when the surgical area is lightly palpated), and the scale for vocalization ranged from 0 (no vocalization) to 2 (vocalizes even if not touched). The sum of scores was calculated (maximum value, 5 [signs of severe pain]).22 A protocol was in place to provide immediate treatment for cats with signs of hyperalgesia in the postoperative period.
Statistical analysis—All statistical analyses were performed with dedicated software.f Results were expressed as mean ± SD for intraoperative variables and postoperative scores. Normality of data distribution was assessed by means of the Shapiro-Wilk test. Because the data were normally distributed, a univariate ANOVA was applied to compare means between treatment groups and between different times of observation. For clinical scores, to determine the effects of treatment on dependent variables, a generalized estimating equation was used. Dependent variables had an inverse Gaussian distribution, with link function power with order = −2. Goodness of fit was assessed with quasi-likelihood under independence model criterion. Values of P < 0.05 were considered significant.
Results
All cats were easily intubated after administration of the ketamine-propofol or ketamine-propofol-dexmedetomidine drug combination without an additional bolus of the ketamine-propofol solution. No adverse effects were observed during or after drug administration in either treatment group.
Surgical and anesthetic variables—Mean duration of surgery was 18 ± 2 minutes. Mean body temperature (36.2 ± 0.7°C [97.2 ± 1.3°F] in the ketamine-propofol group and 36.7 ± 1.2°C [98.2 ± 2.1°F] in the ketamine-propofol-dexmedetomidine group) was not significantly different between treatment groups. Values for respiratory rate and PETCO2 were also similar between groups (Table 1). Mean SpO2 and mNIBP were significantly lower in the ketamine-propofol-dexmedetomidine group than in the ketamine-propofol group at baseline and at 20 minutes, respectively. Mean HR was significantly higher in the ketamine-propofol group at all time points except the last (20 minutes). The time from the end of the infusion to extubation was significantly shorter in the ketamine-propofol group (7.1 ± 2.5 minutes) than in the ketamine-propofol-dexmedetomidine group (29.0 ± 6.9 minutes). Rescue anesthesia was not needed for any cats.
Mean ± SD cardiorespiratory variables and blood gas values in 15 cats that underwent 2 anesthetic protocols (ketamine-propofol or ketamine-propofol-dexmedetomidine) for ovariectomy.
| Variable | Baseline | Time from start of infusion (min) | |||
|---|---|---|---|---|---|
| 5 | 10 | 15 | 20 | ||
| HR (beats/min) | |||||
| KP | 146 ± 26* | 159 ± 34* | 163 ± 26* | 157 ± 17* | 131 ± 32 |
| KPD | 113 ± 12* | 125 ± 21* | 132 ± 18* | 129 ± 17* | 121 ± 13 |
| Respiratory rate (breaths/min) | |||||
| KP | 12 ± 8 | 17 ± 9 | 16 ± 7 | 14 ± 2 | 14 ± 7 |
| KPD | 14 ± 9 | 16 ± 9 | 14 ± 11 | 17 ± 8 | 14 ± 8 |
| Spo2 (%) | |||||
| KP | 100*† | 100† | 100† | 100† | 100† |
| KPD | 98.7 ± 1.3* | 99.2 ± 1.3 | 98.9 ± 2.3 | 99 ± 2.2 | 98.7 ± 2.2 |
| Petco2 (mm Hg) | |||||
| KP | 38.5 ± 13.3 | 37.3 ± 12.4 | 35.9 ± 9.3 | 35.1 ± 9.1 | 34.4 ± 5.5 |
| KPD | 36.5 ± 15 | 36.8 ± 13.7 | 43.7 ± 7.5 | 39.8 ± 9.6 | 41.5 ± 7.5 |
| mNIBP (mm Hg) | |||||
| KP | 72.5 ± 19.7 | 85.6 ± 30.8 | 103.6 ± 36.8 | 124.5 ± 39.4 | 132.3 ± 28.7* |
| KPD | 93.9 ± 19.8 | 111.7 ± 26.1 | 110.4 ± 22.7 | 101.3 ± 9.3 | 99.9 ± 14. 8* |
Anesthesia was induced via IV bolus administration of a ketamine (2.0 mg/kg [0.91 mg/lb])-propofol (2.0 mg/kg) combination (ketamine-propofol group; n = 8) or the same drug combination plus dexmedetomidine (0.003 mg/kg [0.0013 mg/lb]; ketamine-propofol-dexmedetomidine group; n = 7). Anesthesia in both groups was maintained via IV infusion of the ketamine-propofol combination (rate of administration for each drug, 10 mg/kg/h [4.54 mg/lb/h]). Baseline values were obtained immediately after anesthetic induction.
Value is significantly (P < 0.05) different between groups.
All values were the same; no SD is calculated.
KP = Ketamine-propofol group. KPD = Ketamine-propofol-dexmedetomidine group.
Blood sample analysis—Results of blood gas analysis revealed that pH, PCO2, and bicarbonate concentration were within reference ranges and were not significantly different between treatment groups. The PO2 and percentage of oxygen saturation were within laboratory reference ranges for both groups, even though values were significantly higher in the ketamine-propofol group than in the ketamine-propofol-dexmedetomidine group for PO2 at baseline (130 ± 52 mm Hg vs 60 ± 20 mm Hg, respectively; P = 0.006) and for percentage of oxygen saturation (87 ± 6% vs 79 ± 7%; P = 0.02) at the end of the IV infusion.
Anemia (Hct < 37%) was not detected in cats of either group at any time point, and there was no significant increase in Heinz bodies counts following drug administration. The mean percentage of RBCs with Heinz bodies in samples collected at baseline was 3.2 ± 5.3% (range, 0% to 13.7%) and 0.86 ± 0.95% (range, 0% to 2.2%) in the ketamine-propofol group and ketamine-propofol-dexmedetomidine group, respectively. The mean percentage at the next time point (24 hours) was 2.1 ± 3.1% (range, 0% to 8.8%) in the ketamine-propofol group and 2.1 ± 4% (range, 0% to 11%) in the ketamine-propofol-dexmedetomidine group. In the final sample (4 to 8 days after surgery), the mean percentages were 4.6 ± 4.8% (range, 0% to 12%) and 3.4 ± 5.9% (range, 0.3% to 14%) in ketamine-propofol and ketamine-propofol-dexmedetomidine groups, respectively.
Postoperative evaluations—Mean overall sedation scores (derived from assessment of spontaneous positioning, resistance to placement in lateral recumbency, mandibular tone, and responses to noise and noxious stimulus) were summarized (Table 2). Overall sedation scores were significantly higher in the ketamine-propofol-dexmedetomidine group, compared with those of the ketamine-propofol group, from the time of extubation (time 0) through 60 minutes. In general, the reactions to the different stimuli occurred earlier and appeared stronger in the ketamine-propofol group. The degree of overall sedation was considered deep (score > 13) for < 10 minutes after extubation in the ketamine-propofol group and for approximately 30 minutes in the ketamine-propofol-dexmedetomidine group. The duration of deep sedation was significantly (P = 0.01) longer in the ketamine-propofol-dexmedetomidine group. Starting approximately 70 minutes after extubation, the degree of sedation was comparable between groups.
Mean ± SD postoperative scores for primary and alternative indicators of sedation, degree of restlessness, and muscular relaxation in the same 15 cats in Table 1.
| Time (min) | Sedation (primary) | Sedation (alternative) | Restlessness | Muscular relaxation | ||||
|---|---|---|---|---|---|---|---|---|
| KP | KPD | KP | KPD | KP | KPD | KP | KPD | |
| 0 | 14.7 ± 2.8 | 16.0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 2 ± 0 | 2 ± 0 |
| 5 | 14.5 ± 2.9 | 16.0 ± 0 | — | — | — | — | 2 ± 0 | 2 ± 0 |
| 10 | 12.2 ± 3.4 | 16.0 ± 0 | — | — | — | — | 1.9 ± 0.3 | 2.0 ± 0 |
| 15 | 10.8 ± 3.9 | 15.6 ± 1.1 | — | — | — | — | 1.7 ± 0.5 | 1.9 ± 0.4 |
| 20 | 8.4 ± 5 | 15.9 ± 0.4 | — | — | — | — | 1.7 ± 0.5 | 2.0 ± 0 |
| 30 | 5.7 ± 4.8 | 15.3 ± 1 | 2.4 ± 1.3 | 4 ± 0 | 0.4 ± 0.5 | 0 ± 0 | 1.6 ± 0.5 | 1.9 ± 0.4 |
| 40 | 4.1 ± 4.6 | 12.3 ± 3.6 | — | — | — | — | 1.9 ± 0.3 | 2.0 ± 0.6 |
| 50 | 2.7 ± 3 | 6.6 ± 3.3 | — | — | — | — | 1.9 ± 0.3 | 1.9 ± 0.4 |
| 60 | 2.0 ± 2 | 4.0 ± 3.2 | 0.9 ± 0.8 | 1.5 ± 0.7 | 0.5 ± 0.8 | 0.4 ± 0.8 | 1.9 ± 0.3 | 1.6 ± 0.5 |
| 70 | 1.5 ± 2 | 1.7 ± 1.4 | — | — | — | — | 2.0 ± 0 | 1.6 ± 0.5 |
| 80 | 1.0 ± 2 | 1.1 ± 1.5 | — | — | — | — | 2.0 ± 0 | 1.7 ± 0.5 |
| 90 | 0.7 ± 1.8 | 0.6 ± 0.9 | 0.5 ± 0.7 | 0.6 ± 0.7 | 0.2 ± 0.7 | 0.3 ± 0.8 | 2.0 ± 0 | 1.9 ± 0.3 |
| 120 | 0.1 ± 0.3 | 0.6 ± 0.9 | 0.06 ± 0.2 | 0.4 ± 0.8 | 0 ± 0 | 0.1 ± 0.4 | 2.0 ± 0 | 1.9 ± 0.3 |
| 180 | 0 ± 0 | 0 ± 0 | 0.06 ± 0.3 | 0.2 ± 0.6 | 0 ± 0 | 0 ± 0 | 2.0 ± 0 | 2.0 ± 0 |
| 300 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 2.0 ± 0 | 2.0 ± 0 |
| 480 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 2.0 ± 0 | 2.0 ± 0 |
| 720 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 2.0 ± 0 | 2.0 ± 0 |
| 1,020 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 2.0 ± 0 | 2.0 ± 0 |
| 1,440 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 2.0 ± 0 | 2.0 ± 0 |
The time of extubation was considered time 0. Primary indicators of sedation21 included assessment of mandibular tone, spontaneous positioning, resistance to being placed in lateral recumbency, and responses to noise and a noxious stimulus. Each of these variables was scored (0 to 4 for spontaneous positioning and 0 to 3 for all others); the sum of scores was calculated (maximum value, 16 [scores > 13 indicated deep sedation]). Alternative indicators of sedation22 included effects on posture and gait (scale, 0 to 3) and degree of resistance to manipulation (0 to 2); the sum of these scores was calculated (maximum value, 5 [animal laterally recumbent, not easily wakened by light manipulations, with no resistance to manipulation]). Degree of restlessness was assessed as follows: 0 = resting quietly, 1 = slight restlessness, 2 = moderate restlessness, and 3 = substantial restlessness.22 Muscular relaxation was scored as follows: 0 = poor, 1 = moderate, 2 = good, and 3 = excellent.21
See Table 1 for remainder of key.
Recovery was considered smooth for both groups (Table 2). The degrees of restlessness and muscular relaxation were not significantly different between groups at any time point. During most observations, cats did not appear restless (score, 0/3) and slight agitation (score, 1) was observed at only a few time points. Muscular relaxation was assessed as good (score, 2/3) overall.
Scores for postoperative signs of pain were not significantly different between groups at any time point (Table 3). Scores were mostly 0 and occasionally 1 (ie, the cat was quiet and appeared comfortable, interested in the surroundings, not bothered by palpation or had a reaction considered minimal, and had mild or minimal body tension). The score for signs of pain in all cats was ≤ 1 of 4, and rescue analgesia was not required. Observations for additional indicators of pain (movements of eyes or limbs when the surgical site was palpated, or vocalizations) resulted in a maximum score ≤ 1.5 of 5 in all cats.
Mean ± SD scores for signs of postoperative pain in the same 15 cats in Table 1.
| Time (min) | General signs of pain | Additional indicators of pain | ||
|---|---|---|---|---|
| KP | KPD | KP | KPD | |
| 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
| 30 | 0 ± 0 | 0 ± 0 | 1 ± 0 | 1 ± 0 |
| 60 | 0.2 ± 0.5 | 0.1 ± 0.4 | 1.1 ± 0.3 | 1 ± 0 |
| 90 | 0.1 ± 0.3 | 0 ± 0 | 1 ± 0 | 1 ± 0 |
| 120 | 0.1 ± 0.3 | 0 ± 0 | 1.2 ± 0.5 | 1 ± 0 |
| 180 | 0 ± 0 | 0.1 ± 0.4 | 1.2 ± 0.5 | 1.1 ± 0.4 |
| 300 | 0.1 ± 0.3 | 0 ± 0 | 1.4 ± 0.5 | 1.3 ± 0.5 |
| 480 | 0.1 ± 0.3 | 0 ± 0 | 1.5 ± 0.9 | 1. ± 0 |
| 720 | 0 ± 0 | 0 ± 0 | 1.1 ± 0.3 | 1 ± 0 |
| 1,020 | 0 ± 0 | 0 ± 0 | 1.1 ± 0.3 | 1 ± 0 |
| 1,440 | 0 ± 0 | 0 ± 0 | 1.1 ± 0.3 | 1 ± 0 |
The time of extubation was considered time 0. General behavior of the cats and response to palpation of the surgical site was scored as follows: 0 = no signs of pain, 1 = signs are subtle and not easily detected in the clinical setting (cat may or may not react to palpation), 2 = lays or sits in a curled or tucked position, tries to escape or reacts to palpation, 3 = constantly vocalizing or hissing, with aggressive reaction to palpation, and 4 = prostrate and unresponsive to surroundings.23 Additional indicators of pain included eye and limb movement (scale, 0 to 3) and vocalization (0 to 2); the sum of these scores was calculated (maximum value, 5 [signs of severe pain]).22 Scores were not significantly different between groups at any time point.
See Table 1 for remainder of key.
Discussion
Simultaneously administered ketamine and propofol has been reported to provide rapid and effective sedation and analgesia in human adults and children, with short recovery times and no serious adverse events reported.1–3 Patients treated on an emergency basis require rapid and safe interventions, and often, medical history is not completely known. Veterinary practitioners also have to perform various procedures under these conditions. The ketamine-propofol combination could be a useful tool to achieve rapid and effective anesthesia in small animals, even in nonemergency situations. Propofol used at low doses induces sedation without cardiovascular depression, whereas low doses of ketamine produce analgesia and sedation and might help to counteract the possible adverse effects of propofol on the cardiovascular system.1–3 However, the efficacy of coadministration of ketamine and propofol in human medicine has been debated.9 In cats, administration of a low dose of ketamine (IV loading dose, 2 mg/kg, followed by infusion at 23 μg/kg/min) decreased the dose of propofol required to reach the minimum infusion rate needed to attenuate specific reflex activity,24 but cardiopulmonary variables were not improved with low doses of the 2 combined drugs, compared with propofol alone, in another study.25
In the present study, we evaluated the coadministration of ketamine and propofol, with or without dexmedetomidine, in cats undergoing ovariectomy. Anesthesia was induced with a ketamine (2.0 mg/kg)-propofol (2.0 mg/kg) combination, or a ketamine (2.0 mg/kg)-propofol (2.0 mg/kg)-dexmedetomidine (0.003 mg/kg) combination, and was maintained via continuous IV infusion of a 1:1 ketamine-propofol combination (administration rate for each drug, 10.0 mg/kg/h). Intraoperative variables remained within reference intervals, although differences were detected between the 2 treatment groups for HR, SpO2, and mNIBP at some time points.
Intraoperative HR was significantly higher in the ketamine-propofol group than in the ketamine-propofol-dexmedetomidine group at all time points except the last (20 minutes after anesthetic induction). The lower HR in the ketamine-propofol-dexmedetomidine group was likely attributable to the sympatholytic effects of dexmedetomidine, which can reduce HR and inhibit most of the cardiovascular adrenergic effects caused by the surgery.26
The SpO2, supported by administration of 100% oxygen, remained within reference intervals in both groups during the procedure. Although SpO2 appeared lower for the ketamine-propofol-dexmedetomidine group than for the ketamine-propofol group at all time points, the only significant difference was recorded immediately after induction of anesthesia (baseline). This may be attributable to decreased cardiac output induced by dexmedetomidine and a consequent decrease in pulmonary perfusion, which mainly occurs immediately after administration.26
In the present study, all cats breathed spontaneously throughout anesthesia and surgery. No significant differences in PETCO2 or blood gas analysis results were detected between groups; the combination of drugs did not appear to induce respiratory depression in either the ketamine-propofol or ketamine-propofol-dexmedetomidine groups.
The cardiocirculatory effects of dexmedetomidine include hypertension, hypotension, and bradycardia. It is thought that hypertension is due to activation of peripheral 2β-adrenergic receptors, leading to vasoconstriction.27 The decrease in HR associated with dexmedetomidine administration may be caused by a reflex response at the sinus node secondary to peripheral vasoconstriction and decreased sympathetic outflow from the CNS. The moderate vasoconstriction and inhibition of surgically induced sympathetic effects caused by dexmedetomidine did not appear to modify the intraoperative mNIBP in cats of the present study, contributing to hemodynamic stability during anesthesia in the ketamine-propofol-dexmedetomidine group.
Recovery from anesthesia was considered smooth in all cats of the present study. Mean time to extubation was significantly longer in the ketamine-propofol-dexmedetomidine group than in the ketamine-propofol group (29.0 ± 6.9 minutes vs 7.1 ± 2.5 minutes). This could be attributable to additional anesthetic effects resulting from inclusion of dexmedetomidine in this drug combination. However, the possibility of interference in drug metabolism should also be taken into account, given that dexmedetomidine is a potent nonselective inhibitor of human cytochrome P450 in vitro28 and a competitive inhibitor of ketamine demethylation.29
In addition to having a longer extubation time, cats of the ketamine-propofol-dexmedetomidine group had higher sedation scores (assessed according to the methods of Belda et al21) for 1 hour after extubation, compared with cats of the ketamine-propofol group. Thus, the addition of dexmedetomidine to the drug combination used for anesthetic induction was associated with a greater degree and longer duration of sedation.
Conversely, assessment of signs of pain in the postoperative period did not reveal significant differences between groups, although cats of the ketamine-propofol-dexmedetomidine group remained deeply sedated for approximately 30 minutes after extubation and use of the pain assessment scales in this group at those times could have been somewhat unreliable because of this. However, pain scores were low at all time points in both groups, and no rescue analgesia was necessary, even in cats of the ketamine-propofol group that received only ketamine as analgesia. Cats appeared generally quiet and calm. Some cats had minimal signs of pain (score, 1/4), only when the surgical site was strongly palpated, and in most cats, the reaction was negligible.
A pharmacokinetic study17 was performed in 6 cats of the ketamine-propofol group in parallel with the study reported here. Results revealed that the mean propofol concentration in blood ranged from 1.98 ± 0.22 μg/mL (at 5 minutes) to 3.9 ± 3.08 μg/mL (at the end of infusion) and then decreased rapidly; mean ketamine plasma concentration during the infusion ranged between 4.35 ± 1.66 μg/mL and 3.7 ± 1.51 μg/mL and then rapidly decreased after the end of the infusion, with a blood concentration profile similar to that of propofol.17 Norketamine was detected in plasma starting from the first sample after induction (mean, 0.1 ± 0.06 μg/mL), and concentrations increased to a mean of 1.76 ± 0.7 μg/mL at 10 minutes after the end of infusion, decreasing slowly thereafter; starting from 1 hour after the end of the infusion, norketamine concentrations were higher than ketamine concentrations in all cats.17 Data extrapolated from those analyses indicated that, at the time of extubation (approx 7 minutes after the end of the infusion), the mean propofol concentration in blood was 3.5 ± 2.5 μg/mL. At the same time, the mean plasma concentrations of ketamine and norketamine were 3.1 ± 0.8 μg/mL and 1.8 ± 0.7 μg/mL, respectively. We are not aware of studies concerning effective plasma concentrations of propofol-ketamine combinations indicating awakening from anesthesia in cats; however, a plasma concentration of approximately 2 μg/mL was reported when voluntary movement was regained from anesthesia with ketamine alone (25 mg/kg, IV) in cats30 and a concentration of approximately 4 μg/mL was reported at the time of waking from anesthesia with propofol (5 to 15 mg/kg) administered as a single IV bolus in cats.31 In ponies anesthetized via IV infusion of propofol (8.16 mg/kg/h) and ketamine (3 mg/kg/h) together,16 mean plasma concentrations were approximately 2 μg/mL (1.6 to 2.3 μg/mL) for propofol and 0.87 μg/mL (0.75 to 1.02 μg/mL) for ketamine at the time of extubation.
In humans, plasma ketamine concentrations of 0.1 to 0.2 μg/mL have been reported to have analgesic effects.32 To our knowledge, no published reports have described the circulating concentrations of ketamine that produce analgesia in cats; however, plasma ketamine concentrations after low-dose infusion have been evaluated for antinociceptive effects in conscious dogs.33 The results indicated that plasma ketamine concentrations of 0.22 to 0.37 μg/mL are associated with analgesic effects in that species. Norketamine is a pharmacologically active metabolite of ketamine.16,30 Although plasma concentrations of norketamine were greater than those of ketamine in cats of the present study beginning 1 hour after the end of infusion, because the potency of this metabolite in cats is approximately 10% of that of ketamine,30 we assume that its analgesic effect was likely minimal.
Mean percentages of RBCs with Heinz bodies were not significantly increased, compared with baseline values, and anemia did not develop in any of the cats of the present study after drug administration. Percentages of RBCs with Heinz bodies varied among time points during and after drug administration in the present study, but the highest mean value (4.6 ± 4.8%) was not dissimilar to findings described for healthy cats, in which up to 5% of RBCs are reported to have Heinz bodies.34 We believe this result was likely attributable to the low dose of propofol (2.0 mg/kg in the initial bolus and infusion of < 30 minutes' duration at 10.0 mg/kg/h). However, infusion of the ketamine-propofol mixture at a higher dose or for a longer duration should not be used in this species until specific studies on safety of the coadministration are available.
We followed a multimodal anesthetic approach in our study; anesthesia was induced with a ketamine-propofol or ketamine-propofol-dexmedetomidine combination and was maintained with a ketamine-propofol infusion. The ketamine-propofol combination produced a rapid recovery and good analgesia in the postoperative period. Dexmedetomidine added to ketamine diminishes the perception of nociceptive surgical stimuli35; the additional analgesia furnished by the α2-adrenergic receptor agonist could make this anesthetic protocol more advisable for emergency treatment or for surgical procedures that could result in substantial postoperative pain. Further studies should be conducted to investigate the clinical efficacy and safety of infusion of higher doses of the ketamine-propofol drug combination, which could also potentially provide a deeper anesthesia and greater postoperative analgesia in such patients.
ABBREVIATIONS
| HR | Heart rate |
| mNIBP | Mean noninvasively measured arterial blood pressure |
| Petco2 | End-tidal partial pressure of carbon dioxide |
| Spo2 | Oxygen saturation as measured via pulse oximetry |
Ketavet 100, Intervet Production Srl, Naples, Italy.
Propovet, Esteve Veterinaria, Bologna, Italy.
Dexdomitor, Pfizer, Rome, Italy.
Perfusor Secura FT, B. Braun, Melsungen, Germany.
UT4000F Pro monitor, Goldway Inc, Los Angeles, Calif.
PASW, version 18.0 for Windows, SPSS Inc, Chicago, Ill.
References
- 1.↑
Arora S. Combining ketamine and propofol (“ketofol”) for emergency department procedural sedation and analgesia: a review. West J Emerg Med 2008; 9: 20–23.
- 2.
Loh G, Dalen D. Low-dose ketamine in addition to propofol for procedural sedation and analgesia in the emergency department. Ann Pharmacother 2007; 41: 485–492.
- 3.
Andolfatto G, Willman EA. A prospective case series of pediatric procedural sedation and analgesia in the emergency department using single-syringe ketamine-propofol combination (ketofol). Acad Emerg Med 2010; 17: 194–201.
- 4.↑
Plumb DC. Ketamine HCl. Propofol. In: Plumb DC, ed. Plumb's veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008;513, 778.
- 5.
Woolf CJ, Chong MS. Preemptive analgesia: treating postoperative pain by preventing the establishment of central sensitisation. Anesth Analg 1993; 77: 362–367.
- 6.
Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983; 306: 686–688.
- 7.↑
Srivastava U, Sharma N, Kumar A, et al. Small dose propofol or ketamine as an alternative to midazolam co-induction to propofol. Indian J Anaesth 2006; 50: 112–114.
- 8.↑
Mortero RF, Clark LD, Tolan MM, et al. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg 2001; 92: 1465–1469
- 9.↑
Green SM, Andolfatto G, Krauss B. Ketofol for procedural sedation? Pro and con. Ann Emerg Med 2011; 57: 444–448.
- 10.↑
Pascoe PJ, Ilkiw JE, Frischmeyer KJ. The effect of the duration of propofol administration on recovery from anesthesia in cats. Vet Anaesth Analg 2006; 33: 2–7.
- 11.↑
Andress JL, Day TK, Day D. The effects of consecutive day propofol anesthesia on feline red blood cells. Vet Surg 1995; 24: 277–282.
- 12.
Matthews NS, Brown RM, Barling KS, et al. Repetitive propofol administration in dogs and cats. J Am Anim Hosp Assoc 2004; 40: 255–260.
- 13.↑
Bley CR, Roos M, Price J, et al. Clinical assessment of repeated propofol-associated anesthesia in cats. J Am Vet Med Assoc 2007; 231: 1347–1353.
- 14.↑
Christopher MM, White G, Eaton JW. Erythrocyte pathology and mechanisms of Heinz Body-mediated hemolysis in cats. Vet Pathol 1990; 27: 299–310.
- 15.↑
Mair AR, Pawson P, Courcier E, et al. A comparison of the effects of two different doses of ketamine used for co-induction of anaesthesia with a target-controlled infusion of propofol in dogs. Vet Anaesth Analg 2009; 36: 532–538.
- 16.↑
Nolan A, Reid J, Welsh E, et al. Simultaneous infusions of propofol and ketamine in ponies premedicated with detomidine: a pharmacokinetic study. Res Vet Sci 1996; 60: 262–266.
- 17.↑
Zonca A, Ravasio G, Gallo M, et al. Pharmacokinetics of ketamine and propofol combination administered as ketofol via continuous infusion in cats [published online ahead of print Jan 29, 2012]. J Vet Pharmacol Ther doi: 10.1111/j.1365-2885.2012.01377.x.
- 18.↑
Muir WW. Considerations for general anesthesia. In: Tranquilli WJ, Thurmon JC, Grimm KG, eds. Lumb and Jones' veterinary anesthesia and analgesia. 4th ed. Ames, Iowa: Blackwell, 2007:17–30.
- 19.↑
Hedlund CS. Surgery of reproductive and genital system. In: Fossum TW, ed. Small animal surgery. 2nd ed. St Louis: Mosby, 2002; 610–671.
- 20.↑
Tvedten H, Moritz A. Reticulocyte and Heinz body staining and enumeration. In: Weiss DJ, Wardrop KJ, eds. Schalm's veterinary hematology. Ames, Iowa: Wiley-Blackwell, 2010; 1067–1073.
- 21.↑
Belda E, Laredo FG, Escobar M, et al. Sedative and cardiorespiratory effects of three doses of romifidine in comparison with medetomidine in five cats. Vet Rec 2008; 162: 82–88.
- 22.↑
Ansah OB, Vainio O, Hellesten C, et al. Postoperative pain control in cats: clinical trials with medetomidine and butorphanol. Vet Surg 2002; 31: 99–103.
- 23.↑
Shaffran N. Pain management: the veterinary technician's perspective. Vet Clin North Am Small Anim Pract 2008; 38: 1415–1428.
- 24.↑
Ilkiw JE, Pascoe PJ, Tripp LD. Effect of variable-dose propofol alone and in combination with two fixed doses of ketamine for total intravenous anesthesia in cats. Am J Vet Res 2003; 64: 907–912.
- 25.↑
Ilkiw JE, Pascoe PJ. Cardiovascular effects of propofol alone and in combination with ketamine for total intravenous anesthesia in cats. Am J Vet Res 2003; 64: 913–917.
- 26.↑
Kästner SB, Kull S, Kutter AP, et al. Cardiopulmonary effects of dexmedetomidine in sevoflurane-anesthetized sheep with and without nitric oxide inhalation. Am J Vet Res 2005; 66: 1496–1502.
- 27.↑
Bloor BC, Ward DS, Belleville JP, et al. Effects of intravenous dexmedetomidine in humans. II: hemodynamic changes. Anesthesiology 1992; 77: 1134–1142.
- 28.↑
Rodrigues AD, Roberts EM. The in vitro interaction of dexmedetomidine with human liver microsomal cytochrome P4502D6 (CYP2D6). Drug Metab Dis 1997; 25: 651–655.
- 29.↑
Kharasch ED, Herrmann S, Labroo R. Ketamine as a probe for medetomidine stereoisomer inhibition of human liver microsomal drug metabolism. Anesthesiology 1992; 77: 1208–1214.
- 30.↑
Hanna RM, Borchard REB, Schmidt SL. Pharmacokinetics of ketamine HCl and metabolite I in the cat: a comparison of i.v., i.m., and rectal administration. J Vet Pharmacol Ther 1988; 11: 84–93.
- 31.↑
Adam HK, Glen JB, Hoyle PA. Pharmacokinetics in laboratory animals of ICI 35 868, a new i.v. anaesthetic agent. Br J Anaesth 1980; 52: 743–746.
- 32.↑
Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989; 36: 186–197.
- 33.↑
Bergadano A, Andersen OK, Arendt-Nielsen L, et al. Plasma levels of a low-dose constant-rate-infusion of ketamine and its effect on single and repeated nociceptive stimuli in conscious dogs. Vet J 2009; 182: 252–260.
- 35.↑
Willigers HM, Prinzen FW, Roekaerts PM. The effects of esmolol and dexmedetomidine on myocardial oxygen consumption during sympathetic stimulation in dogs. J Cardiothorac Vasc Anesth 2006; 20: 364–370.
