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Comparison of the anesthetic efficacy and cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-β-cyclodextrin and propofol in dogs

Barbara AmbrosDepartment of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada

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Tanya Duke-NovakovskiDepartment of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada

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Kirby S. PasloskeJurox Pty Ltd, 85 Gardiner Rd, Rutherford, NSW 2320, Australia

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Abstract

Objective—To compare the cardiopulmonary effects of continuous rate infusions (CRIs) of alfaxalone-2-hydroxypropyl-β-cyclodextrin (HPCD) and propofol in healthy dogs.

Animals—6 young adult medium-sized healthy crossbred dogs.

Procedures—A crossover design was used with a washout period of 6 days between anesthetic treatments. Each dog was sedated with acepromazine (0.02 mg/kg, IV) and hydromorphone (0.05 mg/kg, IV). Anesthesia was induced with propofol (4 mg/kg) or alfaxalone-HPCD (2 mg/kg). After endotracheal intubation, anesthesia was maintained with the same agent (propofol, 0.25 mg/kg/min; alfaxalone-HPCD, 0.07 mg/kg/min) for 120 minutes. Dogs spontaneously breathed 100% oxygen. Measurements included end-tidal partial pressure of carbon dioxide, heart and respiratory rates, mean arterial blood pressure, thermodilution-derived cardiac output, and body temperature. Paired arterial and mixed venous blood samples were collected for determination of blood pH, PaCO2, and PaO2. Data were recorded prior to induction; 5, 15, 30, 60, 90, and 120 minutes after induction of anesthesia; and 20 minutes after stopping the CRI, when feasible. Stroke volume and systemic vascular resistance were calculated. Quality of anesthetic induction and recovery and interval to recovery were recorded.

Results—Both propofol and alfaxalone-HPCD produced excellent induction of anesthesia, maintenance, and recovery. Respiratory depression was evident with both anesthetics. Clinically acceptable, mild hemodynamic changes were similar for both anesthetics.

Conclusions and Clinical Relevance—Alfaxalone-HPCD produced clinically acceptable anesthetic quality and hemodynamic values ideal for use as a CRI. Ventilation may need to be supported if hydromorphone is used at these propofol and alfaxalone-HPCD infusion rates.

Abstract

Objective—To compare the cardiopulmonary effects of continuous rate infusions (CRIs) of alfaxalone-2-hydroxypropyl-β-cyclodextrin (HPCD) and propofol in healthy dogs.

Animals—6 young adult medium-sized healthy crossbred dogs.

Procedures—A crossover design was used with a washout period of 6 days between anesthetic treatments. Each dog was sedated with acepromazine (0.02 mg/kg, IV) and hydromorphone (0.05 mg/kg, IV). Anesthesia was induced with propofol (4 mg/kg) or alfaxalone-HPCD (2 mg/kg). After endotracheal intubation, anesthesia was maintained with the same agent (propofol, 0.25 mg/kg/min; alfaxalone-HPCD, 0.07 mg/kg/min) for 120 minutes. Dogs spontaneously breathed 100% oxygen. Measurements included end-tidal partial pressure of carbon dioxide, heart and respiratory rates, mean arterial blood pressure, thermodilution-derived cardiac output, and body temperature. Paired arterial and mixed venous blood samples were collected for determination of blood pH, PaCO2, and PaO2. Data were recorded prior to induction; 5, 15, 30, 60, 90, and 120 minutes after induction of anesthesia; and 20 minutes after stopping the CRI, when feasible. Stroke volume and systemic vascular resistance were calculated. Quality of anesthetic induction and recovery and interval to recovery were recorded.

Results—Both propofol and alfaxalone-HPCD produced excellent induction of anesthesia, maintenance, and recovery. Respiratory depression was evident with both anesthetics. Clinically acceptable, mild hemodynamic changes were similar for both anesthetics.

Conclusions and Clinical Relevance—Alfaxalone-HPCD produced clinically acceptable anesthetic quality and hemodynamic values ideal for use as a CRI. Ventilation may need to be supported if hydromorphone is used at these propofol and alfaxalone-HPCD infusion rates.

Total IV anesthesia is an alternative to inhalant anesthesia and has become a clinically acceptable technique in veterinary anesthesia. It is often necessary for certain procedures when access to inhalational anesthesia is not available (eg, for diagnostic imaging). The disadvantages of inhalational anesthesia include the purchase of costly anesthetic machines, vaporizers, and breathing systems. Environmental pollution from anesthetic-gas waste is a potential health hazard for those working around inhalant anesthesia, and this consideration may also make IV anesthesia a better choice than an inhalant agent. Injectable anesthetics propofol and alfaxalone-HPCD share several advantages, compared with other induction agents, including faster onset and shorter duration of action attributable to the fact that both are rapidly redistributed and metabolized.1,a

Propofol (2,6-diisopropylphenol), an IV hypnotic agent, has become a popular injectable anesthetic in small animal practice because of its ease of use and its reliability for induction and maintenance of anesthesia.2,3 Anesthesia produced by propofol is characterized by a rapid, smooth induction and recovery. It also has several important advantages favoring its administration by CRI, and these include a high rate of clearance and lack of active metabolites.1 However, propofol is also associated with a dose-dependent ventilatory depression and decreased systemic blood pressure, cardiac output, and SVR.4,5 Other disadvantages of propofol include pain on injection and support of bacterial growth in the lipid-based vehicle.

Alfaxalone-HPCDb is a new injectable anesthetic for induction and maintenance of anesthesia in dogs and cats. It contains the active agent alfaxalone (3-α-hydroxy-5α-pregnane-11,20-dione), a synthetic neuroactive steroid that interacts with γ-aminobutyric acid receptors within the CNS. Similar to the action of propofol, this interaction with the receptors yields a state of anesthesia and provides good muscle relaxation. Alfaxalone was first introduced into veterinary medicine in 1971 in a formulationc composed of alfaxalone and another synthetic neuroactive steroid, alfadolone. Because of their hydrophobicity, the 2 agents are combined in a castor oil derivative6; however, when injected IV, this polyethoxylated castor oil can induce histamine release, resulting in anaphylactic reactions in dogs and adverse signs in cats (eg, swollen ear pinnae and paws).7 Because of the severe reactions observed in dogs, use of alfaxalone-alfadone acetate is contraindicated in that species.

Alfaxalone has since been reformulated as a solution of 10 mg of alfaxalone/mL in the much safer excipient HPCD and has been registered for clinical use in dogs and cats in several countries.8 The new formulation is chemically stable and nonirritating if administered into perivascular tissue. Alfaxalone-HPCD supports growth of some microorganisms but does so less readily than propofol.9 It has several advantages over other induction agents, including a high acute tolerance, a wide margin of safety, rapid recovery of consciousness and appetite, and good muscle relaxation.a,d,e Furthermore, alfaxalone-HPCD does not appear to accumulate in dogs after repeated doses and therefore could be used for total IV anesthesia.a

Alfaxalone-HPCD has been used to induce anesthesia in dogs and cats; however, limited information exists on the suitability of alfaxalone-HPCD for CRIs in dogs. We hypothesized that alfaxalone-HPCD would induce less cardiopulmonary depression than propofol, when used as a CRI. The purpose of the study reported here was to compare the cardiorespiratory responses of healthy dogs to alfaxalone-HPCD and a propofol emulsionf when administered over 2 hours at equipotent infusion rates.

Materials and Methods

Animals—Six young adult crossbred laboratory dogs (2 sexually intact females and 4 sexually intact males; mean ± SD weight, 22.6 ± 2.1 kg [range, 19.1 to 26.0 kg]) were used. All dogs were cared for in accordance with Canadian Council for Animal Care guidelines. Dogs were housed indoors in individual runs, received water ad libitum, and were provided with commercial dog food twice daily. All dogs were healthy on the basis of results of physical examination, CBC, and serum biochemical analyses. Food was with-held from dogs the night before the study, but free access to water was provided.

Study design—A 2-treatment (alfaxalone-HPCD and propofol) crossover design with a 6-day washout period between treatments was used. Dogs were each evaluated at 2 time points and acted as their own control. Approval from the University of Saskatchewan Animal Care Protocol Review Committee was obtained before commencement.

Results of preliminary trials indicated that equipotent infusion rates for the 2 anesthetics after sedation of dogs with acepromazine and hydromorphone were 0.25 mg/kg/min for propofol and 0.07 mg/kg/min for alfaxalone-HPCD. Equipotency was defined as the point at which dogs in both treatment phases were maintained in a light surgical plane of anesthesia (ie, weak palpebral reflex, medial eye position, and no response to toe-pinch).

Instrumentation—On the day of the study, a 22-gauge, 2.5-cm over-the-needle catheterg was placed in a cephalic vein, and anesthesia was induced with propofol (6 mg/kg). After tracheal intubation was successfully completed by means of a suitably sized, cuffed endotracheal tube, general anesthesia was maintained with sevofluraneh in 100% oxygen. A 22-gauge, 2.5-cm over-the-needle catheter was percutaneously placed into one of the dorsal pedal arteries to allow anaerobic withdrawal of blood samples for analysis of blood gases and pH and for measurement of arterial blood pressure. Blood pressure was transmitted through low-compliance saline (0.9% NaCl) solution–filled tubing with a silicon-chip transducer and displayed on a physiologic monitor.i The transducer had been calibrated by means of a mercury manometer and, for the study, was zeroed to atmospheric pressure at the position of the right atrium in a laterally recumbent dog. The physiologic monitor also continuously displayed the lead II ECG via a conventional 3-lead configuration, and any arrhythmias were recorded. The monitor also provided the heart rate derived from the arterial pressure waveform.

One side of the midcervical region was clipped and aseptically prepared. A 6-F hemostasis introducerj was inserted into a jugular vein to allow the later passage of a pulmonary artery balloon catheter with thermistor. After instrumentation, the dogs were allowed to recover to sternal recumbency. An arterial blood sample was withdrawn to verify that the PaCO2 was approximately 40 mm Hg. This was completed to ensure that the residual effects of sevoflurane anesthesia would not interfere with the subsequent treatment phase of the study.

All blood samples for gas and pH analyses were stored on ice water and analyzed within 30 minutes via a blood gas analyzer,k which measured PaO2, PaCO2, pH, O2 saturation of hemoglobin (co-oximeter), and hemoglobin concentration. Other calculated variables were recorded (bicarbonate and base excess). All blood samples were corrected for core or rectal temperature.

Anesthesia trial—Once dogs had recovered from anesthesia for the purpose of instrumentation, the study began. All dogs were sedated with acepromazine maleatel (0.02 mg/kg) and hydromorphonem (0.05 mg/ kg), which were administered IV concurrently. When the dogs became sedated and recumbent, ECG leads and direct arterial blood pressure monitoring systems were attached. A 55-cm, 5-F, balloon-tipped, flow-directed thermodilution pulmonary arterial cathetern was floated into a position such that the distal tip of the catheter was in the pulmonary artery. Position was confirmed via detection of characteristic blood pressure waveforms on the physiologic monitor. This catheter allowed measurements of MPAP, RAP, PAWP, core body temperature, and cardiac output. Cardiac output was determined by thermodilution at end-expiration in triplicate by use of 5 mL of iced 5% wt/vol dextrose solution. The change in temperature measured by use of the thermistor after injection of dextrose solution was analyzed with a cardiac output computero programmed to adjust for the volume of the injection and gauge of the catheter. The 3 values were averaged, and the mean value was recorded and used in subsequent analyses.

The proximal injection port at the position of the right atrium was also used for anaerobic withdrawal of mixed venous blood samples for gas and pH analyses. This position was used for sample withdrawal to avoid the so-called arterialization of samples that is possible when blood samples are withdrawn from the pulmonary artery. Crystalloid fluidp was administered IV at a rate of 10 mL/kg/h throughout the procedure. Body temperature of each dog was maintained with a circulating warm water bed.q

Thirty minutes after sedatives were administered and after acquisition of baseline hemodynamic measurements and withdrawal of blood samples, anesthesia was induced with propofol (4 mg/kg, IV) or alfaxalone-HPCD (2 mg/kg, IV), which were each administered over 60 seconds. Tracheal intubation was performed, and anesthesia was maintained (propofol, 0.25 mg/ kg/min; alfaxalone-HPCD, 0.07 mg/kg/min) for 120 minutes. After intubation, dogs were connected to an anesthetic machine with a circle breathing system and allowed to spontaneously breathe 100% O2. The quality of induction was scored from 1 to 4 by the same observer (BA), according to the following scoring system: 1 = poor (inability to intubate, obvious excitement, or both), 2 = fair (intubation difficult because of reflexes present, mild excitement, or both), 3 = good (tracheal intubation easy but minimal reflex response or mildly persistent jaw tone), and 4 = smooth. Any episode of apnea was recorded and defined by lack of respiratory movement for > 30 seconds. Inspired and expired CO2, O2, and respiratory rate were measured with a calibrated sidestream gas analyzer.r Measurements of SAP, DAP, MAP, MPAP, PAWP, RAP, heart rate, respiratory rate, and cardiac output were made prior to induction once the dog was stabilized with premedication drugs, and these measurements were considered as baseline values. Stabilization of variables was assumed when the variables did not differ more than 10% for 3 consecutive measurements taken 3 minutes apart. Further measurements were taken 5, 15, 30, 60, 90, and 120 minutes after induction of anesthesia. Systemic arterial and mixed venous blood samples were also drawn simultaneously for blood gas and pH analyses. Systolic arterial blood pressure, MAP, DAP, heart rate, respiratory rate, and arterial blood gases and pH were also measured 140 minutes after induction (20 minutes after termination of anesthetic administration). Ten-milliliter blood samples were collected into tubes containing EDTA before induction of anesthesia, immediately after induction, and 20, 40, 60, 80, 100, and 120 minutes after induction. Another blood sample was collected 20 minutes after termination of the anesthetic.

Depth of anesthesia was assessed via evaluation of palpebral reflex, eye position, and response to toe-pinch (1-second compression of a toe with a hemostat closed to the first ratchet). After the anesthetic infusion was completed, administration of O2 was discontinued and the endotracheal tube removed from the trachea when the swallowing reflex returned. Pulse rate was determined every 10 minutes from the arterial waveform until removal of the arterial catheter and through digital palpation thereafter. Respiratory rate and mucus membrane color were also evaluated every 10 minutes until each dog was fully awake. Intervals to extubation, head lift, sternal recumbency, and standing were observed and recorded, and the quality of recovery was assessed by the same observer (BA). A recovery score ranging from 1 to 4 was assigned to each patient during recovery as follows: 1 = poor (marked excitement or struggling and need for restraint), 2 = fair (minor excitement, restlessness but no need for restraint, or both), 3 = good (relatively smooth recovery and minimal vocalization), and 4 = excellent (smooth recovery).

Cardiac index; stroke volume and stroke volume index; SVR; PVR; O2 delivery, consumption, and extraction ratio; alveolar dead space; and venous shunt fraction were calculated by use of standard formulae.10

Data analysis—All statistical analyses were performed by use of computer software.s Examination of descriptive statistics suggested that data for each measured variable were normally distributed. A 2-way ANOVA for repeated measurements followed by Bonferroni adjustments was used to compare cardiopulmonary data between anesthetics. Within a drug treatment, cardiopulmonary effects over time were compared by use of a repeated-measures 1-way ANOVA with Bonferroni adjustments. Paired t tests were used to compare recovery times. All data are presented as mean ± SD. Values of P < 0.05 were considered significant for all analyses.

Results

Equivalent planes of anesthesia were achieved in dogs during both treatments (propofol or alfaxalone-HPCD). For both anesthetics at the infusion rates administered, dogs had a slight palpebral reflex, eye position was medial, and withdrawal reflex evoked through toe pinch was completely suppressed. Induction of anesthesia was smooth (free of excitement and with adequate loss of reflexes) in all dogs. Apnea during induction of anesthesia was detected in 1 dog for each treatment and lasted 210 seconds with alfaxalone-HPCD and 82 seconds with propofol. All dogs recovered their appetite on the same day.

Systemic and pulmonary artery pressures, heart rate, cardiac output and cardiac index, stroke volume and stroke volume index, SVR, RAP, and PAWP did not vary significantly between anesthetics at any time (Table 1). The only significant change from baseline (sedated but not yet anesthetized) hemodynamic values occurred when dogs were treated with propofol— stroke volume index significantly increased 90 and 120 minutes after induction of anesthesia.

Table 1—

Mean ± SD values for systemic cardiovascular variables in 6 healthy crossbred dogs measured after sedation but immediately before (baseline) and at various intervals after initiation of CRIs of alfaxalone-HPCD or propofol for 120 minutes in a crossover study design.

VariableBaselineTime after induction of anesthesia (min)
515306090120140
Heart rate (beats/min)
 Alfaxalone-HPCD87 ± 21100 ± 2181 ± 1678 ± 577 ± 1080 ± 1575 ± 1197 ± 32
 Propofol99 ± 3477 ± 773 ± 1068 ± 467 ± 866 ± 364 ± 1*72 ± 32
SAP (mm Hg)
 Alfaxalone-HPCD117 ± 9102 ± 12100 ± 11102 ± 12106 ± 10107 ± 3107 ± 13126 ± 7
 Propofol119 ± 7107 ± 9103 ± 17100 ± 11102 ± 11107 ± 9112 ± 12125 ± 13
MAP (mm Hg)
 Alfaxalone-HPCD76 ± 767 ± 663 ± 665 ± 867 ± 1067 ± 1068 ± 1086 ± 6
 Propofol76 ± 867 ± 863 ± 1260 ± 8*62 ± 667 ± 568 ± 875 ± 8
DAP (mm Hg)
 Alfaxalone-HPCD59 ± 954 ± 749 ± 449 ± 653 ± 853 ± 954 ± 967 ± 9
 Propofol61 ± 854 ± 651 ± 948 ± 850 ± 553 ± 455 ± 650 ± 7
RAP (mm Hg)
 Alfaxalone-HPCD1.2 ± 1.21.5 ± 1.42 ± 2.32.2 ± 2.92.3 ± 2.72.0 ± 1.71.0 ± 1.3ND
 Propofol2.0 ± 2.12.7 ± 1.62.2 ± 1.72.2 ± 0.82.5 ± 1.41.7 ± 1.41.8 ± 1.5ND
Cardiac index (mL/min/kg)
 Alfaxalone-HPCD155 ± 45164 ± 47151 ± 59152 ± 43144 ± 45146 ± 61159 ± 47ND
 Propofol126 ± 32109 ± 14113 ± 11113 ± 17111 ± 20121 ± 11120 ± 18ND
Stroke volume index (mL/kg)
 Alfaxalone-HPCD1.7 ± 0.341.6 ± 0.371.8 ± 0.461.9 ± 0.551.8 ± 0.501.8 ± 0.592.0 ± 0.45ND
 Propofol1.3 ± 0.271.4 ± 0.171.6 ± 0.211.7 ± 0.221.7 ± 0.321.8 ± 0.21*1.9 ± 0.30*ND
SVR (dynes/s/cm5)
 Alfaxalone-HPCD1,826 ± 4101,580 ± 5911,621 ± 5981,580 ± 4541,764 ± 6161,808 ± 7461,519 ± 308ND
 Propofol2,165 ± 5162,140 ± 5271,900 ± 3501,970 ± 4071,978 ± 5431,882 ± 2941,888 ± 172ND
PVR (dynes/s/cm5)
 Alfaxalone-HPCD98 ± 48146 ± 77114 ± 65128 ± 85108 ± 95129 ± 118111 ± 59ND
 Propofol153 ± 86191 ± 79136 ± 40150 ± 20178 ± 42167 ± 41185 ± 57ND

Significantly (P < 0.05) different from baseline value.

ND = Not determined.

Respiratory rate, arterial pH, PaO2, PaCO2, bicarbonate concentration, alveolar dead space, shunt fraction, and O2 delivery and consumption between groups did not change significantly at any time (Table 2). However, significant changes from baseline values of other variables were detected. The arterial pH decreased significantly after both anesthetics, from 5 minutes after induction to the end of anesthesia. When dogs were treated with propofol, PaCO2 was significantly higher than the baseline value at 5 minutes after anesthetic induction through to termination of the CRI, whereas when dogs were treated with alfaxalone-HPCD, PaCO2 was significantly higher than the baseline value only at 5 minutes after anesthetic induction. For both anesthetics, shunt fraction was significantly higher than baseline values only at 5 minutes after induction; afterward, it returned to baseline values.

Table 2—

Mean ± SD values for respiratory variables in 6 healthy crossbred dogs measured after sedation but immediately before (baseline) and at various intervals after initiation of CRIs of alfaxalone-HPCD or propofol for 120 minutes in a crossover study design.

VariableBaselineTime after induction of anesthesia (min)
515306090120140
Respiratory rate (breaths/min)
 Alfaxalone-HPCD24 ± 197 ± 109 ± 128 ± 87 ± 47 ± 47 ± 418 ± 9
 Propofol21 ± 87 ± 37 ± 46 ± 4*6 ± 3*8 ± 48 ± 323 ± 17
Arterial pH
 Alfaxalone-HPCD7.35 ± 0.017.23 ± 0.03*7.25 ± 0.03*7.25 ± 0.03*7.25 ± 0.05*7.26 ± 0.04*7.27 ± 0.04*7.38 ± 0.02*
 Propofol7.36 ± 0.027.27 ± 0.04*7.26 ± 0.03*7.24 ± 0.02*7.24 ± 0.04*7.25 ± 0.03*7.25 ± 0.03*7.34 ± 0.05*
Paco2(mm Hg)
 Alfaxalone-HPCD45.7 ± 6.164.4 ± 11.8*61.1 ± 12.360.6 ± 11.662.5 ± 15.260.8 ± 16.459.4 ± 12.342.8 ± 6.6
 Propofol44.4 ± 5.356.9 ± 6.8*57.3 ± 4.9*62.1 ± 9.9*64.1 ± 9.6*61.4 ± 10.0*61.5 ± 9.0*47.7 ± 7.0*
Pao2 (mm Hg)
 Alfaxalone-HPCD89 ± 9283 ± 135504 ± 66523 ± 67553 ± 59574 ± 65566 ± 55110 ± 13
 Propofol99 ± 23321 ± 136504 ± 59516 ± 73549 ± 55482 ± 173490 ± 171347 ± 195
Bicarbonate (mmol/L)
 Alfaxalone-HPCD24.4 ± 3.925.9 ± 3.825.7 ± 3.525.8 ± 3.716.3 ± 3.826.3 ± 4.426.7 ± 3.924.7 ± 3.6
 Propofol24.2 ± 2.625.1 ± 2.225.2 ± 2.325.7 ± 3.726.9 ± 3.726.4 ± 3.626.4 ± 2.725.2 ± 2.7
Shunt fraction (%)
 Alfaxalone-HPCD0.3 ± 0.412.5 ± 8.0*3.8 ± 4.04.1 ± 4.82.7 ± 3.41.5 ± 2.02.8 ± 3.2ND
 Propofol0.1 ± 0.215.9 ± 4.1*6.2 ± 5.16.1 ± 6.33.8 ± 2.74.9 ± 2.23.9 ± 2.7ND
Alveolar deadspace (%)
 Alfaxalone-HPCDND15.5 ± 11.313.2 ± 9.510.7 ± 7.011.4 ± 10.710.8 ± 9.611.5 ± 5.5ND
 PropofolND12.5 ± 4.110.8 ± 6.011.6 ± 10.610.6 ± 11.310.2 ± 10.19.4 ± 7.4ND
Oxygen delivery (mL/min)
 Alfaxalone-HPCD585 ± 205642 ± 183599 ± 238577 ± 176554 ± 171579 ± 276637 ± 201ND
 Propofol494 ± 115434 ± 60441 ± 78469 ± 105448 ± 82490 ± 67496 ± 69ND
Oxygen consumption (mL/min)
 Alfaxalone-HPCD152.6 ± 42134.1 ± 35116.1 ± 41107.8 ± 28104.9 ± 35113.5 ± 48117.2 ± 38ND
 Propofol92.4 ± 2887.4 ± 3382.4 ± 1579.0 ± 2879.8 ± 2483.9 ± 2284.7 ± 27ND

See Table 1 for key.

After cessation of anesthesia, intervals to extubation, head lift, sternal recumbency, and standing were not significantly different between the 2 anesthetics (Table 3). Recovery scores also did not differ significantly between anesthetics. The quality of recovery from propofol CRI was assessed as excellent (n = 5 dogs) and fair (1), whereas recovery from alfaxalone-HPCD CRI was assessed as excellent (4), good (1), and fair (1). The same dog was rated as having fair recovery for both anesthetics.

Table 3—

Mean ± SD values (in minutes) for duration of anesthesia in 6 premedicated, healthy crossbred dogs after 120 minutes of CRIs of alfaxalone-HPCD or propofol in a crossover study design.

VariableAlfaxalone-HPCDPropofol
Extubation14 ± 7 (7 – 25)18 ± 7 (10 – 28)
Head lift35 ± 5 (27 – 44)9 ± 17 (20 – 68)
Sternal recumbency43 ± 9 (33 – 56)52 ± 22 (29 – 84)
Standing52 ± 10 (36 – 57)62 ± 18 (46 – 94)

Values in parentheses are ranges.

Discussion

Alfaxalone-HPCD and propofol produced satisfactory anesthetic induction and maintenance in the healthy, young dogs used in the present study. The tracheas of all dogs in the study were easily intubated after either agent was administered. Both drugs, however, induced significant respiratory depression after sedation with acepromazine and hydromorphone.

In preliminary trials, we found that alfaxalone-HPCD infused at 0.1 mg/kg/min resulted in hypotension (MAP < 60 mm Hg) and hypoventilation (respiratory rate < 3 breaths/min and PaCO2 > 90 mm Hg). In the study reported here, alfaxalone-HPCD administered at 0.07 mg/kg/min did not cause hypotension and hypoventilation yet still produced a suitable light plane of anesthesia. An equipotent infusion rate of propofol (0.25 mg/kg/min) was determined. Because the plane of anesthesia appeared to be equivalent with both anesthetics, effective comparison of individual anesthetic effects on cardiopulmonary systems was deemed possible. Muscle relaxation was considered to be excellent for endotracheal intubation, and although muscle relaxation was not scored during maintenance, it appeared satisfactory with both anesthetics. We believe the plane of anesthesia produced by both anesthetics was sufficient to allow noninvasive diagnostic procedures or minor surgery; however, additional research is required to adjust the infusion rates to clinical situations.

The quality of recovery from anesthesia was similar with both anesthetics and was considered excellent overall. Excitatory effects following the administration of alfaxalone-HPCD to cats and dogs have been reported,8,t although similar effects were not observed in the present study. Some researchers reported that unpremedicated dogs anesthetized with alfaxalone-HPCD appeared agitated when handled for the purpose of blood collection during recovery from anesthesia.8 In the present study, dogs were kept in a quiet environment during the recovery period but were handled to obtain measurements. One dog recovered with minor restlessness and whining but exhibited the same behavior after propofol anesthesia. The majority of dogs, however, recovered smoothly from anesthesia, and it is possible that the quality of recovery in our study was positively affected by the administration of preanesthesthetic medications. A similar positive influence of premedication was also detected in cats anesthetized with alfaxalone-HPCD.u In that study,u the quality of recovery after administration of acepromazine (1.1 mg/ kg) or medetomidine (100 μg/kg) was superior to that of recovery from alfaxalone after premedication with saline solution.u

Intervals to extubation, head lift, sternal recumbency, and standing were not significantly different between the 2 anesthetics, but when dogs were anesthetized with alfaxalone-HPCD, they appeared to have a faster recovery than when they received propofol, although the intervals to recovery were not significantly different. Preanesthetic medication and duration of CRI appear to influence the duration of recovery from anesthesia. In another study,11 anesthetic recovery times were evaluated in unpremedicated dogs after continuous infusion of propofol (0.44 mg/kg/min) for 3 hours. Mean interval to extubation was 13.5 minutes versus 18 minutes in our study, interval to sternal recumbency was 33.8 minutes versus 52 minutes, and interval to standing was 32 versus 62 minutes. Dogs that were premedicated with acepromazine (0.025 mg/kg, IM) and atropine (0.02 mg/kg, IM) and anesthetized with propofol CRI (0.4 mg/kg/min) for 60 minutes had shorter recovery times than those of dogs in the present study. In this other study,12 dogs were, on average, extubated 6 minutes after termination of the propofol CRI and moved to sternal recumbency and standing 15 and 28 minutes after termination of the propofol CRI, respectively. In the present study, IV administration of the combination of acepromazine and hydromorphone likely lengthened the recovery period.

The most clinically relevant effect of both anesthetics after sedation with acepromazine and hydromorphone was respiratory depression, which was reflected in a significant decrease in respiratory rate and retention of CO2. Associated with increased CO2 was a significant decrease in arterial pH, which indicated respiratory acidosis. Tidal volume was not measured, so it remains unclear how much of the increase in CO2 was also attributable to changes in tidal volume. Respiratory depression is a well-reported complication of anesthetic induction or maintenance with propofol in cats and dogs4 and is believed to be caused by direct depression of the inspiratory drive and the ventilatory response to increased PaCO2.13 The degree of respiratory depression depends on a variety of factors, including choice of premedication and dose and speed of administration of propofol.14,15 To help prevent the possibility of apnea after induction of anesthesia, both anesthetics were administered as a bolus given over 60 seconds; however, apnea still developed in 1 dog with both drugs. The speed of administration of propofol can greatly affect the degree of respiratory depression. One study16 revealed that apnea occurred in 5 of 6 dogs when the rate of propofol administration was rapid (30 seconds), in 4 of 6 dogs when propofol was administered over 45 seconds, and in 1 of 6 dogs with a slower administration of 60 seconds. Those results are similar to the results of the present study.

Respiratory depression is also a dose-dependent phenomenon of anesthesia. For example, in unpremedicated dogs treated with alfaxalone-HPCD at the clinically recommended induction dose of 2 mg/kg, apnea (identified by the difference in seconds between the onset of anesthesia and the first inspiratory effort > 25% of baseline tidal volume) was observed in 1 of 8 dogs. However, when propofol was administered at 6 mg/kg, 6 of 8 dogs were identified as apneic, although the mean duration of apnea was only 36 seconds.c Although there is increasing evidence of respiratory compromise after induction of anesthesia with propofol in dogs, alfaxalone-HPCD and propofol caused similar respiratory depressant effects during the 2-hour anesthetic maintenance period used in this study.

Premedication agents may decrease the dose required to induce anesthesia3,17,18 and reduce but not eliminate the incidence of adverse cardiopulmonary effects.14 In our study, however, the actions of an opioid μ-receptor agonist (ie, hydromorphone) may have compounded the respiratory depressant effects of both anesthetics. Depression of response of the respiratory center to hypercapnia is a recognized adverse effect of opioids. This effect is compounded by the coadministration of sedatives, anesthetics, or both.19 Acepromazine is a phenothiazine derivate that is commonly used in combination with an opioid to produce neuroleptanalgesia in dogs. Administration of acepromazine to conscious or anesthetized dogs has little effect on pulmonary function. In conscious dogs receiving IV administration of acepromazine, respiratory rate decreases, but arterial PaCO2 and PaO2 do not change.20 In the present study, respiratory depression only became apparent after induction of anesthesia. Hence, ventilation during anesthesia with propofol or alfaxalone-HPCD in combination with an opioid μ-receptor agonist may require ventilatory support to prevent hypercapnia.

It must also be recognized that we examined dogs maintained at a light plane of anesthesia without any surgical stimulation. A certain level of surgical stimulation may have improved ventilation but may have also required a different anesthetic infusion rate to provide a deeper level of anesthesia. Additional studies are required to determine infusion rates applicable to clinical situations.

A decrease in MAP after induction of anesthesia was detected with both drugs. Propofol produced a significant decrease from baseline MAP at 30 minutes after induction. When dogs received alfaxalone-HPCD, baseline MAP tended to be restored earlier than in dogs that received propofol. Arterial blood pressure also appeared to increase more rapidly after termination of anesthetic when dogs received alfaxalone-HPCD, and this increase may have reflected the apparently more rapid recovery from anesthesia with alfaxalone-HPCD.

Cardiac index appeared to be better preserved in dogs when they received alfaxalone-HPCD in the present study and even increased slightly immediately after induction of anesthesia. However, mean initial baseline values differed between treatment groups, making it difficult to assess the true relevance of the apparently higher cardiac index in the alfaxalone-HPCD group. Although there were no differences between groups, heart rate appeared to be better preserved with alfaxalone-HPCD. The increase in heart rate after induction of anesthesia with alfaxalone-HPCD may have helped maintain the cardiac index. In contrast, heart rate in dogs that received propofol decreased over time, becoming significantly different from baseline at 120 minutes after induction. When dogs were anesthetized with propofol, heart rate decreased during the anesthetic period, despite the decrease in arterial blood pressure. This can be best explained by reported effects of propofol on the baroreceptor reflex, which indicate propofol resets the reflex to produce slower heart rates, despite a decrease in arterial pressure.21

Systemic vascular resistance appeared to be lower when dogs received alfaxalone-HPCD than when they received propofol, and this finding indicated more vasodilatation in alfaxalone-HPCD–treated dogs. The hemodynamic effects of various rates of infusion of althesin (9 mg of alfaxalone/mL and 3 mg of alfadolone/mL) to supplement nitrous oxide anesthesia were investigated in spontaneously breathing and ventilated humans.22 Althesin infusion was associated with a dose-dependent decrease of SAP as a result of decreased SVR. Cardiac output was maintained at lower rates of infusion but increased at higher rates because of an accompanying increase in heart rate. Thus, in humans, the main effect of alfaxalone on the cardiovascular system was decreased SVR. These results may not be comparable with those of the present study because the alfaxalone used in the other study was formulated with alfadolone and a noninonic polyoxyethylated emulsifying agent. In humans and dogs, the emulsifying agent can elicit clinically significant adverse effects on cardiac output and MAP via release of histamine.23 However, in the present study, the decrease in arterial blood pressure in dogs when treated with alfaxalone appeared to be the result of decreased SVR because cardiac index was well preserved. Given the lack of significance in the changes in SVR, it is difficult to ascertain the actual mechanisms of the decrease in arterial blood pressure. The aforementioned study22 of hemodynamic effects of althesin in humans also revealed high cardiovascular stability associated with infusions of althesin, which is consistent with the reported high tolerance for alfaxalone-HPCD in dogs.d In that studyd in dogs, cardiovascular values after induction of anesthesia with alfaxalone at 10 times the recommended dose returned to baseline values within 30 minutes. The decrease in SAP was accompanied by an increase in heart rate and a corresponding increase in cardiac output.

In the present study, when dogs received propofol, SVR decreased in comparison with measurements taken immediately before induction. These findings are consistent with results of other studies in humans24 and dogs.11 Propofol decreases SVR via direct venodilatory effects, causing a reduction in preload.4,5 Findings in the present study, however, might be difficult to interpret, owing to the use of preanesthetic drugs. Acepromazine produces dose-dependent effects on the cardiovascular system in conscious and anesthetized dogs. In conscious dogs, values for stroke volume, cardiac output, and MAP decrease by 20% to 25% in 15 minutes following IV administration of a supraclinical dose of acepromazine (0.1 mg/kg)25 and MAP remains decreased for at least 120 minutes.20,26 With phenothiazines such as acepromazine, decrease in blood pressure is caused by blocking the α-1 adrenergic receptors, which leads to vasodilation.27 In the present study, reduction in plasma concentrations of acepromazine over time might have positively affected cardiovascular parameters, as was evident in the nonsignificant increase in SAP, with pressure starting to rise 30 minutes after induction of anesthesia with either anesthetic.

After sedatives were administered and dogs received propofol, stroke index was lower than that associated with alfaxalone-HPCD at the same time point, but as the anesthetic period progressed, the stroke index increased. Because cardiac index was also lower when dogs were treated with propofol versus alfaxalone-HPCD, this might reflect a greater degree of myocardial contractility depression associated with administration of propofol versus alfaxalone-HPCD during the early part of the anesthetic period. On the other hand, when dogs were anesthetized with propofol, stroke volume index significantly increased relative to preinduction values at 90 and 120 minutes after induction, which contradicts the depressant effects of propofol on myocontractility. Whether propofol depresses myocardial contractility is controversial. Results of some in vitro studies28,29 suggest that propofol had direct myocardial depressant effects only at supraclinical concentrations, whereas results of in vivo studies30,31 indicate that myocardial depressant effects occur at clinically relevant concentrations.

When dogs received alfaxalone-HPCD, values of cardiac and stroke volume indices were constant during the anesthetic period, which could be interpreted as indicating that alfaxalone-HPCD had no or little negative effects on myocardial contractility. Effects of alfaxalone-alfadone acetate on myocardial contractility are conflicting. In humans, only minor negative inotropic effects are associated with treatment with 1 formulation of alfaxalone-alfadone.32 In cats, significant decreases in cardiac output and stroke volume are evident after induction with supraclinical doses of a different formulation of alfaxalone-alfadone (12 mg/kg), whereas SVR does not change.33 When dogs receive a combination of althesin, fentanyl, and pancuronium for 24 hours, only minimal hemodynamic changes occur.34 In our study, cardiac parameters (cardiac index, heart rate, SVR, and arterial blood pressure) were remarkably stable (ie, did not change significantly). Caution needs to be taken when making direct comparisons of the cardiovascular findings of alfaxalone-HPCD in this study with those for saffan and althesin in other studies because the drug formulations are very different.

The constant rate of infusion of alfaxalone-HPCD CRI used in the study reported here was satisfactory and was suitable for maintenance of anesthesia in healthy, sedated dogs. Cardiorespiratory variables were similar after induction of anesthesia with alfaxalone-HPCD and propofol. Respiratory depression can be associated with either agent, and controlled ventilation may be necessary during CRI after the use of potent opioid μ-receptor antagonists.

ABBREVIATIONS

CRI

Continuous rate infusion

DAP

Diastolic arterial blood pressure

HPCD

2-hydroxypropyl-β-cyclodextrin

MAP

Mean arterial blood pressure

MPAP

Mean pulmonary arterial pressure

PAWP

Pulmonary artery wedge pressure

PVR

Pulmonary vascular resistance

RAP

Right atrial pressure

SAP

Systolic arterial blood pressure

SVR

Systemic vascular resistance

a.

Pasloske K, Gazzard B, Perkins N, et al. A multicenter clinical trial evaluating the efficacy and safety of alfaxan-CD RTU administered to dogs for induction and maintenance of anaesthesia (abstr), in Proceedings. 48th Annu Br Small Anim Vet Cong 2005;556.

b.

Alfaxan-CD RTU, Jurox Pty Ltd, Rutherford, NSW, Australia.

c.

Saffan, Glaxo Laboratories Ltd, Harefield, England.

d.

Muir WW, Lerche P, Wiese AJ, et al. Anesthetic and cardiorespiratory effects of the steroid anesthetic alfaxan-CD RTU in dogs (abstr), in Proceedings. 22nd Annu Forum Am Coll Vet Intern Med 2004;832.

e.

Schnell M, Weiss C, Heit M, et al. Margin of safety of the anesthetic alfaxan-CD RTU in dogs at 0, 1, 3 and 5× the intravenous dose of 2 mg/kg (abstr), in Proceedings. 22nd Annu Forum Am Coll Vet Intern Med 2004;849.

f.

Rapinovet, Schering-Plough Animal Health, Kirkland, QC, Canada.

g.

BD Insyte-W (22-gauge, 2.5 cm), Becton Dickinson Infusion Therapy Systems Inc, Sandy, Utah.

h.

Abbott Laboratories, Saint Laurent, QC, Canada.

i.

PB 240, Puritan-Bennett Corp, Hazelwood, Mo.

j.

Fast-Cath, Daig, St Jude Medical Co, Mississauga, ON, Canada.

k.

Rapidlab 865, Bayer, Toronto, ON, Canada.

l.

Atravet, Ayerst Laboratories, Montreal, QC, Canada.

m.

Sabex, Boucherville, QC, Canada.

n.

Pediatric oximetry thermodilution catheter, Edwards Lifesciences, Mississauga, ON, Canada.

o.

Hemodynamic profile computer, model SP1445, Gould Inc, Oxnard, Calif.

p.

Normosol R, Hospira, Montreal, QC, Canada.

q.

Arizant Healthcare Inc, Eden Prairie, Minn.

r.

POET IQ anesthesia gas monitor, Critical Care Systems Inc, Waukesha, Wis.

s.

GraphPad Prism 2003, version 4.0 for Windows, GraphPadSoftware Inc, San Diego, Calif.

t.

Pearson M, Best P, Patten B. New therapeutic horizons: choosing a new drug for induction of anaesthesia: propofol or alfaxalone (abstr), in Proceedings. 13th Biennial Symp Am Acad Vet Pharmacol Ther 2003;66–69.

u.

Heit M, Schnell M, Whittem T, et al. Cardiovascular and respiratory safety of alfaxan-CD RTU in cats premedicated with acepromazine, medetomidine, midazolam or butorphanol (abstr), in Proceedings. 22nd Annu Forum Am Coll Vet Intern Med 2004;831.

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Contributor Notes

Supported by Jurox Propriety Limited.

Presented in part at the Association of Veterinary Anaesthetists/European College of Veterinary Anaesthesia and Analgesia Autumn Meeting, Leipzig, Germany, September 2007.

The authors thank Dr. Baljit Singh and Dr. Tony Carr for technical support.

Address correspondence to Dr. Ambros.