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Le bâillement, du réflexe à la pathologie
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mise à jour du
1 mars 2010
J Anesth
2010;24(2)168-172
Inhibitory effects of landiolol and nicardipine on thiopental-induced yawning in humans
 
Tsutomu Oshima, Tatsuo Murakami, Yuhji Saitoh, Miyuki Yokota, Yoshiko Kasuya
Department of Anesthesia, Gifu Red Cross Hospital, Japan

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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