Department of Anesthesia,
Gifu Red Cross Hospital, Japan
Abstract Purpose Either the calcium
(Ca2+)-channel blocker nicardipine or the
b1-adrenoceptor antagonist landiolol may be
intravenously (IV) administered to reduce the
hemodynamic responses to tracheal intubation. In
this study, we examined the effects of these
drugs on the yawning response elicited by
intravenous thiopental in humans.
Methods After Institutional Review Board
approval, 180 consenting American Society of
Anesthesiologists (ASA) I or II patients
undergoing elective surgery were recruited. In a
double-blind, randomized design, three groups of
60 patients each received one of the following
intravenous injections: (1) landiolol 0.1 mg/kg
(L-group), (2) nicardipine 0.02 mg/kg (N-group),
or (3) saline (S-group).
In all patients, anesthesia was subsequently
induced IV with 4 mg/kg thiopental. Thereafter,
the occurrence of the yawning response
(characterized by mouth opening) was
continuously assessed as the only clinical
endpoint for 1 min. Throughout the study, mean
arterial blood pressure and heart rate were also
recorded at 1-min intervals. Results The
incidence of the yawning response was lower in
both the L-group (6.7%) and the N-group (16.7%)
than in the S-group (46.7%) (each,
P<0.01).
Introduction One of the most
frequently encountered clinical situations
during which yawning occurs is the IV induction
of general anesthesia. Without prior
administration of an opioid, such as fentanyl, a
yawning response may occur within 1 min after IV
injection of thiopental or propofol (occurrence
rate approximately 50%) [1&endash;3].
Moreover, we recently demonstrated in humans
that this type of yawning is associated with a
transient arousal shift during continuing loss
of consciousness [2].
Either a b1-adrenoceptor blocker or a
calcium-channel antagonist or both has been
adjunctively administered to reduce the
hemodynamic response to tracheal intubation
during the induction of general anesthesia
[4&endash;6]. Interestingly, in animal
experiments using male rats, calcium-channel
blockade has been demonstrated to prevent the
yawning response [7], and how
b-adrenoceptor antagonism affects this
behavioral response is controversial [8,
9]. However, there are still no data
regarding the effects of these pharmacological
modulations on the occurrence of yawning in
humans.
This study explored whether prior
administration of either the highly selective
b1-adrenoceptor blocker landiolol or the
calcium-channel antagonist nicardipine might
alter the incidence of the yawning response
elicited by IV injection of thiopental in
humans. Positive findings could provide insights
into the physiologic and pharmacological aspects
of yawning in humans.
Discussion Our main finding was that
in patients undergoing IV induction of general
anesthesia, prior IV administration of either
landiolol or nicardipine significantly reduced
the incidence of the thiopental-induced yawning
response. This indicates that the incidence of
thiopental-induced yawning response can be
greatly reduced by a blockade of either
b1-adrenoceptors or calcium channels in humans.
The neurochemical mechanism of yawning is
briefly reviewed.
The
paraventricular nucleus (PVN) of the
hypothalamus is essential for spontaneous yawns,
because microinjection of several substances,
including apomorphine [10], L-glutamate,
or NOC-7 as a nitric-oxidereleasing compound
[11] into the PVN increases the
frequency of spontaneous yawns. Furthermore,
Sato- Suzuki and coworkers demonstrated that the
stereotyped yawning responses evoked by
microinjection of these drugs into the PVN are
mediated by nitric oxide synthase-positive
oxytocinergic parvocellular neurons in the PVN
projecting to the lower brain stem and the
spinal cord [11].
As to the neurochemical mechanism through
which microinjection of L-glutamate into the PVN
induces the stereotyped yawning response, Melis
and Argiolas [12] provided the most
plausible explanation that activation of
N-methyl- D-aspartic acid (NMDA) receptors
increases intracellular calcium (Ca2+)
concentration in cell bodies of oxytocinergic
neurons in the PVN, mediating this behavioral
response by increasing Ca2+ influx through Ca2+
channels coupled to NMDA receptors.
The increase in intracellular Ca2+ activates
nitric oxide synthase to produce nitric oxide,
thereby facilitating oxytocinergic transmission
in the PVN of the hypothalamus [13].
Therefore, the neurochemical mechanism
underlying the yawning responses both evoked by
L-glutamate and nitric oxide may be a common one
that is linked. Inhibition of the yawning
response by systemic b1-adrenoceptor antagonism
observed in our study may be related to opioid
mimetic/sparing effects. Besides their
cardioinhibitory effects, short-acting
b1-adrenoceptors landiolol and esmolol are
reported to exert antinociceptive and opioid
mimetic/sparing effects in animals [14,
15] and humans [16, 17].
For example, intrathecal administration of
landiolol [14] and IV administration of
esmolol [15] inhibit nociception in the
mouse and rat formalin tests, respectively.
Furthermore, intraoperative infusion of esmolol
has been reported to be effective in sparing the
required dose of opioids intraoperatively
[16] and postoperatively [17] in
humans. b-adrenoreceptors and opioid receptors,
members of G-protein-coupled-receptor
superfamily, are known to functionally and
physically cross-talk via multiple hierarchical
mechanisms, including heterodimerization of
these receptors, counterbalance of functional
opposing G-protein signaling, and interface at
downstream signaling events [18].
On the other hand, the hypothetical
mechanism by which IV-administered landiolol
might suppress the thiopental- induced yawning
response through an opioid mimetic/sparing
effect is supported by our recent finding in
humans that the probability of a
thiopental-induced yawning response is decreased
by prior use of IV-administered fentanyl
[3]. Indeed, yawning is one of the
commonest signs of opiate withdrawal syndrome in
opiate addicts. In rats, however, the situation
is less clear, as systemic administration of
b-adrenoceptor antagonists such as propranolol
and pindolol has been reported either to
potentiate the yawning response [8] or
to have no effect on it [9].
Although these inconsistent results may be
attributed to either species-related differences
or the roles of b1- and b2-adrenoceptor subtypes
associated with the central pattern generator
for yawning with particular reference to opioid
mimetic/sparing effects, or both, the inhibitory
mechanism of yawning by landiolol will remain
unclear until these problems are elucidated. The
effect induced by systemic calcium-channel
blockade demonstrated in this study supports a
possible role for thiopental-induced Ca2+ influx
into the cell bodies involved in the central
pattern generator for yawning in humans, which
is consistent with the results obtained from in
vitro experiments using dog cerebral arteries
[19] and rat aortic smooth muscle
[20].
If we can extrapolate from the
aforementioned neurochemical mechanism of
yawning, thiopental may, in humans, induce an
intracellular Ca2+ increase that activates
nitric oxide synthetase, thereby producing
nitric oxide, and this in turn may activate
oxytocinergic transmission in the PVN of the
hypothalamus [13], leading to yawning.
In this study, two distinct hemodynamic
differences were observed among the three groups
after IV administration of the test solutions.
These differences (viz. a lower MAP following
nicardipine and the rank order
landiolol\saline\nicardipine for HR) are
consistent with several previous reports
regarding the effects of esmolol and nicardipine
on the hemodynamic reaction to tracheal
intubation [4, 5].
Despite these hemodynamic differences in our
study, changes in MAP and HR observed after
IV-administered thiopental did not differ among
the three groups. Sato-Suzuki and colleagues
previously demonstrated in the anesthetized,
spontaneously breathing rat that a fall in
systemic blood pressure always precedes yawning
behavior [11].
On that basis, the falls in MAP seen
following IV-administered thiopental might be
expected to be closely related to yawning.
However, our results suggest that the inhibitory
effect of neither landiolol nor nicardipine on
the yawning response is attributable to its
hemodynamic effects. On the other hand, these
hemodynamic differences (viz. a lower MAP
following nicardipine and the rank order
landiolol\ saline\nicardipine for HR) may
deteriorate the blindness of the test drugs in
this study. Aside from the test solutions they
were given, we believe that there were no
significant differences in the risk factors
affecting the incidence of thiopental-induced
yawning among our L-, N-, and S-groups.
No patient in any group received prior
opioid administration, such as IV-administered
fentanyl or remifentanil, or clonidine
premedication. Furthermore, there were no
significant differences in gender among the
three groups. In conclusion, IV administration
of either landiolol or nicardipine (prior to
anesthesia induction) reduced the incidence of
the thiopental-induced yawning response in
humans.
The inhibitory effects of these drugs on the
yawning response may be attributable to a
blockade of b1-adrenoceptors or calcium channels
per se, respectively.
Kasuya Y,
Murakami T, Oshima T, Dohi S. Does yawning
represent a transient arousal-shift during
intravenous induction of general anesthesia?
Anesth Analg 2005;101(2):382-3
Morton
HJV Yawning during thiopentone induction Br.
J. Anaesth 1962;34:133-134
Oshima T et
al. Inhibitory effects of landiolol and
nicardipine on thiopental-induced yawning in
humans J Anesth 2010
