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ANESTHETIC PHARMACOLOGY

Anesthetic Properties of a Propofol Microemulsion in Dogs

Timothy E. Morey, MD^*, Jerome H. Modell, MD, DSc (Hon)^*, Dushyant Shekhawat, BS, Dinesh O. Shah, PhD^*, Brian Klatt, BS, George P. Thomas, MSc, PhD, Frank A. Kero, BS^*||, Matthew M. Booth, PhD^*, and Donn M. Dennis, MD, FAHA^*¶#

From the Departments of *Anesthesiology, Chemical Engineering, ||Chemistry, ¶Pharmacology and Experimental Therapeutics, and #Psychiatry, University of Florida, Gainesville, Florida; NanoMedex, Inc., Alachua, Florida; and Calvert Laboratories, Inc., Olyphant, Pennsylvania.

Address correspondence and reprint requests to Donn M. Dennis, MD, FAHA, Department of Anesthesiology, University of Florida, PO Box 100254, Gainesville, FL 32610-0254. Address e-mail to DDennis{at}ufl.edu.

	Abstract

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Microemulsions of propofol with nanometer droplet diameter are alternatives to soybean macroemulsions for inducing anesthesia, and may have important advantages. We used a propofol (10 mg/mL) microemulsion (particle diameter 24.5 ± 0.5 nm) and a commercial macroemulsion to induce anesthesia in dogs (n = 10) using a randomized, crossover design separated by a 7-day rest interval. The end points were loss of leg withdrawal after a toe pinch and changes in vital signs. Venous blood samples were acquired at multiple times to measure plasma propofol concentrations and indices of erythrocytes, leukocytes, and coagulation. All dogs were rendered insensitive to pain followed by successful recovery without noticeable complications. Comparing indices between microemulsion and macroemulsion formulations, no differences were noted with respect to dose (10.3 ± 1.2 and 9.7 ± 1.6 mg/kg, respectively, P = 0.39), time to induction (1.0 ± 0.1 and 1.0 ± 0.2 min, P = 0.39), time to recovery (17.4 ± 4.6 and 18.2 ± 3.8 min, P = 0.70), heart rate (P = 0.62), arterial blood pressure (P = 0.81), respiratory rate (P = 0.60), hemogram variables, prothrombin time (P = 0.89), activated partial thromboplastin time (P = 0.76), fibrinogen concentration (P = 0.52), platelet concentration (P = 0.55), or plasma propofol concentrations (P = 0.20). Induction with a propofol microemulsion or macroemulsion did not significantly vary with respect to vital signs, the hemogram, clotting variables, and plasma propofol concentrations.

	Introduction

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Propofol is a popular IV drug for inducing anesthesia, and is conventionally formulated in a soybean oil macroemulsion. However, propofol can also be combined with biocompatible surfactants to form transparent, colorless, and thermodynamically stable, oil-in-water microemulsions of nanometer diameter without the need for excipient oils, such as soybean oil (1). In these microemulsions, propofol serves the physical role as the core of the particles, as this drug exists as an oil at room temperature and as the active drug to induce anesthesia. Microemulsion technology offers theoretical advantages over macroemulsions if the release of free propofol is delayed with this technology (2–4). Some of these potential advantages include less pain with injection, longer shelf life due to the thermodynamic stability of microemulsions, and a decreased propensity to support bacterial growth due to the absence of soybean oil as a nutrient.

We (1) have shown that these microemulsions can be used in vivo to induce anesthesia in rat. In that report, however, the limited blood volume (e.g., 50 mL) of the rat compared with that volume (e.g., 30 mL) necessary to repeatedly sample blood precluded determining possible interactions between the propofol particles and blood (the first biological tissue encountered with IV injection) and measurement of propofol concentrations in blood. Therefore, the present study was conducted in a larger animal model (i.e., dog) using a randomized, crossover design to determine possible alteration of erythrocytes, leukocyte, and platelet cell populations, and potential changes in coagulation variables caused by microemulsions and macroemulsions of propofol. In addition, the concentrations of propofol in blood and some clinical effects of anesthesia were measured.

	METHODS

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Propofol Formulations
Propofol (molecular weight 178.27) used in this study was a generous gift from the Albemarle Corporation (Baton Rouge, LA). Purified poloxamer 188, a nonionic coblock polymer consisting of polyethylene and polypropylene monomers, was acquired from the BASF Corporation (Florham Park, NJ). The sodium salts of C₈ fatty acid were supplied by Sigma Chemical (St. Louis, MO). The propofol microemulsion was prepared by combining propofol (10 mg/mL) with purified poloxamer 188 (50 mg/mL), and a fatty acid salt (2.1 mg/mL) in a normal saline (0.90 mg/mL NaCl) bulk media. Water was ultrapurified using a water purification system (Nanopure, Barnstead/Thermolyne, Dubuque, IA) to provide a minimal electrical resistance of 18.2 M. After agitation with a magnetic stirrer, these components combined to form microemulsions. We then adjusted the pH to 7.40 using either HCl or NaOH as necessary. The microemulsion was kept under a nitrogen head to delay oxidation of propofol as occurs with commercial formulations of propofol. Before administration, the propofol microemulsion was filtered through a 0.45-µm sterile filter, but the macroemulsion (Diprivan®, AstraZeneca Pharmaceuticals, Wilmington, DE) was not filtered, as it was assumed to be sterile as packaged by the manufacturer. Synthesis of microemulsions resulted in clear, colorless formulations of propofol. The mean diameter of the particles was 24.5 ± 0.5 nm as measured using a submicron particle size analyzer (90Plus, Brookhaven Instruments Corporation, Holtsville, NY) as described previously with other physical variables (5).

Preparation of Animals
The Institutional Animal Care and Use Committee of Calvert Laboratories (Olyphant, PA) approved the study protocol before investigation. Treatment of animals was in accordance with the conditions specified in the Guide for the Care and Use of Laboratory Animals (6). Ten purpose-bred and experimentally naive beagles (Marshall Bioresources, North Rose, NY) aged 7–8 mo and weighing 7.0–8.9 kg were identified by ear tattoo. All animals had access to certified canine diet (Teklad, Harlan, Indianapolis, IN) up to 400 g/day. Tap water was available ad libitum to each animal via an automatic watering device. Study animals were acclimated to their housing for a minimum of 5 days before entering the experimental protocol. After being fasted for 16–20 h, dogs were weighed and prepared for the experiment. Peripheral IV catheters were inserted in the right and left leg veins for IV administration of propofol formulations and the collection of whole blood samples, respectively.

Experimental Protocol
On the day of experimentations, dogs (n = 10) were randomized to receive either the propofol microemulsion (n = 5) or macroemulsion (n = 5) IV at a rate of 10 mg · kg^–1 · min^–1 via a microprocessor-controlled syringe pump to obviate potential confounding influences caused by variable administration rates from manual injection. During the infusion, the end point of anesthetic induction was the time necessary to cause the loss of reflexive withdrawal of the leg after a toe pinch every 15 s with a rubber-shod clamp. After loss of withdrawal of the leg, the infusion was discontinued. The total drug dose to cause induction was the mass of propofol required to cause loss of leg withdrawal. Thereafter, the subject was observed for recovery of the withdrawal to a toe pinch. Also, we measured the heart rate by electrocardiography (Pagewriter, Hewlett Packard Company, Palo Alto, CA), indirect peripheral blood pressure (9301V, Cardell Veterinary, MINRAD, Buffalo, NY), and respiratory rate for each subject at the following time points: predose, immediately after induction at 1 min, and every 5 min thereafter until dogs emerged from anesthesia. The electrocardiogram was examined for arrhythmias. In addition to these parameters, animals were observed for apnea or other signs of respiratory distress. The dogs were allowed to recover and were then returned to the kennel. After the first set of experiments, dogs recovered for at least 7 days before being crossed over to receive the formulation in the opposite limb of the study. Thus, dogs that received microemulsion (or macroemulsion) first were switched to then receive the opposite formulation. After anesthetic induction in the second limb of the investigation, dogs were allowed to recover for a least 7 days before the investigation was terminated.

Blood Sample Acquisition and Processing
During these experiments, blood samples were taken for two purposes. First, samples were secured 1 min before induction and at 1, 5, 10, 15, and 20 min after induction (or until the dog emerged from anesthesia) to measure the propofol concentration in plasma. The blood samples were acquired from a second IV cannula placed in a vein on a leg contralateral to that used for propofol injection. These blood samples (1–2 mL each) for assessment of propofol concentration were stored in nonadditive blood tubes and centrifuged at 3000 rpm. The resultant supernatant was aspirated and stored at –80°C until thawed for measurement of propofol concentrations using a liquid chromatography/mass spectrometry technique (API 4000, Applied Biosystems, Foster City, CA) using a method described by this laboratory (7,8). Second, blood samples (4 mL each) were drawn to determine the effects of the propofol formulations on the hemogram (Advia-120 Analyzer, Bayer Diagnostics, Tarrytown, NY), prothrombin time, activated partial thromboplastin time, and fibrinogen concentrations (MLA-900 Coagulation Timer, Becton Dickinson, Sparks, MD). These blood samples were collected before induction, immediately after induction when the concentration of propofol and excipients would be expected to peak in the plasma, and during recovery from anesthesia. In all cases, the maximum amount of blood collected during this investigation was limited to <1% of the body weight of each animal.

Statistical Analysis
The sample size calculation was centered around the dose to cause pain insensitivity so as to estimate a probable sample size. We considered a 25% reduction in dose of 10 mg/kg to be clinically relevant. Assuming a sd in all groups of 2.0 mg/kg for this variable, a two-sided type I error protection of 0.05, and a power of 0.80, approximately eight to nine dogs in each group were required to reveal a statistically significant difference among study groups using an analysis of variance design that allows sample size calculation for results with paired data (StatMate 2 for Windows, GraphPad Software, San Diego, CA).

Measurements are reported as mean ± sd. Statistical analysis was performed with SigmaStat 3.1 (Systat Software, Point Richmond, CA). Before parametric testing, the assumption of normality was validated using the Kolmogorov-Smirnov test with Lilliefors’ correction. For normally distributed data with two groups, the paired t-test was used with two-tailed protection. For normally distributed data with more than two groups, two-way (Factor 1, propofol formulation; Factor 2, time) repeated measures analysis of variance was used to test for overall statistical significance followed by Tukey post hoc pairwise testing, when appropriate, to analyze multiple comparisons between different formulations of propofol. Missing data points in the dog pharmacokinetic analysis were accounted for using Type IV sums of squares averaging to compensate for empty cells (9). For nonparametric data, Friedman repeated measures analysis of variance on ranks was used followed by Tukey testing when appropriate. P < 0.05 was considered to be statistically significant.

	RESULTS

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Anesthetic Induction Properties in the Dog
All dogs had anesthesia induced with subsequent recovery when injected with either formulation of propofol. The mean doses of microemulsion (n = 10) or macroemulsion (n = 10) to cause loss of leg withdrawal were 10.3 ± 1.2 and 9.7 ± 1.6 mg/kg, respectively, (P = 0.39) at 1.0 ± 0.1 and 1.0 ± 0.2 min, respectively. Although anesthetic induction caused marked changes in the heart rate (P < 0.001), arterial blood pressure (P < 0.001), and respiratory rate (P < 0.001) over time, these changes occurred in both groups of animals that received either the microemulsion or macroemulsion (Fig. 1). There were no significant differences with respect to group assignment in the heart rate (P = 0.62), arterial blood pressure (P = 0.81), or respiratory rate (P = 0.60) for dogs administered the microemulsion or macroemulsion. There was no electrocardiographic evidence of arrhythmias. Neither apnea nor respiratory distress was observed. The durations of loss of pain insensitivity caused by these doses of propofol were 17.4 ± 4.6 and 18.2 ± 3.8 min for the microemulsion and macroemulsion, respectively (P = 0.70).

View larger version (12K): [in this window] [in a new window]   Figure 1. Time-dependent effects of a propofol microemulsion or macroemulsion on heart rate (A), mean arterial blood pressure (B), and respiratory rate (C) in dogs. Data are expressed as mean ± sd. The dogs were subjected to a randomized, crossover design with dogs receiving both the microemulsion (closed squares) and macroemulsion (open circles) propofol formulations.

Effects on Blood
Data stratified by group assignment (microemulsion, macroemulsion) and time (preinduction, postinduction, recovery period) for parameters of the erythrocyte population are presented in Table 1. No differences were observed between formulations with respect to indices of erythrocyte populations as noted by the statistical values in Table 1. However, significant reductions in some indices were observed with respect to time. There were decrements in the red blood cell count (P < 0.001), hemoglobin concentration (P < 0.001), hematocrit (P < 0.001), absolute reticulocyte count (P = 0.002), and relative reticulocyte count (P = 0.030) over time for both groups. A decrease in the total concentration of white blood cells also occurred (P = 0.004). Neither the microemulsion nor macroemulsion of propofol affected platelet concentration, fibrinogen concentration, prothrombin time, or activated partial thromboplastin time (Table 1). In one dog that received the propofol macroemulsion, the platelet concentration was measured to be 8000 platelets/µL in the recovery period although the concentrations in the same dog determined at preinduction and postinduction were 240,000 and 233,000 platelets/µL, respectively. Light microscopic examination of the specimen showed no clumping of platelets. Therefore, this outlying data point was retained and accounts for the large standard deviation for this group (111,000 platelets/µL) compared with the standard deviations for other groups (39,000–50,000 platelets/µL).

Propofol Concentrations
The plasma concentrations of propofol were measured at various times after administration of propofol as noted in Table 2. After a bolus of propofol at 0 min, a large peak propofol concentration was measured followed by rapid decrements in the concentrations at 1, 5, and 10 min. At 15 and 20 min, increases in the propofol concentrations were observed for both the macroemulsion and microemulsions groups. Notwithstanding these time-related changes, no significant differences in plasma propofol concentrations were noted at 1, 5, 10, 15, or 20 min between the dogs receiving the microemulsion or macroemulsion formulations.

	DISCUSSION

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In this study, we investigated the dose of propofol, micro- or macroemulsions, administered to dogs to induce anesthesia, along with possible effects on blood, the first tissue encountered by the formulations. The measured variables of anesthesia, vital signs, indices of blood cell populations or thrombosis, and plasma concentrations of propofol did not significantly differ between the groups of animals given either the propofol microemulsion or macroemulsion.

Anesthetic Properties
In these studies, all animals experienced rapid induction of anesthesia, as assessed by loss of leg withdrawal to a noxious stimulus, with mean propofol doses of approximately 10 mg/kg for both the microemulsion and macroemulsion. This dose of propofol is larger than that reported in other studies investigating anesthetic induction in unpremedicated dogs using propofol formulated in a macroemulsion, although direct comparison is problematic because drug administration in the studies differed with respect to dose and type (bolus versus infusion). In those reports (10–15), the mean dose of propofol ranged from 3.8–6.9 mg/kg, with a mean ± se of the mean calculated from those 6 studies of 5.8 ± 0.5 mg/kg. Because the mean dose observed by the present investigators was larger for both the macroemulsion and microemulsion, this increase may have been due to differences in the study protocol, including a faster rate of propofol infusion (10 mg · kg^–1 · min^–1) and, possibly, the use of younger animals (i.e., 8-mo-old dogs vis-à-vis adult dogs) in the present report. Although we can not identify any studies detailing age-related effects on propofol dose in dogs, previous investigations conducted in rats and humans demonstrate that larger doses are required in younger, compared with older, subjects (16). For example, Schnider et al. (17) elegantly demonstrated that younger (25 yr) adult patients need more rapid infusion rates of propofol than do older (50 and 75 yr) subjects. Others have shown that the dose of propofol required for anesthetic induction in children is inversely related to age (18–20). Likewise, we observed a proportional increase in propofol macroemulsion dose (9.7/5.8 mg/kg or 1.67-fold greater) for younger dogs when compared with that for the mixed age dog populations calculated from the previously reported dog studies (10–15). In addition, the duration of anesthesia (from induction to recovery) was similar to that reported for dogs (i.e., we observed a mean duration of pain insensitivity to be 18.2 min whereas Watkins et al. (10) reported a value of 18 min). Therefore, the effects of propofol administered in either formulation are consistent with reported values in dogs. One limitation of this type of investigation is that any conclusions are limited to the dose studied. Extrapolation to other doses and sustained infusion of propofol require additional work and evidence. In addition, any extrapolation of these data to potential human use should be done cautiously because of possible species differences and the need for safety investigations (e.g., dose escalation studies).

Propofol Concentrations
The plasma propofol concentrations reported in the present study demonstrated a high peak concentration (25–32 µM) followed by rapid decline. Similar findings for the propofol macroemulsion were noted by Zoran et al. (21), who observed peak concentrations of 2.3 µg/mL (12.9 µM) and 3.29 µg/mL (18.5 µM) in mixed breed dogs and Greyhounds, respectively. Similarly, Cockshott et al. (22) noted peak concentrations of approximately 4 µg/mL (22.4 µM) in specimens obtained from dogs after injection of a 7 mg/kg propofol bolus. The lesser concentrations reported for previous investigations may have been due to the fact that the dogs enrolled in their previous studies received less propofol (5 mg/kg) over a longer time period than did dogs in our investigation. The observation of secondary peaks in plasma propofol concentrations at 15–20 min in our study was unexpected. We had previously hypothesized the existence of a single, large peak concentration of propofol immediately after bolus injection followed by steady decrements. Two possible reasons may account for these secondary peaks in propofol concentrations. First, this finding may be an artifact of the protocol. We stopped sampling blood for propofol concentrations when dogs emerged from anesthesia. Therefore, dogs with the least plasma propofol concentrations were excluded from the summary data at 15 and 20 min. This event would tend to cause the mean propofol concentrations to increase. Second, this phenomenon has been observed by others studying the pharmacokinetics of propofol in both dogs (21) and humans (23,24). For example, Zoran et al. (21) described a secondary peak concentration of propofol in five of eight mixed breed dogs and eight of ten Greyhounds. Similar to the present investigation, they noted that this peak occurred at the time that the dogs emerged sufficiently to achieve a sternal position (i.e., righting reflex). The exact cause of this secondary peak is unknown, but previously suggested reasons include changes in cardiac output associated with movement after anesthesia, influx of propofol from peripheral tissues with loss of venodilation caused by propofol, use of venous (vis-à-vis arterial) sampling, and changes in blood components due to splenic contraction in dogs associated with the phlebotomy necessary for acquiring multiple blood specimens (21).

In summary, we have shown that propofol formulated as a microemulsion can be used successfully to induce anesthesia in dogs in a manner that does not significantly vary from induction caused by a commercially available propofol macroemulsion.

	Footnotes

 
Accepted for publication June 26, 2006.

Supported by the National Institute of General Medical Sciences (Bethesda, MD) 1R43GM072142-01 and by NanoMedex (Alachua, FL).

The methodology for preparation of the propofol microemulsion used in this study is protected by United States Patents 6,623,765 and 6,638,537, which are assigned to University of Florida, Research Foundation, Incorporated (Gainesville, FL) and licensed to NanoMedex, Inc. Drs. Morey, Modell, Shah, and Dennis own stock in NanoMedex, Inc. and as such may benefit financially as a result of the outcomes of the research reported in this publication.

	REFERENCES

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