Continuous infusion of remifentanil versus sufentanil in videolaparoscopic surgeries: a comparative study

LETTERS TO THE EDITOR

This study compares two drugs that, although used in total intravenous anesthesia (TIVA), have very distinct pharmacological profiles that sometimes can take us to an arid terrain.

As mentioned by the authors, the study stresses the relationship of potency versus the doses of remifentanil and sufentanil used and discusses the results always establishing this relationship. Some aspects have called my attention:

1) In the discussion, the authors lead one to believe that the relationship of the mass of the opioids administered during the procedures (described as 1:18) refers to the relationship of their potency. However, the relationship between the potency of two drugs is not a consequence of the dose used or the total mass of the drug used, but of its plasma concentration and, more precisely, the concentration at the effector site ⁴. Therefore, the same opioid used in the same doses in different patients can have totally different results. This is an example of what happens on both extremes of life, in which the distribution volumes generate different concentrations, even when the total mass administered is the same ⁴. Thus, the potency relationship is described as the plasma concentration (Cp) capable of generating a measurable clinical effect. For example, the Cp50 (ng.mL^-1) of sufentanil and remifentanil to block responses to skin incision are 0.3 to 0.4 and 4 to 6, respectively ². This results in a potency relationship of 1:13. Although the mean total doses of sufentanil (0.016 µg.kg^-1.min^-1) and remifentanil (0.29 µg.kg^-1.min^-1) administered have been described as 1:18 in the present study, this does not mean that this is the potency relationship between the drugs studied. Extrapolating mean doses used and transforming them on probable plasma concentrations explains what I am saying. When simulating the plasma concentrations (Cp) of sufentanil and remifentanil, using Bovill's and Minto's models, respectively, considering the mean consumptions described in the study, the result is as follows ⁵: the maximal sufentanil Cp (considering the initial bolus) was 0.6 ng.mL^-1 and maximal sufentanil Cp was 7.8 ng.mL^-1. How interesting! This corresponds to a 1:13 relationship (7.8/0.6), exactly the same reported in the literature. Therefore, the statement that the amount of sufentanil used was smaller than that of remifentanil seems erroneous because the potency relationship was maintained in the study. This is a positive aspect of the study. Only the interpretation seemed to be mistaken.

2) The authors go on to discuss the synergism between remifentanil and sufentanil, raising the question whether sufentanil may be more synergic than remifentanil when associated with propofol. In my opinion, this possibility is mistaken because it is based only on the doses of propofol necessary to maintain BIS between 40 and 50. According to reports in the literature, an opioid does not change the EEG signal in clinically recommended Cps to block nociceptive responses ². Electroencephalographic changes start only after the administration of higher doses. The Cp₅₀ (ng.m^-1L) of remifentanil and sufentanil to cause EEG depression varies between 10-15 and 0.5-0.75, respectively ². Plasma concentrations obtained with the doses used in the present study were not, at any time, high enough to change the EEG, not even in less than 50% of the patients. Thus, assuming the thesis presented in item 1 is wright, i.e., that the mass of opioids were in fact equivalent, one can say that the amount of propofol used in both groups was equivalent because the blockade of nociceptive responses was adequate and of similar intensity. The bispecral index confirmed exactly that - similar needs of propofol when similar plasma concentration of opioids were used; otherwise, the depression of the EEG would have been greater (with consequent fall in BIS and greater incidence of correction) in the group in which the mass of opioid was greater, since the dose of propofol was similar in both groups.

3) Regarding recovery, we should consider the following: the Cps in which the return of spontaneous ventilation in 50% of the patients when sufentanil and remifentanil are used are 0.2 and 2, respectively ². This means a potency relationship of 1:10 for recovery of ventilation, slightly different from the prior relationship (1:13). The simulation of context-dependent half-lives of sufentanil and remifentanil, for the mean doses used, generated a return time of Cp for those drugs for 0.2 and 2 ng.mL of 38 and 9 minutes, respectively ⁵. Since the infusion of remifentanil was interrupted 20 minutes before the end of the procedures, this explains why analgesia was better in this group and why one patient developed respiratory depression. The final Cp of sufentanil was, in most cases, 4 to 5 times higher than necessary (0.05 ng.mL^-1) to provide satisfactory postoperative analgesia during, at last, for another 18 minutes. I prefer to call it "real" analgesia caused by sufentanil and not residual analgesia. It is not residual. It is deliberate, since it was not caused by residual circulating amounts of the drug, but by a considerable circulating dose of the drug.

4) Finally, I think it is important to mention that the approach of potency relationships between two drugs is currently related not only to the Cp of each drug with a measurable effect, but Cp versus drug versus a third variable, which is the effect to be measured. This is explained by the fact that effect should be considered when determining the potency. For example: the C₅₀ of alfentanil for the return of spontaneous ventilation is 40% of the C₅₀ of that drug that causes changes in EEG ^1,2. Thus, one can see that the potency relationship between two drugs can be altered according to the clinical effect measured: skin incision, change of the EEG, blockade of the responses to intubation, return of spontaneous ventilation, etc. It is complex, but that is what has been described. Rigid potency relationships for all clinical outcomes have not been described. This has explained, for example, why patients awake after TIVA with propofol and remifentanil before hemodynamic changes become apparent. The rate of remifentanil removal from the vascular smooth muscle is lower than the rate of removal from the opioid receptor ³. I would like to congratulate the authors for the study. It was well designed and, for this reason, their results are in accordance with the results reported in the literature.

Dr. Fernando Squeff Nora

E-mail: [e-mail]

Continuous infusion of remifentanil versus sufentanil in videolaparoscopic surgeries. A comparative study

Dear Editor,

Publication Dates

• Publication in this collection
  04 Sept 2008
• Date of issue
  Oct 2008