Propofol, 2,6-diisopropylphenol, is an anesthetic agent commonly administered IV to dogs for IoA. It results in smooth and rapid IoA, but it can be accompanied by respiratory depression and apnea.1,2 Propofol causes a decrease in blood pressure variables as the result of decreased myocardial contractility and SVR or decreased sympathetic activity.3–5 The reduction of CO from the negative inotropic effect has also been linked to a reduced preload in human studies.6,7
Ketamine hydrochloride is another commonly used injectable anesthetic agent. It is characterized as an N-methyl-d-aspartate receptor antagonist with antihyperalgesic and anesthetic properties. The cardiovascular stimulation associated with ketamine is characterized by increases in HR, CO, and arterial blood pressure variables as a result of increased sympathetic efferent activity.8,9 Administration of clinically applicable or lower doses of ketamine can cause respiratory depression in dogs9,10; however, the severity of the respiratory depression is usually of no clinical importance in healthy animals. The addition of diazepam to ketamine for IoA is characterized by stable cardiovascular and respiratory variables,10,11 possibly related to diazepam's ability to minimize the cardiovascular stimulating properties of ketamine.12
The combination of K-P has been studied in humans for several years.13 The use of this combination has gained popularity because of its theoretical benefits in mitigating some of propofol's negative cardiovascular effects and reducing the propofol dose needed. The latter is especially attractive in times when availability of drugs is limited. In humans, the combination of K-P is reported to provide a more stable hemodynamic and respiratory profile than propofol13,14; however, there are some reports of a longer duration of apnea.15 To date, there is no strong evidence to conclude that administration of the K-P combination is safer and more efficacious than administration of either agent alone.13
An early attempt to assess the potential advantage of K-P administration in dogs involved comparison of propofol alone with propofol followed by ketamine for IoA.16 Heart rate and SAP decreased after IoA in both treatment groups, yet in the dogs treated with propofol followed by ketamine, HR was higher for the remainder of the 30-minute observational period. However, the study evaluated the treatment while halothane and nitrous oxide were also administered, and other cardiovascular variables, such as CO, were not evaluated. Hence, it was not possible to determine whether the sequential administration of propofol and ketamine had any clinical benefit during IoA in dogs. The objective of the study reported here was to evaluate the cardiorespiratory effects of IV administration of propofol (4 mg/kg), a mixture of K-P (2 mg of each drug/kg), or a mixture of ketamine (5 mg/kg) and diazepam (0.2 mg/kg) before and after IoA in dogs sedated with acepromazine maleate and oxymorphone hydrochloride. We hypothesized that for IoA in dogs, a K-P combination (the 2 drugs administered IV simultaneously) would prevent development of the cardiovascular depression associated with administration of propofol alone as well as prevent development of the cardiovascular stimulation associated with administration of K-D (the 2 drugs also administered IV simultaneously). Additionally, we hypothesized that K-P administered simultaneously would not cause as much respiratory depression as that associated with administration of propofol alone but would cause more respiratory depression than K-D administered simultaneously.
Materials and Methods
Animals—Ten healthy purpose-bred adult Beagles (mean ± SD weight, 10.6 ± 1.4 kg) were included in the study. The dogs were considered healthy on the basis of physical examination findings, PCV, and blood concentrations of total protein, BUN, and glucose. Each dog was individually housed. Food was withheld for 12 hours prior to each experiment, but the dogs had access to water ad libitum. Each dog was used in 2 experiments at a 1-week interval; in each experiment, 1 of the 3 treatment protocols was evaluated (2 of 3 treatment protocols/dog). The dogs were housed and cared for according to the Association for Assessment and Accreditation of Laboratory Animal Care guidelines. The study protocol was approved by the institutional animal care and use committee.
Instrumentation—For each dog on the day of each experiment, anesthesia was initially induced and maintained with isofluranea in oxygen delivered via a face mask. The vaporizer was adjusted (1.5% to 2%) to maintain a light plane of anesthesia, defined as absent palpebral reflexes, relaxed jaw tone, and ventrally rotated eyes. Each dog was placed in left lateral recumbency. A 20-gauge, 1.25-inch IV catheter was placed in the right cephalic vein, and a 22-gauge, 1-inch catheter was placed in the left dorsal pedal artery. A small area on both lateral aspects of the thoracic region was clipped, and conductive pads (1 on the right side and 2 on the left side) were applied to the skin for lead II ECG monitoring. After instrumentation, each dog was allowed to recover completely from anesthesia (ie, able to stand and walk without assistance or ataxia).
Experimental design and procedures—A minimum of 40 minutes after discontinuation of isoflurane administration was allowed to elapse before starting any procedures. Each dog remained in a sitting position or in lateral recumbency, with minimal restraint, during the baseline (ie, prior to premedication) determination of CO. A single determination of CO was performed with a lithium dilution technique as previously described.17 Two minutes prior to the CO determination, an arterial blood sample (0.5 mL) was collected to assess plasma sodium and hemoglobin concentrations as required by the monitor.b A bolus injection of lithium indicatorc (1 mL [0.15 mmol]) followed by 2 mL of saline (0.9% NaCl) solution was given IV over a period of 10 seconds through the cephalic catheter. Subsequent determinations of CO were obtained from the monitorb by use of pulse contour technology. The monitor also acquired invasive blood pressure measurements through an electronic disposable transducer connected to a nondistensible saline solution–filled extension line attached to the dorsal pedal artery catheter. The transducer was previously calibrated with a calibration device,d then placed and zeroed at the level of the sternum.
Acepromazine maleatee (0.02 mg/kg) and oxymorphone hydrochloridef (0.05 mg/kg) were administered IV to each dog for sedation. Fifteen minutes after premedication, anesthesia was induced with 1 of 3 protocols assigned randomly by use of a balanced incomplete block design. Over the study period, each dog underwent 2 of the 3 protocols (1-week washout period between treatments). The treatments were as follows: propofolg (4 mg/kg) administered IV, a 1:1 mixture of K-P (2 mg of ketamineh/kg with 2 mg of propofol/kg) mixed in the same syringe and administered IV, or a combination of K-D (5 mg of ketamine/kg with 0.2 mg of diazepami/kg) mixed in the same syringe administered IV. The assigned drug or drug combination was administered IV by hand over a period of 60 seconds by a technician who was not involved in data collection. Each dog remained in left lateral recumbency after IoA. Following data collection, each dog's trachea was intubated, and isoflurane in 100% oxygen was administered through a rebreathing circuit. All dogs were maintained under inhalation anesthesia for an undetermined amount of time as part of an unrelated study.18 Recovery from anesthesia was not assessed in the present study.
Data collection and calculations—Data were collected before premedication (baseline), 15 minutes after administration of the premedicants and immediately before IoA, immediately after IoA, and 5 minutes after IoA. At each time point, an arterial blood sample (0.3 mL) was collected after 1 mL of blood was removed and returned to the patient after the sample was collected; the sample was analyzed immediately for arterial blood pH, Pao2, Paco2, arterial oxygen saturation, and hemoglobin concentration with a disposable cartridgej and a calibrated handheld gas analyzerk (validated for use in dogs19) and at a standard temperature of 37°C. Mean values of measurements of HR, CO, stroke volume, SVR, SAP, MAP, and DAP recorded from the monitorb during a 15-second period were calculated to provide a value for each variable at each time point. Respiratory rate was determined by observing movements of the thoracic wall during a period of 1 minute. Postinduction apnea was defined as absence of spontaneous respiratory effort for a span of 20 seconds in the period following IoA. If no spontaneous return of thoracic excursions occurred after 1 minute, the plan was to intubate the dog and provide manual ventilation. Temperature was recorded with a rectal thermometer.
At each time point, Pao2 and Pao2-Pao2 were calculated by use of standard equations20 (barometric pressure used was 708 mm Hg, which was the barometric pressure measured by the gas analyzer in the research laboratory). Arterial oxygen content and oxygen delivery were calculated21 as follows:
where Hb is hemoglobin and Sao2 is the arterial oxygen saturation.
Statistical analysis—Normal probability plots revealed that all data followed a normal distribution. Subsequently, the variables were summarized as mean ± SD. For comparison of data obtained at baseline with those obtained before IoA, the means were calculated for all dogs. For comparisons of data obtained at the 3 time points other than baseline, means for each treatment group were calculated. The premedication effect on variables was assessed by use of a mixed-model ANOVA. The linear model specified time period (baseline vs before IoA) as a fixed effect, dog identification as a random effect, and the Kenward-Roger option for computing the denominator degrees of freedom. Values of P were adjusted for multiple comparisons with the Benjamini-Hochberg false discovery rate method. Effects of additional time periods (before IoA, after IoA, and 5 minutes after IoA) and protocol (propofol, K-P, and K-D treatments) on variables were assessed with a mixed-model ANOVA. The linear model specified time, protocol, and time × protocol as fixed effects with the Kenward-Roger denominator degrees of freedom. Dog identification was specified as the random effect. Interactions between time and protocol (ie, comparisons between time points within each protocol and comparisons between protocols within each time point) were examined by means of generalized linear mixed model procedures. l–n
For comparisons between time points within each protocol, P values across all variables were adjusted for multiple comparisons with the Benjamini-Hochberg false discovery rate method. For each of those comparisons with a significant P value (after the Benjamini-Hochberg adjustment), P values for comparisons between protocols within each time point were adjusted for multiple comparisons with a Tukey procedure. Incidence of apnea was analyzed with a Fisher exact test. Significance was set at α < 0.05. All analyses were performed with statistical software.l–n
Results
Random assignment of treatment protocols resulted in 6 dogs undergoing the propofol treatment, 7 dogs undergoing the K-P treatment, and 6 dogs undergoing the K-D treatment. Data from 1 dog assigned to receive K-D treatment was removed from the study because of a technical error. In all 19 experiments, dogs remained in lateral recumbency after premedication and until the end of data collection. In each instance, IoA proceeded smoothly and without any signs of distress in any dog. None of the dogs had purposeful movement immediately after IoA and for 5 minutes thereafter. Cardiorespiratory data were collected before premedication (baseline), 15 minutes after administration of the premedicants and immediately before IoA, immediately after IoA, and 5 minutes after IoA and subsequently analyzed (Figures 1 and 2; Tables 1–3).
Mean ± SD HR (A), MAP (B), CO (C), and calculated oxygen delivery (D) measured in healthy dogs 15 minutes after administration of premedication (0.02 mg of acepromazine maleate/kg and 0.05 mg of oxymorphone hydrochloride/kg, IV) and immediately before IoA, immediately after IoA, and 5 minutes after IoA with propofol (4 mg/kg, IV; circles), a 1:1 mixture of K-P (2 mg of ketamine/kg with 2 mg of propofol/kg, IV; squares), or a combination of K-D (5 mg of ketamine/kg with 0.2 mg of diazepam/kg mixed in the same syringe, IV; triangles). Ten dogs were used in the study, but each dog underwent only 2 of the 3 protocols (1-week washout period between protocols); 6 dogs received only propofol, 7 dogs received K-P, and 6 dogs received K-D. *Within a treatment, value differs significantly (P < 0.05) from the value before IoA. †Within a treatment, value differs significantly (P < 0.05) from the value after IoA. ‡Within a time point, value differs significantly (P < 0.05) from the value for dogs treated with K-P. §Within a time point, value differs significantly (P < 0.05) from the value for dogs treated with K-D.
Citation: American Journal of Veterinary Research 75, 3; 10.2460/ajvr.75.3.231
Mean ± SD respiratory rate (A), Pao2 (B), and Paco2 (C) measured in the dogs in Figure 1 at 15 minutes after administration of premedication and immediately before IoA, immediately after IoA, and 5 minutes after IoA with propofol (circles), K-P (squares), or K-D (triangles). See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 75, 3; 10.2460/ajvr.75.3.231
Mean ± SD values for cardiorespiratory and blood gas variables and rectal temperature measured in 10 healthy dogs before (baseline) and 15 minutes after administration of premedication (0.02 mg of acepromazine maleate/kg and 0.05 mg of oxymorphone hydrochloride/kg, IV) prior to IoA with propofol, K-P, or K-D.
| Variable | Baseline | Before IoA | Reference range22,23 |
|---|---|---|---|
| Respiratory rate (breaths/min) | 26.2 ± 6.1 | 19 ± 5.9* | 10–30 |
| HR (beats/min) | 121.5 ± 26.8 | 70 ± 16.7* | 60–140 |
| SAP (mm Hg) | 146.6 ± 20.3 | 141.6 ± 20.9 | 90–140 |
| MAP (mm Hg) | 108.7 ± 9.4 | 80.3 ± 7.6* | 60–100 |
| DAP (mm Hg) | 85.4 ± 11.4 | 58.2 ± 7.4* | 50–80 |
| CO (L/min) | 2.2 ± 0.9 | 1.7 ± 0.8 | 2.0 ± 4.6 |
| Stroke volume (mL/beat) | 19.9 ± 4.8 | 25.3 ± 7.8* | –10.6 ± 42.5 |
| SVR (dynes•s/cm5) | 3,851.6 ± 961 | 3,991 ± 1,569 | 1,600–2,500 |
| Oxygen delivery (L/min) | 0.42 ± 0.1 | 0.27 ± 0.1* | 0.2–0.35 |
| Arterial blood oxygen content (mL/L) | 183.1 ± 23.4 | 156.9 ± 17.9* | 190–210 |
| Arterial blood pH | 7.38 ± 0.02 | 7.35 ± 0.01* | 7.35–7.46 |
| Pao2 (mm Hg) | 91.4 ± 8 | 88.5 ± 9.3 | 80–110 |
| Paco2 (mm Hg) | 32.1 ± 2.3 | 35.7 ± 2.3* | 32–43 |
| Arterial blood oxygen saturation (%) | 96.9 ± 0.7 | 96.4 ± 0.9 | 95.4 ± 97.2 |
| HCO3 (mmol/L) | 19.6 ± 1.6 | 20.2 ± 1.2 | 18–26 |
| Base excess (mmol/L) | –5.2 ± 1.8 | –5.2 ± 1.3 | –8 to +2 |
| Rectal temperature (°C) | 37.8 ± 0.6 | 37.2 ± 0.5* | 37.8 ± 39.0 |
For a given variable, value differs significantly (P < 0. 05) from the baseline.
Mean ± SD cardiovascular variables measured in the dogs in Table 1 at 15 minutes after administration of premedication (0.02 mg of acepromazine maleate/kg and 0.05 mg of oxymorphone hydrochloride/kg, IV) and immediately before IoA, immediately after IoA, and 5 minutes after IoA with propofol (4 mg/kg, IV), a 1:1 mixture of K-P (2 mg of ketamine/kg with 2 mg of propofol/kg, IV), or a combination of K-D (5 mg of ketamine/kg with 0.2 mg of diazepam/kg mixed in the same syringe, IV).
| Variable | Anesthetic Induction treatment | Before IoA | After IoA | 5 minutes after IoA |
|---|---|---|---|---|
| Stroke volume (mL/beat) | Propofol | 21 ± 6 | 21 ± 5 | 20 ± 6 |
| K-P | 25 ± 5 | 24 ± 5 | 23 ± 5 | |
| K-D | 25 ± 10 | 25 ± 10 | 23 ± 10 | |
| SAP (mm Hg) | Propofol | 138 ± 23 | 125 ± 13 | 132 ± 9 |
| K-P | 152 ± 23 | 139 ± 28 | 133 ± 19 | |
| K-D | 142 ± 14 | 144 ± 13 | 146 ± 15 | |
| DAP (mm Hg) | Propofol | 58 ± 8 | 44 ± 10*§ | 50 ± 6*‡§ |
| K-P | 55 ± 5 | 46 ± 6*§ | 55 ± 6†§ | |
| K-D | 58 ± 7 | 62 ± 8 | 69 ± 9* | |
| Arterial blood oxygen content (mL/L) | Propofol | 167 ± 12 | 125 ± 21* | 152 ± 14*† |
| K-P | 158 ± 24 | 124 ± 17* | 142 ± 18*† | |
| K-D | 141 ± 13 | 124 ± 15 | 132 ± 11 | |
| SVR (dynes•s/cm5) | Propofol | 4,326 ± 1,692 | 2,563 ± 908* | 2,934 ± 843*‡ |
| K-P | 3,779 ± 1,056 | 2,984 ± 897* | 2,301 ± 482* | |
| K-D | 3,749 ± 1,624 | 3,385 ± 1,405 | 2,674 ± 1,207* |
Ten dogs were used in the study, but each dog underwent only 2 of the 3 protocols (1-week washout period between protocols); 6 dogs received propofol only, 7 dogs received K-P, and 6 dogs received K-D.
Within a row, value differs significantly (P < 0.05) from the value before IoA.
Within a row, value differs significantly (P < 0.05) from the value after IoA.
For a given variable at this time point, value differs significantly (P < 0.05) from the value for dogs treated with K-P.
For a given variable at this time point, value differs significantly (P < 0.05) from the value for dogs treated with K-D.
Mean ± SD values for additional blood gas variables, Pao2, Pao2-Pao2, and rectal temperature measured in the dogs in Tables 1 and 2 at 15 minutes after administration of premedication and immediately before IoA, immediately after IoA, and 5 minutes after IoA with propofol, K-P, or K-D.
| Variable | Anesthetic induction treatment | Before IoA | After IoA | 5 minutes after IoA |
|---|---|---|---|---|
| Arterial blood pH | Propofol | 7.35 ± 0.03 | 7.31 ± 0.04* | 7.31 ± 0.03* |
| K-P | 7.36 ± 0.01 | 7.31 ± 0.02* | 7.30 ± 0.02* | |
| K-D | 7.36 ± 0.02 | 7.32 ± 0.02* | 7.33 ± 0.02* | |
| Arterial blood oxygen saturation (%) | Propofol | 96 ± 1 | 79 ± 3*§ | 93 ± 3† |
| K-P | 96 ± 1 | 79 ± 6*§ | 90 ± 4*† | |
| K-D | 96 ± 1 | 88 ± 4* | 95 ± 1† | |
| HCO3 (mmol/L) | Propofol | 20.1 ± 1.6 | 20.4 ± 3.7 | 20.5 ± 1.8 |
| K-P | 20.5 ± 1.1 | 21.6 ± 2.0 | 22.1 ± 1.1 | |
| K-D | 20.1 ± 1.0 | 20.9 ± 1.8 | 20.5 ± 0.9 | |
| Base excess (mmol/L) | Propofol | –5.3 ± 1.8 | –6.0 ± 4.2 | –5.7 ± 2.3 |
| K-P | –5.1 ± 1.1 | –4.7 ± 2.1 | –4.1 ± 1.1 | |
| K-D | –5.3 ± 1.0 | –5.2 ± 1.6 | –5.7 ± 1.0 | |
| Pao2 | Propofol | 93.2 ± 3.2 | 88.5 ± 8.2 | 89.5 ± 2.3‡ |
| K-P | 92.9 ± 2.3 | 85.5 ± 4.1* | 83.2 ± 3.6* | |
| K-D | 94.7 ± 3.1 | 88.3 ± 5.5 | 91 ± 3.7‡ | |
| Pao2-Pao2 | Propofol | 5.5 ± 9.9 | 40.8 ± 8.5* | 13.3 ± 9.6† |
| K-P | 6.8 ± 10 | 36.9 ± 7.4* | 13.2 ± 8.2† | |
| K-D | 8.5 ± 7.9 | 29.3 ± 7.7* | 9.7 ± 5.6† | |
| Rectal temperature (°C) | Propofol | 37.4 ± 0.7 | 37.3 ± 0.6 | 37.1 ± 0.8 |
| K-P | 37.4 ± 0.4 | 37.1 ± 0.5 | 37.0 ± 0.5* | |
| K-D | 37.4 ± 0.4 | 37.2 ± 0.5 | 37.2 ± 0.5 |
See Table 2 for key.
The administration of acepromazine and oxymorphone caused decreases in mean HR, MAP, DAP, respiratory rate, arterial blood oxygen concentration, and calculated oxygen delivery, along with increases in stroke volume and Paco2, compared with findings at baseline (Table 1). Compared with data obtained from dogs immediately after IoA with K-P or K-D, a significant (P < 0.001) increase in HR was detected at 5 minutes after IoA (Figure 1). At 5 minutes after IoA in dogs undergoing the K-P treatment, HR was significantly lower than it was in dogs undergoing the K-D treatment (P = 0.038) but no different (P = 0.145) than it was in dogs undergoing the propofol treatment. Heart rate in dogs undergoing the propofol protocol was also significantly (P < 0.001) lower than that in dogs undergoing the K-D treatment.
No significant changes in SAP were detected throughout the experimental period (Table 2). After IoA with K-P or K-D, the MAP remained stable; however, after IoA with propofol, MAP decreased significantly (P = 0.002) from the before IoA value (Figure 1). At this time point, MAP in dogs undergoing the K-P treatment was significantly (P = 0.027) lower than it was in dogs undergoing the K-D treatment, but significantly (P = 0.044) higher than it was in dogs undergoing the propofol treatment. At 5 minutes after IoA, MAP in all treatment groups had returned to values similar to those before IoA, although MAP in dogs undergoing the propofol treatment remained significantly (P < 0.001) lower than the value in dogs undergoing the K-D treatment. Compared with findings before IoA, DAP was decreased significantly after IoA in dogs undergoing the K-P treatment (P = 0.177) and in those undergoing the propofol treatment (P < 0.001). Both of those treatments resulted in significantly (P < 0.001) lower values of DAP, compared with findings in dogs undergoing the K-D treatment. Five minutes after IoA with K-P, DAP returned to the value before IoA. This effect was not evident in dogs treated with propofol, in which DAP remained significantly (P = 0.045) lower than the value before IoA. A progressive increase in DAP was observed after IoA with K-D, but the change was significant (P = 0.002) only at 5 minutes after IoA. At this point, DAP in dogs undergoing K-P treatment was significantly (P = 0.001) lower than the value in dogs undergoing K-D treatment but significantly (P = 0.024) higher than the value in dogs that were administered propofol.
Cardiac output in dogs undergoing K-P or K-D treatment was increased significantly at 5 minutes after IoA (P = 0.022 and P = 0.001 respectively), compared with before IoA and after IoA findings (Figure 1). At this time point, CO was similar for dogs treated with K-P or K-D, but both values were higher than that for dogs treated with propofol (P = 0.029 and P < 0.001, respectively).
Compared with findings before IoA, SVR decreased immediately after IoA in dogs treated with K-P (P = 0.041) or propofol (P < 0.001; Table 2). Five minutes after IoA with any of the 3 treatments, SVR was lower than the respective value before IoA. At this time point, SVR in dogs undergoing the K-P treatment was significantly (P = 0.007) lower than the value in dogs undergoing the propofol treatment.
Respiratory rates decreased significantly (P < 0.001) after IoA with K-P or propofol (Figure 2). Several dogs developed apnea for a period of at least 20 seconds, but no more than 60 seconds. The incidence of apnea following IoA was not significantly different (Fisher exact test P value = 0.88) among treatments (3, 5, 2 dogs that received propofol, K-P, or K-D, respectively). Five minutes after IoA, respiratory rate had increased significantly with all 3 treatments and was similar to the respective values before IoA; there were no differences among treatments. Despite the decrease in respiratory rate with all treatments after IoA, Paco2 increased significantly (P = 0.002) only after IoA in dogs treated with K-P. At 5 minutes after IoA, Paco2 remained significantly (P < 0.001) higher than the value before IoA; however, throughout the experimental period, values remained within reference range.
Hypoxemia (defined as Pao2 < 80 mm Hg) was detected after administration of each of the treatments (Figure 2). Five minutes after IoA, the dogs’ Pao2 had increased regardless of treatment; however, Pao2 returned to the value before IoA only in dogs treated with K-D. Dogs that had received K-P or propofol remained hypoxic (70 ± 8 mm Hg and 76 ± 11 mm Hg, respectively) at 5 minutes after IoA. There were no differences in Pao2 among groups at any time point. Compared with the value before IoA, Pao2 decreased in dogs following administration of K-P (Table 3). Five minutes after IoA, Pao2 in dogs administered K-P was lower than that in dogs administered propofol (P = 0.017) or K-D (P = 0.004). Moreover, the Pao2-Pao2 increased significantly after IoA with each of the 3 treatments; at 5 minutes after IoA, the Pao2-Pao2 had returned to the respective treatment group.
Calculated values for arterial blood oxygen content decreased significantly after IoA with K-P (P < 0.001) or propofol (P < 0.001; Table 1). At 5 minutes after IoA with K-P or propofol, the arterial blood oxygen content had increased significantly (P < 0.05) yet remained lower than the respective treatment group value before IoA. Arterial blood oxygen content did not differ among dogs undergoing treatment with K-P, K-D, or propofol at any time point. Calculated oxygen delivery was unchanged immediately after IoA with each of the 3 treatments. However, at 5 minutes after IoA, oxygen delivery was increased significantly in dogs treated with K-P (P = 0.003) and in dogs treated with K-D (P = 0.01); values for both treatments were significantly higher than that for dogs treated with propofol.
Dog-to-dog variation (the block effect) was negligible for arterial blood pH with a variance component of 0.00 and highest for SVR with a variance component of 961,911. The median dog variance component across all variables was 1.67 (interquartile range, 0.73 to 25.53).
Discussion
In the dogs used in the present study, IoA with K-P or K-D caused an increase in HR, CO, and calculated oxygen delivery at 5 minutes after IoA; did not change MAP or stroke volume; and decreased SVR. Administration of propofol on the other hand, decreased MAP and SVR and did not change HR or CO. However, changes observed with K-P treatment were not as pronounced as those observed with K-D or propofol treatment. All anesthetic induction treatments caused some degree of apnea, respiratory depression, and hypoxemia.
The combination of acepromazine and oxymorphone administered as the preanesthetic medication in all dogs had expected effects such as decreases in MAP and DAP, which were probably attributable to peripheral α1-adrenergic receptor blockade or depression of the central vasomotor center caused by acepromazine,24 along with a decrease in HR, which was most likely attributable to a centrally mediated increase in vagal tone caused by oxymorphone.25 An additional explanation would be that dogs were sufficiently sedated to simulate values observed during sleep. The values for HR and arterial blood pressure variables were within the physiologic ranges for dogs and similar to those reported for dogs treated with this drug combination in a previous study.26
Administration of the preanesthetic medications caused a decrease in the respiratory rate with a consequent slight increase in Paco2. These changes were not considered clinically important and were not as severe as the marked oxymorphone-related respiratory depression in dogs that has been previously described.27 We chose to administer the premedicant combination IV instead of IM in an effort to avoid major differences in rate of absorption of the drugs from muscles.
The increase in HR with the K-P or K-D treatment probably reflected the slower onset of action of the ketamine component as well as its stimulating effects on the cardiovascular system. In the human medical literature, similar changes in HR were detected in female patients 5 minutes after IoA with ketamine.28 In 1 study16 in which dogs received either propofol followed by ketamine (2 mg/kg each, IV) or propofol alone (4 mg/kg, IV), it was observed that the HR decreased after IoA with both treatments; however, from that point on, the HR remained higher in the dogs that received K-P. In that study,16 mean HR before IoA was approximately 110 beats/min in both treatment groups, which was higher than the HR for dogs receiving K-P or propofol in the present study. It is possible that the effects of the preanesthetic medications used in the present study were more pronounced or that we were able to eliminate external sources of stimulation, such as noise and direct manipulation of the dogs, thereby establishing a lower baseline HR without blunting the stimulating effects of ketamine observed at 5 minutes after IoA in the dogs treated with K-P or K-D.
In the present study, either the presence of ketamine or the reduction of the propofol dose in the K-P combination appeared to mitigate the decrease in MAP associated with propofol alone. Despite the decrease in SVR with both the K-P and K-D treatments, the increase in CO (as a result of increased HR with no change in stroke volume) accounted for the lack of change in MAP. These results were similar to those detected previously28 in humans during the 5-minute period after administration of propofol, ketamine, or their combination as well as those previously reported for dogs anesthetized with K-D.12 On the other hand, the administration of propofol caused a clinically important reduction in MAP, most likely because of the decrease in SVR given that CO did not change. The degree of hypotension after IoA with propofol has been associated with the drug's vasodilatory effect on the peripheral vasculature in addition to its ability to cause myocardial depression.3,4,29 The results of the present study were similar to those of another study,1 in which no apparent depressant effects on CO or cardiac index were evident after administration of propofol in healthy mixed-breed dogs.
Respiratory depression has been reported as a complication after administration of propofol30 or K-D12 as well as with a combination of K-P.31 In the present study, all regimens caused some degree of respiratory depression, defined as an increase in Paco2; however, this increase was not clinically important. Five minutes after IoA with K-P, the Paco2 had not returned to the value before IoA despite improvement in respiratory rate; nonetheless, the values were still close to the reference range of 36 to 43 mm Hg for dogs.22 Other investigators16,32 have reported exacerbation of incidence of apnea when ketamine was combined with propofol. In the present study, there was little evidence of ketamine-induced exacerbation of the respiratory depression associated with propofol, given the incidence of apnea. It is possible that evaluation of a greater number of dogs may have revealed differences in the incidence of apnea among treatment groups.
In the present study, we elected to delay the administration of oxygen to the dogs to evaluate the effects of each of the 3 IoA regimens on respiratory gas exchange while the dogs were breathing room air. Arterial hypoxemia has been defined as a Pao2 < 80 mm Hg.33 Clinically important hypoxemia was observed in dogs in all 3 treatment groups after IoA, with the lowest Pao2 (41 mm Hg) observed in dogs undergoing the K-P treatment. Considering that the Pao2-Pao2 increased significantly immediately after IoA with all treatments, the decrease in Pao2 can be partially explained by a decrease in pulmonary gas exchange, most likely as a result of ventilation-perfusion mismatch.34 The degree of hypoventilation was not sufficient to be the primary cause of the hypoxemia. Some degree of atelectasis was probably present in the study dogs because of their positioning in lateral recumbency during the interval between premedication and IoA. A previous investigation10 in healthy dogs revealed greater hypoxemia 10 minutes after IoA with K-D (mean ± SD, 61 ± 4 mm Hg), compared with findings after IoA with propofol (76 ± 6 mm Hg), and this difference was attributed to ketamine's greater duration of effect. Perhaps measurement of Pao2 at a later time point in the present study would have revealed greater hypoxemia after administration of K-D but not after administration of propofol because it appears that oxygen saturation returns to reference range within 10 minutes after administration of a single dose of propofol in unpremedicated dogs.35 The severity of hypoxemia associated with the treatments containing propofol was probably responsible for the decrease in arterial blood oxygen content after IoA. Despite the reduction in calculated oxygen content, calculated oxygen delivery increased 5 minutes after IoA with K-P or K-D as a result of an increase in CO.
It is possible that some of the cardiovascular effects in the dogs in the present study were caused by the acute hypoxemia, which has been linked to increases in concentrations of circulating catecholamines and subsequent cardiovascular stimulation.36 However, the period of hypoxemia was short-lived, and results of the present study were very similar to those of studies1,9,10 in which animals either breathed room air or were intubated and administered 100% oxygen.
The present study had some limitations. First, all dogs received a precalculated dose of the anesthetic induction agents. The doses were selected on the basis of previous evidence of satisfactory IoA and intubation16 following their administration and on clinical experience. Because the drug doses were not titrated, it may be possible that these doses were greater than necessary to achieve adequate anesthetic level and consequently led to excessive cardiovascular and respiratory responses after IoA. However, a dose of 0.5 mg of ketamine/kg—less than the dose used in the present study—coadministered for IoA with a target-controlled infusion of propofol in dogs has been previously associated with a higher incidence of apnea but no dose-sparing effect with regard to propofol.32 An additional factor to consider is the rate of administration used in the present study. All treatments were given over a 60-second period, which provided a total approximate dose of 40 mg of propofol/min, 20 mg of ketamine/min with 20 mg of propofol/min, or 50 mg of ketamine/min with 5 mg of diazepam/min. The total dose of propofol was close to the administration rate of 50 mg/min suggested previously37 as an optimal rate in sheep to achieve adequate brain concentrations and anesthesia while avoiding high arterial concentrations related to hypotension and excessively slow IoA. Therefore, it could be reasonable to assume that just by giving half of the dose of propofol to dogs undergoing the K-P protocol over the same period of time, the risk of hypotension after IoA was decreased.
The present study involved healthy dogs, and they were able to tolerate the treatments well. Because our objective was to evaluate the effects of propofol, K-P, and K-D during IoA, we eliminated the potential cardiovascular effect of laryngoscopy and intubation and did not administer any inhalation anesthetic agent to allow correlation of the effects directly to the drugs administered. However, further studies are needed to elucidate whether the combination of K-P, at the doses used in this study, really provides better hemodynamic stability over other protocols in different patient conditions.
In the present study, it was not possible to expose each dog to all 3 treatments; therefore, an incomplete block design was used, which can lead to possible block effects. However, the statistical analysis took this issue into consideration, thereby minimizing the effect.
Results of the present study indicated that the combination of K-P provides an additional option for IoA in healthy dogs and has a few advantages over the other 2 protocols. Compared with the propofol treatment, reduction of the dose of propofol to half and addition of ketamine resulted in better maintenance of MAP; the K-P treatment also increased CO and calculated oxygen delivery, similar to that achieved with the K-D treatment, as well as increased HR but to a lesser degree. Depression of respiration and oxygenation was clinically similar for all 3 treatments. Therefore, close monitoring of respiratory function and administration of supplemental oxygen should be performed in dogs during IoA with any of the 3 regimens.
ABBREVIATIONS
| CO | Cardiac output |
| DAP | Diastolic arterial blood pressure |
| HR | Heart rate |
| IoA | Induction of anesthesia |
| K-D | Ketamine hydrochloride and diazepam |
| K-P | Ketamine hydrochloride and propofol |
| MAP | Mean arterial blood pressure |
| Paco2 | Arterial partial pressure of carbon dioxide |
| Pao2 | Arterial partial pressure of oxygen |
| Pao2 | Alveolar partial pressure of oxygen |
| Pao2-Pao2 | Alveolar-arterial difference in partial pressure of oxygen |
| SAP | Systolic arterial blood pressure |
| SVR | Systemic vascular resistance |
Isoflo, isoflurane USP, Abbott Laboratories, North Chicago, Ill.
LiDCO plus hemodynamic monitor, LiDCO Ltd, London, England.
Lithium chloride, LiDCO Ltd, London, England.
Delta-Cal, Utah Medical Products Inc, Midvale, Utah.
Acepromazine maleate injection (2 mg/mL), Phoenix Scientific Inc, St Joseph, Mo.
Numorphan, oxymorphone HCl (1 mg/mL), Endo Pharmaceuticals Inc, Chadds Ford, Pa.
PropoFlo, Propofol (10 mg/mL), Abbott Laboratories, North Chicago, Ill.
Ketaset, Ketamine HCl (100 mg/mL), Fort Dodge Animal Health, Fort Dodge, Iowa.
Valium, Diazepam (5 mg/mL), Abbott Laboratories, North Chicago, Ill.
CG8+ I-STAT cartridge, Abbot Point of Care Inc, East Windsor, NJ.
I-STAT, Abbot Point of Care Inc, East Windsor, NJ.
GLIMMIX, SAS, version 9.2, SAS Institute Inc, Cary, NC.
SLICE, SAS, version 9.2, SAS Institute Inc, Cary, NC.
SLICEDIFF, SAS, version 9.2, SAS Institute Inc, Cary, NC.
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