Download The Effect of Propofol Administered Intravenously on Appetite

The Effect of Propofol Administered Intravenously
on Appetite Stimulation in Dogs
JOHN P. LONG, DVM
AND
SUELLEN C. GRECO, DVM
Abstract _ Anorexia is defined as diminished appetite or aversion to food. Clinical manifestations of anorexia have multiple
etiologies, which include systemic illness, pain, fever, stress, metabolic disorders, and decreased palatability and learned aversion
to food. Disorders of appetite are common in companion and laboratory animal medicine. Anecdotal evidence and personal
experience suggest that propofol (2, 6-diisopropylphenol), when given intravenously at subhypnotic doses, causes acute appetite
stimulation in dogs. The establishment of a dose-response effect could have important clinical applications; therefore, this study
attempts to qualify and quantify the effect of propofol on appetite stimulation in healthy young adult dogs. Six purpose-bred male
dogs (age, 6 months) were obtained from a Class A vendor. Dogs were housed individually and provided water ad libitum throughout the study period. All dogs were fed ad libitum to ensure that test conditions and degree of satiety were identical. Each dog was
assigned randomly to either an experimental group or control each day of the study. The experimental groups received single
bolus intravenous injections of propofol at different dosage levels (0.5, 1.0, 1.5, 2.0, or 3.0 mg/kg of body weight), and the control
group received saline. The administrator was blinded to the animal’s identification and dose. Dosages greater than 3.0 mg/kg
resulted in profound sedation and ataxia, which physically inhibited the dogs from obtaining the food; therefore 3.0 mg/kg was the
highest dose tested. Dogs were weighed daily to ensure accurate dosing. Dosing was performed at the same time each day to
minimize variability. Food intake amounts were recorded at 15, 30, 60, 120, and 1440 min after injection. Food intake was expressed as [food intake (g)/ body weight (kg)/ unit time (min)]. After a 1-w rest period, the study was repeated. Data were analyzed
with a type RBF-65 randomized-block factoral design (ANOVA). Each dog served as its own control. The two experiments were
analyzed separately, and a P-value of less than 0.05 was used to declare statistical significance. A significant ( P , 0.05) increase in
food consumption was observed solely during the 0-to-15-min time interval; no significant increase in food consumption was
observed at any other time point. This data supports propofol’s appetite stimulating effect in the initial 15 min after injection.
Additional studies are required to explore the mechanism for this effect and to determine whether it occurs in other species.
Anorexia is defined as a diminished appetite or an aversion to
food (1). It is a common initial complaint in companion animal
medicine. The clinical manifestation of anorexia has multiple
etiologies that include (but are not limited to) systemic illness,
pain, fever, stress, learned aversion to available food, decreased
palatability of food, metabolic disorders, and other unknown
causes (2). Control of appetite and its pharmacologic modulation are complex and not understood completely. There are long
and short-term control mechanisms for food intake. Appetite is
regulated by hunger centers in the lateral hypothalamus and
satiety centers located in the ventromedial hypothalamus as well
as by other components of the limbic system (3). The neurons
involved are responsive to concentrations of blood glucose,
amino acids, and hormones in blood and to neural input from
receptors in the oropharynx, stomach, and duodenum (3). In
addition, long-term control may be dependent on fat stores in
the body. The net effect of these appetite-regulating mechanisms
in clinically normal animals is an adjustment of caloric intake to
meet energy requirements.
Correction of the underlying problem is usually curative in
anorexic dogs, but cases do exist in which the underlying cause
is unknown, and empirical treatment is unsuccessful. Such refractory cases can be managed by dietary rehabilitation,
force-feeding, parenteral nutrition, and administration of appetite stimulants and anabolic compounds (4). Agents used to
promote appetite in small animals include B-vitamins, glucocorticoids, anabolic steroids, cyproheptadine, and diazepam (4).
Few data exist to support use of these agents, but clinically these
drugs can induce variable degrees of appetite stimulation in
healthy and anorexic patients.
Anecdotal evidence and personal experience suggests that
propofol (2, 6- diisopropylphenol, Rapinovet, Schering-Plough
Veterinary; Union, NJ), an injectable anesthetic agent, causes
appetite stimulation in healthy and anorexic dogs when administered intravenously at subhypnotic dosages. The purpose of
this study is to determine whether propofol has an effect on appetite stimulation in dogs.
Materials and Methods
Animals and treatments. This study was approved by the Institutional Animal Care and Use Committee (IACUC) at
Washington University School of Medicine. We obtained six 6month-old, male, purpose-bred, mixed-breed dogs (Canis
familiaris) from a class A vendor (Butler Farms USA, Inc, Clyde,
NY). Upon arrival at the animal facility, dogs were given a complete physical examination and were determined to be in good
general health. Each dog was individually housed, and fresh water
was provided ad libitum throughout the study. Dogs were given
a 14-d acclimation period prior to beginning the study. During
this period, each dog was offered increasing amounts of food
(Lab Diet 45006, PMI Nutrition International, St. Louis, MO) to
prevent overeating. By the tenth day, all dogs were being fed ad
libitum, and fresh food was provided each morning of the study.
Ad libitum feeding ensured that test conditions and the degree
of satiety were identical between dogs.
Each dog was assigned randomly to either an experimental or
control group each day of the study. The experimental groups
received single bolus intravenous injections of propofol at different dosage levels (0.5, 1.0, 1.5, 2.0, or 3.0 mg/kg of body
weight), and the control group received saline. The administrator was blinded to the animal’s identification and dose. Dosages
greater
than 3.0 mg/kg resulted in profound sedation and ataxia,
Division of Comparative Medicine, Box 8061, Washington University School
of
Medicine, St. Louis, MO 63110
which physically inhibited the dogs from obtaining the food;
Volume 39, No. 6 / November 2000
CONTEMPORARY TOPICS© 2000 by the American Association for Laboratory Animal Science
43
therefore, 3.0 mg/kg was the highest dose tested. Dogs were
weighed daily to ensure accurate dosing. Dosing was performed
at the same time each day to minimize variability. Food intake
amounts were recorded at 15, 30, 60, 120, and 1440 min after
injection. After completion of the first study, the dogs were rested
for 1 w, and the study was repeated.
Measurements. A measured amount of food was placed into
each dog’s food hopper each day of the study. Food intake was
calculated by weighing the remaining food at given time points
and subtracting this weight from the original amount. Food spillage was accounted for, and intake measurements were adjusted
to reflect the loss. Intake was expressed as [food intake (g)/body
weight (kg)/unit time (min)].
Statistical analysis. Data were analyzed as a randomized-block
factorial design (ANOVA) with six levels of time and five propofol
dosages (5). ANOVA and all follow-up tests were done by using
SAS version 6 software (PROC GLM, SAS Institute, Cary, NC).
To simplify analysis, the two experiments were analyzed separately. A P-value of , 0.05 was used to declare significance.
Results
Experiment 1. There was a significant dose-by-time interaction (F20, 154 = 22.11, P , 0.0001; Figure 1), which suggested that
the effects of dosage depended on the time interval considered.
The main-effects tests of the dose and time also revealed significant differences (P , 0.0001). Subsequent trend analysis (5)
revealed a linear trend (F1, 154 = 414.95, P , 0.0001) and a quadratic trend (F1, 154 = 13.19, P = 0.0004) for the 0-to-15-min time
interval. The significant linear trend is evidence of a dose-response effect, and the significant quadratic or curvilinear trend
suggests a ceiling effect. Linear or quadratic trends were not
significant at any other time interval.
Contrasts were calculated to determine at which dosages food
intake in the propofol-treated group differed from that of control animals. During the 0–15 min time interval, food
consumption at all dosages except 1.0 mg/kg was greater than
that in control dogs.
Experiment 2. Results were similar to those obtained in Experiment 1. A dose-by-time interaction (F20, 154 = 15.97, P , 0.0001;
Figure 2) and main effects of time and dose (P , 0.0001) were
observed. A linear trend was present during the 0-to-15-min time
interval (F1, 154 = 325.68, P , 0.0001), suggesting a dose-response
effect. In addition, a quadratic trend occurred during the 0-to15-min time interval (F1, 154 = 68.21, P , 0.0001). No linear or
quadratic trends were found at any other time intervals.
Contrast analysis showed that food consumption was higher
than that in control animals for all doses at the 0-to-15-min interval (P , 0.0001). There was no difference in food consumption
between the control and treated dogs at any other time interval.
Tukey-Kramer tests were used to analyze the results for 24-h
food intake (5). No significant difference in 24-h food consumption occurred in experiment 1. In experiment 2, a significant (P
, 0.05) increase in 24-h food consumption was observed at the
1.5, 2.0, and 3.0 mg/kg doses when compared that of controls;
no significant difference was observed for the two lower dosages.
In experiment 1, the control group only consumed 13% of the
total intake within the first 2 h of the experiment; in experiment
2, the control animals only consumed 1% of the total within the
first 2 h. The majority of the food consumed by the control groups
(experiment 1, 86%; experiment 2, 98%) occurred within the 2to-24-h time interval. Mean food intake amounts were recorded
for each time interval, dose, and experiment (Tables 1 and 2).
Discussion
Intravenous administration of propofol at subhypnotic dosages resulted in a significant increase in food consumption in
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FIG. 1. Experiment 1 - Mean food intake in adult healthy dogs (N = 6)
after IV administration of propofol or saline (0.9% NaCl) solution (control) recorded at various timepoints post-administration. Error bars
represent one standard error.
FIG. 2. Experiment 2 - Mean food intake in adult healthy dogs (N = 6)
after IV administration of propofol or saline (0.9% NaCl) solution (control) recorded at various timepoints post-administration. Error bars
represent one standard error.
clinically normal, male, young-adult dogs within 15 min after
injection of all dosages. The decrease in food consumption observed during the 0-to-15-min time interval in Experiment 1 at
the 1.0 mg/kg dosage was attributed to three of the six dogs
consuming half as much food as their cohorts. No reasonable
explanation can be given as to why these animals consumed less
food. The test conditions were identical, and the animals appeared to be clinically normal at the time of testing.
A dose-response effect was observed in both studies. As the
Volume 39, No. 6 / November 2000
Table 1. Mean food consumption (%) by dose for each time interval in experiment 1
Dose
0–15 min
15–30 min
30–60 min
60–120 min
120–1440 min
control
0.5 mg/kg
1.0 mg/kg
1 (6 1)
23 (6 14)
5 (6 4)
1 (6 3)
4 (6 8)
3 (6 2)
4 (6 6)
0 (6 4)
6 (6 4)
8 (6 9)
4 (6 11)
1 (6 6)
86 (6 14)
69 (6 15)
70 (6 12)
1.5 mg/kg
2.0 mg/kg
42 (6 15)
31 (6 11)
0 (6 0)
1 (6 2)
1 (6 3)
3 (6 5)
0 (6 0)
0 (6 0)
57 (6 15)
64 (6 8)
3.0 mg/kg
62 (6 20)
4 (6 6)
0 (6 0)
0 (6 0)
34 (6 19)
Standard deviations are in parentheses.
Table 2. Mean food consumption (%) by dose for each time interval in experiment 2
Dose
0–15 min
15–30 min
30–60 min
60–120 min
120–1440 min
control
0 (6 0)
0 (6 0)
0 (6 0)
2 (6 2)
98 (6 12)
0.5 mg/kg
1.0 mg/kg
1.5 mg/kg
30 (6 24)
54 (6 12)
44 (6 10)
3 (6 1)
1 (6 1)
5 (6 3)
2 (6 4)
0 (6 0)
0 (6 0)
0 (6 0)
2 (6 4)
0 (6 0)
65 (6 16)
43 (6 10)
51 (6 13)
2.0 mg/kg
3.0 mg/kg
49 (6 12)
53 (6 7)
6 (6 6)
4 (6 1)
0 (6 0)
0 (6 0)
0 (6 0)
0 (6 0)
45 (6 9)
43 (6 14)
Standard deviations are in parentheses.
dose increased, the amount of food consumed significantly increased. Administration of greater than 3.0 mg propofol/kg
resulted in profound sedation and a significant decrease in the
amount of food consumed. This data may suggest a ceiling effect to propofol’s ability to stimulate appetite. More likely the
decrease was a direct result of the dog’s inability to obtain food.
Propofol administration did not significantly increase the 24h food consumption or calorie intake in any dog when compared
to those of controls. The significant difference in food consumption was seen within 15 min after administration. This effect most
likely is due to propofol’s quick onset of action and rapid elimination. Dogs given an induction dose of propofol (5.5 to 7.0
mg/kg) generally remain anesthetized for 5 to 7 min and are
fully recovered by 10 to 20 min (6). The fact that we administered a subhypnotic dose allowed a much quicker recovery from
sedation and shorter duration of action. No carryover effect was
identified, which was attributed to the elimination of the propofol
from each dog prior to the next dosage.
Dogs were covertly observed from the time of administration
throughout the recording period to detect any adverse effects
of the propofol infusion. Adverse effects were not observed in
the dogs given 0.5, 1.0, 1.5, or 2.0 mg propofol/kg of body weight.
At the 3.0 mg/kg dose, all dogs exhibited some degree of sedation and ataxia, but these effects were transient. All dogs
completely recovered within 2 min and began consuming food
as soon as they were physically able. Two dogs managed to pull
themselves to the food hoppers and ate while in lateral recumbency. The remaining four dogs would eat only after they became
ambulatory.
Propofol is a relatively new sedative-hypnotic agent that induces a dose-dependent depression of the central nervous system
similar to that of barbiturates and benzodiazepines (6). This depression is thought to be induced by enhancing the inhibitory
neurotransmitter gamma-aminobutyric acid and decreasing the
brain’s metabolic activity (7–10). Propofol was approved for veterinary use in 1997. In veterinary medicine, propofol is primarily
used intravenously as an induction or maintenance anesthetic
agent (11). The dosage for induction of anesthesia in
unpremedicated dogs is 6 to 8 mg/kg (12). The primary advantage of propofol (compared with other injectable anesthetic
agents) is a quick induction and smooth recovery as a result of
redistribution from the brain to other tissues and efficient elimiVolume 39, No. 6 / November 2000
nation from plasma by metabolism (7). Complete recovery from
propofol anesthesia in dogs takes approximately 20 min, whereas
complete elimination from the body can take as long as 5 h (6).
As propofol’s use gains increasing acceptance by the veterinary
community, potential nonhypnotic therapeutic applications will
need to be explored.
Propofol administered intravenously at subhypnotic dosages
less than 3.0 mg/kg in young, clinically normal, male dogs results in a significant increase in food consumption within the
first 15 min after injection. In addition, our personal experience
supports the use of propofol in anorexic dog. In particular,
propofol is a potent appetite stimulator in postoperative dogs as
well as cancer patients. Clinicians should exercise extreme caution when choosing to use propofol in dogs to increase appetite
and should use the lowest dosage that will achieve the desired
effect. Propofol should not be used in dogs with a known hypersensitivity to the agent or when sedation or general anesthesia is
contraindicated. Propofol has been associated with pain on injection (13, 14), anaphylaxis (15), respiratory (16, 17) and
cardiovascular (16–18) depression, excitation (19), and vomiting (20). Propofol should not be used in dogs in which any of
these systems are compromised or have exhibited a previous hypersensitivity.
Propofol is highly bound (98 to 99%) to serum proteins in a
nonsaturable process (21). In accordance with this protein-binding behavior, it is unlikely that there will be an exaggerated
pharmacological response in patients with renal and hepatic
disease following the administration of a standard propofol dose
(22). However, due to individual patient variability, careful titration is recommended. The fraction of free propofol is slightly
increased in patients with severe hypoproteinemia, who may require reduced doses to achieve a pharmacologic response. This
observation supports the idea that propofol should be used with
great care in critically ill patients, especially if they have significant hypoproteinemia
Daily use of propofol does not appear to pose any significant
health threat to the patient. This belief is supported by a study
that was performed to determine the toxicity of repeated doses
of propofol in the dog over a 30-d period (23). A dose of propofol
(10 mg/kg, 1.5-times the recommended induction dose) was
administered daily for 30 d. This study showed no adverse effects and supports the safe daily use of propofol as an anesthetic
CONTEMPORARY TOPICS
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45
agent at doses exceeding the indicated induction dose. Therefore, the daily use of subhypnotic dose of propofol for 30 d or
less should be safe.
Currently no literature exists that supports the use of propofol
as an appetite stimulant or cites a plausible mechanism. The
scope of this study was to identify a cause-and-effect relationship
between the administration of propofol and appetite stimulation. Our focus was not to identify a mechanism of action.
Additional studies are needed to identify the mechanism by which
propofol stimulates appetite and whether a similar response is
seen in other species.
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