DISCUSSION

When initiating intravenous infusion of remifentanil targeting C_eff during induction of anaesthesia, the regimen using multiple stepwise increase of Ceff could prevent severe remifentanil-induced coughing and significantly reduce the incidence of coughing, compared to the method of direct increase to a final target of 4.0 ng/ml of Ceff.

Among previous studies of opiod-induced cough, several are based on different methods of opioid injection. Schapermeier et al. reported that intravenous injection speeds of 1.5 μg/kg fentanyl did not influence the incidence of cough.(Schapermeier, 2008) However, Lin et al. reported that prolonged injection time of fentanyl decreased the incidence of cough.(Lin, 2005) Chen et al. demonstrated a decreasing incidence of cough for the intravenous injection rate of fentanyl and the influence of injection site on the cough.(Chen, 2009) A pre-emptive small dose of 25 μg/kg of fentanyl was reported to significantly reduce cough, followed by 125 μg/kgof fentanyl.(Hung, 2010) Lim et al. reported that administration of graded escalation of C_eff of remifentanil effectively suppressed the cough, and their method and result were quite similar to those of our study.(Lim, 2010) However, most of these studies are focused on simply decreasing the incidence. Therefore, we attempted to investigate the relationship between provocation and suppression of cough in the context of PK/PD.

In putting the results of our preliminary study together with the previous simulation work,¹ we were able to make tentative conclusions as follows: (1) Remifentanil-induced cough assumed a dose-dependent manner of increase. (2) If Ct-eff was increased to 4.0

ng/ml (bolus of 0.82 μg/kg) while Ceff was maintained at 1.0 ng/ml, 7.3% (5/68) of patients coughed. That is, 1.0 ng/ml of C_eff was not considered sufficient for prevention of coughing.

(3) When there was no remifentanil in the body, 0.52 μg/kg of remifentanil, in order to increase to 2.0 ng/ml of C_t-eff, made 13.2% of patients cough. However, if only C_eff was maintained at 2.0 ng/ml, none of the patients coughed, even though a similar amount was administered (0.60 μg/kg) in order to increase to 4.0 ng/ml of C_eff. As a result, we were able to anticipate that with addition of one more step, infusion of 1/3 increment Ceff in the second step of R_1-4, incidence at the second step might decrease by less than 2%, and overall incidence might decrease by less than 5%, which was proposed as a final endpoint of cough incidence in this study. Using this 3 stepwise increase of TCI, one patient showed just one cough, and we were able to significantly decrease the incidence of cough. This regimen, of course, would be somewhat cumbersome in a routine clinical setting, because it requires that the targets be properly increased following the time elapsed. However, all TCI pumps display C_p, C_eff, and C_t-eff in real time, and some delay of C_t-eff increase might be beneficial because it offers enough time for reaching the pseudo-steady state of remifentanil.

Simulations of the infusion regimens used during the study have shown the time courses of Cp and Ceff. Coughing also showed a tendency to develop while Cp was maintained higher than C_eff, and as discrepancies between C_p and C_eff became smaller, or during the steady-steady equilibrium state, coughing never occurred (Fig. 2, 3). Meanwhile, we found that the concentration-response relationship was difficult to account for, because the scattered plots of Cp of patients who coughed were not distributed around the peaks on visual inspection. Rather, they showed a tendency to disperse after the peak of C_p, and the range

of Cp was also widely distributed. Intravascular space might not be the action site of coughing, and that in order to trigger cough, remifentanil should diffuse from the intravascular space into the cough receptor sites, somewhere in the extra-vascular pulmonary structures. Therefore, in order to describe the concentration at the cough-triggering site, additional tussive effect-site compartment would be helpful to describe the PK/PD relationship of cough.

One of the findings associated with remifentanil-induced coughing that attracted our attention is its very rapid onset. Occurrence of coughing was as fast as 5-6 s in 3 patients of Group R4. Coughing occurred prior to completion of the injection of a whole bolus amount of remifentanil. During this short interval, it could not be believed that remifentanil, injected into the vein of the dorsum of the hand or forearm, reached the central nervous system (CNS). Hoffmann et al. reported that ‘arm-to-head time’, the interval between the start of infusion of the echo-contrast agent injected into the antecubital vein and the beginning of signal amplification in the carotid artery, was 14.3 ± 3.0 s (min-max 9.0-22.0 s).(Hoffmann, 2000) Blumgart et al. reported that an active deposit of radium injected into the antecubital vein had been detected in the right chamber of the heart at 2.5- 14.0 s (arm-to-heart time), and pulmonary circulation time was estimated as 5.5 - 17.5 s.(Blumgart, 1927) Therefore, the possibility that remifentanil could have entered the CNS within 5 s is considered to be very low. Rather, it is supposed that remifentanil triggered coughing during pulmonary circulation. These cough-onset data might hold some important clues to a tussive effect via a peripheral acting mechanism. This peripheral tussive mechanism offers certain logic to our multi-stepwise increase regimen. Priming a small bolus amount

of remifentanil that is not sufficient to trigger cough, while passing the pulmonary circulation, eventually enters the systemic circulation and the drug will reach the CNS.

Thereafter, if only the Ceff of the CNS increases up to a level sufficient for inhibition of cough, coughing will never occur, even though the infusion of a large amount of remifentanil follows.

Several caveats require discussion here. First, we must consider the large variation of remifentanil concentration in the body during the initial rapidly mixing period immediately after injection into the vein.(Egan, 1996) In particular, considering its onset time, the predicted concentrations in the plasma and lung could be much different from the measured concentrations. Prior to entry into the central circulation, remifentanil might be diluted into the volume, which is different from that of the central compartment. Second, the target concentrations of remifentanil of this study were limited only to 1.0, 2.0, and 4.0 ng/ml.

And we considered 2.0 ng/ml of Ceff as an effective antitussive concentration. However, it is not guaranteed for higher targets. Therefore, more attention should be paid when high concentrations of remifentanil are targeted in clinical settings.