Yawning is a stereotyped behavioral pattern
that usually occurs during normal physiologic
and pathologic conditions. The psychophysiologic
significance of yawning seems to be an arousal
reflex to increase attention. Yawning is
regarded as a primitive reflex that is activated
in the hypothalamus and projected to the
hippocampus, ventral medulla, or spinal cord.
Most information about the mechanism of yawning,
however, comes from animal models such as
rats.
Numerous neurotransmitters, such as
gamma-aminobutyric acid (GABA), acetylcholine,
norepinephrine, and opioid peptides, are
involved in the generation of yawning. In
contrast, less is understood about
anestheticinduced yawning in human beings. The
clinical significance of yawning as a monitoring
for depth of anesthesia with GABA agonists
recently has been studied.
Propofolinduced yawning is not uncommon;
whether such yawning is affected by
anticholinergics or opioids is not known. We
conducted a clinical observational study to
investigate the proportion of propofol-induced
yawning and the possible effects of opioids and
anticholinergics on such yawning in human
subjects. In addition, yawning has been observed
in many clinical conditions such as vasovagal
reaction, drug effects, and central nervous
system diseases, among others.
Recently, heart rate variability (HRV)
studies have been widely applied to many
clinical conditions for the noninvasive
investigation of autonomic function in human
beings. Therefore, using the tool of HRV, we
conducted a pilot study to examine the
sympathovagal balance during propofol-induced
yawning in anesthetized patients.
.........
4. Discussion Yawning, either
spontaneous or drug-induced, is a complex
pathophysiologic psychosocial behavior and
defense
reflex. Its underlying neurophysiologic
mechanisms are sophisticated, and most
information is obtained from animal models.
Although anesthetic-induced yawning is commonly
observed during induction of anesthesia,
systemic investigation of this universal
phenomenon in human beings is still lacking. In
a recent study, the proportion of
propofolinduced yawning was reported to be 63%
(30 patients in each group) [4].
Similarly, our results from 386 patients
show that the proportion of propofol-induced
yawning was 53.5%. The slight difference in the
proportion might be due to different anesthetic
administration modalities (target-controlled
infusion vs IV bolus injection), population
characteristics, or sample sizes between the two
studies. Neuropharmacology of drug-induced
yawning has been extensively reviewed
[3]. For example, apomorphine induced
yawning can be inhibited by morphine acting
through receptors in neurons located in the
paraventricular nucleus of the hypothalamus
[12].
This finding from an animal study is
supported by our results showing that proportion
of propofol-induced yawning in human subjects
was dramatically decreased by pretreatment with
fentanyl. It should be noted, however, that
fentanyl may potentiate the propofol-induced
apnea and therefore affect the measurement of
yawning. Except for opioids, yawning is also
associated with interactions among many other
neurotransmitters and secondary messengers in
the hippocampus, pons, and medulla oblongata
from animal model studies [3,13,14]. For
example, acetylcholine facilitates yawning via a
centrally cholinergic response in rats
[15], but scopolamine has no effect on
spontaneous yawning in men [16]. Our
results, however, show that pretreatment with
atropine did not inhibit propofol-induced
yawning (Table 1). This finding is not in
agreement with a previous report, showing that
atropine could enhance drug-induced yawning in
rats [17]. It is worth mentioning that
yawning could be completely inhibited by
centrally acting antimuscarinic drugs
(scopolamine) but not by peripherally acting
methylscopolamine in rats [18]. Because
atropine also crosses blood-brain barrier and
exhibits mild stimulant effects on the medullary
center, the exact effect of atropine on
propofolinduced yawning in human beings remains
unknown.
Activation of GABAA receptors in the
paraventricular nucleus reduced drug-induced
yawning in rats [14,19]. Interestingly,
this concept contradicts our results, showing
that propofol (a GABA agonist) can elicit
yawning in human subjects. The exact explanation
for this contradictory result is not clear,
although different subtypes of GABA receptors,
species, and drugs used in the studies might
lead to the different results.
Yawning has been regarded as an early
manifestation of the vasovagal reflex, but solid
evidence is still lacking. The association of
yawning with alternation of autonomic nervous
system activation in human beings is not known.
In rats, a depressor (sympathoinhibitory)
response always precedes yawning behavior
[20]. It also has been claimed that the
initial inspiration phase of yawning showed
sympathetic withdrawal, followed by sympathetic
activation during the expiratory phase in one
healthy volunteer with a microneurographic
technique over the common peroneal nerve
[21]. The differing results in our study
might be due to different sample size (27
subjects vs one subject), different subject
groups (patients vs healthy persons), different
methods (HRVanalysis vs direct nerve recording
technique), and different study phenomenon
(propofol-induced yawning vs spontaneous
yawning).
Recently, HRV study has been widely applied
to many clinical conditions as a noninvasive
tool to investigate autonomic functions in vivo.
Clinically, HRV has been used as a monitoring
tool evaluate the effect of propofol
[22-24]. It has been reported that
propofol significantly reduces HF and
significantly increases LF/HF power (LF/HF)
ratio during anesthesia [24]. However,
HRV has not been used to investigate the
relationship between propofol-induced yawning
and autonomic function. In our pilot study, the
SPWVD algorithm in HRV analysis was applied to
evaluate the instantaneous sympathovagal balance
during propofol-induced yawning. Our results
show accelerated HR and prominent elevation of
instantaneous LF/HF as yawning occurred (Fig.
1). Meanwhile, our results also show a
significant elevation of mean LF/HF in stage 3
as compared with that in the baseline stage when
yawning occurred. Most important, a significant
increase in mean LF/ HF ratio during stage 3 in
the yawning group was noted, in comparison with
that in patients without yawning.
These findings may reflect the significant
fluctuation of autonomic functions during
propofol-induced yawning. Similarly, a
significant increase in normalized LF
(LF[nu]) and a decrease in normalized HF
(HF[nu]) during stage 3 were noted in
patients with propofol-induced yawning (data not
shown). The combination effect of LF(nu) and
HF(nu) resulted in the elevation of LF/HF ratio
in stage 3. The elevation in LF/HF could be
caused by parasympathetic withdrawal or
sympathetic activation during propofolinduced
yawning.
The exact time sequence of interaction
between sympathetic and parasympathetic
activation in such scenario needs further
investigation. The origin of parasympathetic
withdrawal during yawning in our study remains
unclear. Transient arousal-shift may be one
possibility. Anesthetic-induced yawning has been
represented as a transient arousal-shift during
induction of anesthesia [25]. In a sleep
study, arousal is accompanied by a sudden HR
increase, which is a result of withdrawal of
vagal tone and an increase in heart sympathetic
outflow [26].
Our results seem to parallel those of the
above-cited investigations. Interestingly,
instantaneous shortening of the R-R interval
with prominent elevation in LF/HF during yawning
in our pilot study also seems to be consistent
with the respiratory sinus arrhythmia, in which
HR accelerates during inspiration and
decelerates during expiration (Fig. 1). The HF
power part in an HRV study can be influenced by
respiration, so the effect of respiration might
be one of the possible origins of significant
elevation of LF/HF during yawning. The
limitations of our HRV study include its small
sample size and the possible confounding effects
of sleep status and psychologic stress.
Simultaneous monitoring of other physiologic
parameters (brain activity, HR, blood pressure,
and R-R) during yawning could help to further
understand the role of sympathovagal balance in
propofolinduced yawning.
In conclusion, propofol-induced
yawning may be inhibited by pretreatment with
opioids. Heart rate variability analysis showed
a significant change of sympathovagal balance at
the time of yawning.
