Subhypnotic Doses of Propofol Possess Direct
Antiemetic Properties
Alain Borgeat, MD, Oliver H. G. Wilder-Smith,
Kaplan Rifat, MD
Department of Anaesthesiology, University of Geneva, Geneva, Switzerland
Propofol is associated with a low incidence of post-
operative nausea and vomiting. In a prospective,
randomized, double-blind, placebo-controlled study,
we investigated the possible direct antiemetic prop-
erties of a subhypnotic dose of propofol. Fifty-two
ASA physical status I or I1 patients, aged 15-60 yr
with nausea and vomiting after minor gynecologic,
orthopedic, or digestive tract surgery, were included
in the study and received either propofol (10 mg =
1 mL) or placebo (1 mL Intralipid) intravenously in
the postanesthesia care unit. Patients treated with
propofol experienced a larger reduction in nausea
and vomiting than patients treated with placebo (81%
N ausea and vomiting are distressing symp-
toms after anesthesia, resulting in significant
morbidity an d longer stays in the recovery
room. General anesthesia conducted with propofol is
associated with less nausea an d vomiting during the
early postoperative period than any other anesthetic
technique (1-3). Some of these studies have sug-
gested that propofol may have direct antiemetic prop-
erties (3). We therefore undertook a prospective,
randomized, double-blind, placebo-controlled study
to investigate the possible antiemetic properties of
propofol in the early postoperative period.
Methods
We studied 52 ASA physical status I or I1 patients of
both sexes between the ages of 15 an d 60 yr, weigh-
ing between 50 an d 80 kg, with nausea an d vomiting
after minor elective gynecologic, digestive tract, or
orthopedic surgery. Patients with a known allergy to
propofol or a history of epilepsy were excluded from
the study. All patients gave informed consent before
Accepted for publication December 10, 1991.
Address correspondence to Dr. Borgeat, Department of Anaes-
thesiology, University Hospital of Geneva, 1211 Geneve 4, Swit-
zerland.
01992 by the International Anesthesia Research Society
0003-2999/921$5.00
MD, Michele Saiah, MD, and
vs 35% success rate; P < 0.05). Patients successfully
treated had a similar incidence of relapse (propofol
28%; placebo 22%) within the first 30 min after
therapy. Thirty-three percent of the propofol-treated
patients and 44% of the placebo-treated patients
showed a minor increase in sedation. The level of
postoperative pain did not change in either group.
Hemodynamic values remained unchanged in both
groups. Pain on injection (7.6%)or dizziness (3.6%)
only occurred in the propofol group. We conclude
that propofol has significant direct antiemetic prop-
erties.
(Anesth Analg 1992;74:539-41)
inclusion in the study. Patients were enrolled into the
study postoperatively if they exhibited vomiting of
grade 4 or 5 severity as assessed by one of the
investigators. Institutional and ethical committee ap-
proval was obtained for the study.
One hour preoperativeIy, midazolam 0.1 mg/kg
IM, was given. Anesthesia was induced with thio-
pental 4 mg/kg IV and maintained with fentanyl,
enflurane, and vecuronium. No patient had received
neostigmine to reverse neuromuscular blockade.
Medication was blinded and randomized by our
pharmacy, which delivered coded vials of either
propofol or Intralipid. Recovery room patients com-
plaining of nausea and/or vomiting were initially
assessed by one of the investigators a s to the severity
of nausea and vomiting by means of a five-point
rating scale (Table 1). Patients with a score of 4 or 5
received 1 mL of the treatment drug (propofol =
10 mg or placebo) intravenously. Sixty seconds later,
patients were reevaluated with the rating scale. A
score of 1 or 2 was considered a success; patients with
a score greater than 2 were given a second milliliter of
the treatment drug. Patients with a score greater than
2 60 s after the second dose were documented as
definitive treatment failures. An observation period
of 30 min after treatment ensued, during which time
relapses of nausea and vomiting together with their
Anesth Analg 1992,74.53941 539
540 BOKGtAT kT AL ANESTH ANALG
A h 1 EMETIC PROPERTIES OF PROPOFOl 1992;74:53941

Table 1. Nausea and Vomiting Rating Scale Table 4. Treatment Results

1= N o nausea and vomiting Propofol (70) Placebo (70)
2= Residual nausea without vomiting
I1 26 26
3- Minor but persistent vomiting with nausea
Success after first injection 18/26 (69) 9126 (35)
4= Maior nausea with vomiting Additional successes after 3126 (12) -
5 = 5evere nausea with vomiting
- second injection
Relapses within 30 min 6121 (29) 219 (22)

Table 2. Sedation Rating Scale

1 = Patient fully awake
2 = Patient somnolent, response to call
3 = Patient somnolent, no response to call, response to tactile
stimulation
4 = Patient asleep, response to painful stimulation
Table 3. Characteristics of Patients
Propofol
group
I1 26
Age (L r) 42 ? 4
5ex (M b) 917
Operating time (min) 98 i 10
5urgen t\ pe (GsO D) 1 52,9
_-___ -
G gvne~olc~gic 0 orthopedic, D, digestn e \urger\
Ldlue\ for age and operating time are mean 2
rdting scale were recorded. Relapse was defined as a
score of more than 2. No drug treatment other than
aspirin was given during the study period; the 0.5 g
of aspirin was given intravenously for postoperative
pain. Other variables documented in the course of
the study were sedation (four-point rating scale,
Table 2) and postoperative pain (10-point verbal rat-
ing scale from 0 = no pain to 10 = worst pain
possible) after each drug administration, the presence
of pain on injection (verbal complaints), dizziness,
mood change, and the presence of hallucinations.
Statistical analysis was performed using non-
parametric methods with the Mann-Whitney and
Fishers exact tests. We compared demographic data
for the groups using Students t-test. A P < 0.05 was
considered significant.
Iiesults
Both groups were comparable with regard to demo-
graphic data, type and dose of anesthetics (including
fentdnyl), and type and duration of surgical proce-
dure (Tdble 3). In the propofol group, 73% had grade
5 nausea and vomiting; in the placebo group, 81%
showed grade 5 nausea and vomiting (NS). Twenty-
one of 26 (81%)patients in the propofol group and 9
of 26 (35%)patients in the placebo group were treated
successfullv ( P < 0.05). Of these, six patients in the
propofol gioup and two patients in the placebo group
relapsed within the next 30 min. In the propofol
group, three patients (3126 = 12%) needed a second
administration of the study drug to achieve a success-
ful outcome. (None required a second administration
in the placebo group; Table 4.) The sedation scale
increased bv one point in 33% of the patients success-
Placebo fully treated with propofol and in 44% of patients
group
successfully treated with placebo (NS). No change in
26 sedation was noted for failures in both treatment
36 5 3 groups. N o patient showed a change in postoperative
i21 pain score.
89 2 13
17 I 7
We observed pain on injection in 7.6% of propofoi
treatments, none in the placebo group (NS). Dizzi-
ness occurred in one patient (3.6%) in the propofol
group onlv (NS). No changes in mood and/or hallu-
cinations were reported. Hernodynamic changes
were similar in both groups and nonsignificant.
Discussion
This is the first study to have investigated the direct
antiemetic properties of propofol. Previous studies
on this topic (4-6) have noted that propofol anesthe-
sia is accompanied by significantly less postoperative
nausea and vomiting. Our study showed that propo-
fol exhibits significant direct antiemetic properties
compared with placebo. Recently, Oestman et al. (7)
found that Intralipid (the soya-oil emulsion in which
propofol is formulated) possesses no significant anti-
emetic effects. Thus Intralipid is a valid placebo for
propofol, particularly in the context of emesis inves-
tigations. The placebo success rate in this study is
also in accordance with the rate quoted in the litera-
ture (8). Relapse rates within the first 30 min of
treatment were similar between the groups; we have
no explanation for this phenomenon. In the course of
pilot investigations for the present study, we found
that propofol has a very rapid onset of action in
treating nausea and vomiting, with no or little further
improvement in nausea or vomiting 60 s after appli-
cation. We therefore considered this period to be an
adequate interval before injecting a second dose.
Interestingly, there was no significant difference in
sedation change between groups for successfully
ANESTH ANALC
1992;74:53941
treated patients; there was no change for the failures.
This strongly suggests that propofol was truly sub-
hypnotic in the doses administered (10 mg) in this
study. Vigilance is obviously strongly influenced by
the act of vomiting, hence patients vomiting are more
awake than those not vomiting. However, the design
of our study cannot categorically exclude more sub-
tle, subclinical differences in sedation between the
groups.
Propofol causes pain on injection (9), particularly
for small catheters or veins (10). Pain on injection was
slight and only occurred in the propofol group. The
occurrence of pain did not unblind the investigator as
it is not clear or proven that when comparing propo-
fol and Intralipid, only the injection of propofol
causes pain. Moreover, this side effect was only
expressed after the end of the emetic episode. Dizzi-
ness occurred only once in the propofol group (no
significant difference between groups).
Both groups were well-matched for factors (e.g.,
sex, duration and type of surgery, anesthetic tech-
nique) known to affect the incidence and severity of
postoperative nausea and vomiting. Both treatments
were identical in appearance to minimize psycholog-
ical effects, which are known to play an important
role in the etiology of nausea and vomiting. Pain on
injection, when present, was slight, and is therefore
unlikely to have affected treatment outcome. Thus, it
is likely that the differences observed were due to the
treatment. It is of interest that 80% of the failures in
the propofol group were related to a type of surgery
associated with vagal stimulation (digestive sur-
gery)-a relationship not present in the placebo
group.
In our pilot study, a dose of 10 mg of propofol
proved effective without side effects. Our initial study
was not designed to investigate the effects of varying
dosages. PropofoI 10 mg was effective for our patients
who weighed between 50 and 80 kg. We cannot
recommend dosages for patients outside this weight
range; however, a larger dosage of propofol may be
associated with undesirable effects.
Perhaps hypnotic agents exert their antiemetic
action primarily via sedation (11). In our study we
observed no significant sedative effects owing to
propofol. Additionally, the duration of antiemetic
action in our study was much longer than the normal
duration of hypnotic action (5-7 min 1121) achieved
with the 15-fold higher doses of propofol used for
anesthetic induction. This is also seen in the pro-
longed decrease in nausea and vomiting after propo-
fol anesthesia, still evident for a long time after any
anesthetic or hypnotic effect of propofol has worn off.
BORGEAT ET AL. 541
ANTIEMETIC PROPERTIES OF PROPOFOL
Both these factors make hypnosis an unlikely expla-
nation for propofols antiemetic properties. Propofol
has a profile of central nervous system depression
that differs significantly from other anesthetic drugs
(13). In contrast to thiopental, for example, propofol
uniformly depresses central nervous system struc-
tures, including subcortical centers (13). Most drugs
of known antiemetic efficacy exert their therapeutic
effects via subcortical structures (14,15). We therefore
suggest that propofol exerts its antiemetic action by
the modulation of some subcortical pathways. Fur-
ther studies are needed to elucidate the precise mech-
anisms involved in the antiemetic properties of
propofol as well as to optimize the dosage regimen.
In conclusion, this study demonstrated that propo-
fol in subhypnotic doses possesses direct antiemetic
properties in the context of minor elective surgery. At
the dose administered (10 mg), side effects were rare
and minor.
References
1. Doze V, Shafer A, White P. Propofol-nitrous oxide versus
thiopental-isoflurane-nitrous oxide for general anesthesia. An-
esthesiology 1988;69:63-71.
2. Korttila K, Oestman PL, Faure E, et al. Randomized compari-
son of recovery after propofol-nitrous oxide versus thiopental-
isoflurane-nitrous oxide anaesthesia in patients undergoing
ambulatory surgery. Acta Anaesthesiol Scand 1990;34:400-3.
3. McCollum JSC, Milligan KR, Dundee J W , The antiemetic
action of propofol. Anaesthesia 1988;43:23940.
4. Gunawardene RD, White DC. Propofol and emesis. Anaesthe-
sia 1988;43(Suppl):6!%7.
5. McCollum JSC, Milligan KR, Dundee J W . Has propofol an
antiemetic action? Br J Anaesth 1987;59:654P-W.
6. Borgeat A, Popovic V, Meier D, Schwander D. Comparison of
propofol and thiopentalihalothane for short-duration ENT
surgical procedures in children. Anesth Analg 1990;71:511-5.
7. Oestman PL, Faure E, Glosten B, Kemen M, Robert MK,
Bedwell S. Is the antiemetic effect of the emulsion formulation
of propofol due to the lipid emulsion? Anesth Analg 1990;71:
536-40.
8. Beecher HK. The powerful placebo. JAMA 1955;159:16024.
9. Nightingdale P, Healy TEJ, Hargreaves J , McGuiness K, Kay B.
Propofol in emulsion form: induction characteristics and
venous sequelae. Eur J Anaesthesiol 1985;2:361-8.
10. Kawar P, Dundee JW. Frequency of pain on injection and
venous sequelae following the IV administration of certain
anaesthetics and sedatives. Br J Anaesth 1982;54:935-9.
11. Moyer JH. Effective antiemetic agents. Med Clin N Am 1957;
41:40532.
12. Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ.
Disposition of propofol in patients undergoing surgery. A
comparison in men and women. Br J Anaesth 1986;58:10759.
13. Cavazzuti M, Porro CA, Barbieri A, Galetti A. Brain and spinal
cord metabolic activity during propofol anaesthesia. Br J
Anaesth 1991;66:490-5.
14. Lerman J, Eustis S, Smith DR. Effect of droperidol pretreat-
ment on post anesthetic vomiting in children undergoing
strabismus surgerv. Anesthesiology 1986;65:322-5.
15. Cohen SE, Woods WA, Wyner 1. Antiemetic efficacy of dro-
peridol and metoclopramide. Anesthesiology 1984;60:67.