This study demonstrated that pretreatment with remifentanil at a small dose of 0.3 μg/kg reduced the incidence and severity of sufentanil-induced cough without influencing the hemodynamics during anesthetic induction. The incidence of cough was 31% in group C and decreased to 4.8% in Group R.
Coughing following the administration of opioid drugs during general anesthesia induction is often reported. In this study, the incidence of cough induced by sufentanil was 31%. In an study by Agarwal et al(2) sufentanil 0.3μg/kg injected over 5 seconds elicited cough in 15.8% of patients while in another study by Li et al(14) the incidence of cough was 37% after the injection of sufentanil 0.5μg/kg within 3 seconds. With a high dose of sufentanil (1μg/kg), the incidence of sufentanil-induced cough could be up to 45.8%(1). The various incidence among different studies might be due to the different doses of sufentanil used and the differences in concentrations, administration rate，race and age(1, 15).
Various mechanisms have been proposed to explain opioid-induced cough. A plumonary chemoreflex mediated by either vagal C-fiber receptors close to pulmonary vessels or irritant receptors may play a role in opioid-induced cough (16). Opioid-induced histamine release(17) and muscle rigidity leading to sudden closure of the vocal cords or supraglottic obstruction by soft tissue(18) may be another possible casual factor. In addition, some prior studies found that opioid receptor dualism might also be an important mechanism (3, 8, 19) .
Various pretreatments with drugs such as lidocaine, Terbutaline, Dezocine, Dexmedetomidine and Magnesium sulfate have been reported to reduce the incidence of opioid-induced cough(1, 5, 6, 8, 20), but all of these drugs might add variable extra side effects and potential risks. In a study of He et al. (5), injection of dexmedetomidine 0.5 μg/kg or 1.0 μg/kg over 10 min inhibited the cough induced by the following fentanyl (4 μg/kg) intravenous push. However, this dose of dexmedetomidine has the potential to cause bradycardia and hypotension, and the too long injection time is also a problem. In another study (1), 30 or 50 mg/kg of MgSO4 inhibited the cough induced by the following 1.0 μg/kg of sufentanil，but several patients dropped out the study due to an obvious burning sensation during the injection of MgSO4 and the injection of MgSO4 could also increase the plasma magnesium level. Inhalation of terbutaline (5 mg in 2 ml normal saline; via a jet nebulizer) fifteen minutes before bolus fentanyl (5μg/kg, iv) has also been reported to be able to inhibit cough (6), but the inaccessibility of terbutaline, long operating time, and complicated operation are the limitations of this method. Injecting lidocaine 0.5 mg/kg has also been proved effective to suppress fentanyl-induced cough (20) , but its cardiac inhibition may be a potential risk. Dezocine 0.1 mg/kg 2 min prior to intravenous sufentanil (0.5 mug/kg) can also effectively suppress fentanyl-induced cough(8), but in short surgeries, the excessive sedation time of this dose of dezocine may be a problem.
Some other studies used a pre-emptive small dose of the opioids to inhibit opioid-induced cough which could avoid those additional side effects or potential risks of other kinds of drugs. Hung et al. (4) reported that a pre-emptive small dose of fentanyl (25μg) significantly reduced cough induced by the following 125μg fentanyl and Phua et al.(3) found that intramuscular morphine pretreatment 1 hour before induction could also decrease the incidence of fentanyl-induced cough. However, either fentanyl or morphine has its limits because of long onset or long duration time.
In this study, we found that remifentanil, an opioid readily available, with both short onset and duration time, could decrease the incidence and severity of sufentanil-induced cough during anesthetic induction.
It has not been very clear that how small doses of opioids inhibit the cough caused by opioids themselves. In the study of Hung et al. (4), a pre-emptive small dose of fentanyl (25μg) significantly reduced cough induced by the following 125μg fentanyl and this phenomenon was thought to be associated with the smaller plasma concentration fluctuation of fentanyl.
However, in this study, we found that a pre-emptive small dose of 0.3 μg/kg remifentanil could also reduce cough induced by the following 0.5 μg/kg sufentanil though what we used as a pretreatment was another opioid, remifentanil, not sufentanil itself. Thence, the theory of sufentanil concentration flustuation in plasma mentioned above seems unlikely to explain the result.
We guess that opioid receptor dualism may be a possible mechanism to partly explain this phenomenon. One of the common and useful side-effects of opioid analgesics is suppression of the cough reflex which is the basis of their use in oral cough suppressants(3). Sufentanil, fentanyl and remifentanil infusion before recovery from general anesthesia were all also reported to be able to suppress coughing on extubation (9, 21, 22). Opioids may inhibit the cough reflex by a direct effect on the cough center in the medulla, at doses lower than those required for analgesia(3). Therefore, we suppose that the anti-tussive effect of pre-emptive remifentanil in the present study might be related to this kind of centrally-acting effect. The small priming dose of remifentanil might have firstly exerted its central anti-tussive effect and then inhibited the cough-inducing effect of the following large dose of sufentanil. This hypothesis was partly supported by the study of Phua et al(3) in which the incidence of fentanyl-induced cough was reduced by intramuscular morphine pretreatment 1 hour before. However，this speculation still lacks definitive evidence; more studies are still needed to verify this hypothesis and to reveal the exact mechanism.
In addition, since remifentanil has respiratory depression effect, possible apnea related absence of cough after remifentanil administration must also be considered. It was also possible that the dose of remifentanil caused a transient apnea that caused us to see absence of coughing. For example，50~60 seconds for the remifentanil to reach effect site, apnea for another probably 40~50 seconds and then resume breathing, which can partially or even almost cover the observation time after the administration of sufentanil.
Remifentanil may induce muscle rigidity and blood pressure and heart rate decline (15). In a study performed by Shen et al (15), three patients in the rernifenranil group had muscle rigidity and one had significant bradycardia requiring treatment with atropine. However, in our study, there was none patient had such adverse reactions, which might be due to the very small dose of remifentanil we used.
There was a limitation in our study. As few studies have shown how many doses of remifentanil can be used to suppress cough caused by opioids, we used a dose of remifentanil that was close to the dose of fentanyl used in the study of Hung et al. (4) in which a pre-emptive small dose of fentanyl (25μg) was used to reduce cough induced by the following 125μg fentanyl. Therefore，we only used a single dose of remifentanil, so we couldn’t know whether it at different doses such as 0.1 μg/kg，0.2 μg/kg，0.4 μg/kg would be effective in suppressing the cough reflex induced by sufentanil. Further studies need to be done to explore the relationship between dose and the cough suppressing effect of remifentanil.