mise à jour du
1 juin 2008
J Clin Anesth.
Clinical assessment of propofol-induced yawning
with heart rate variability: a pilot study
Tsou CH, Kao T, Fan KT, Wang JH, Luk HN, Koenig HM.
Dpt of Pulmonology, Ren-Ai Branch, Taipei City Hospital, Taiwan
yawning and anesthesia


1. Introduction
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.