We appreciate the interest of Dr. Hagihira et al.  regarding our recent article.1We would like to address their concerns regarding our methodology and recommendations.

In our volunteer experiments, we were careful to allow adequate time for equilibration after each step change in sevoflurane to achieve a pseudo–steady state. At each time point, we confirmed a stationary anesthetic level by directly measuring the end-tidal concentration of sevoflurane using a calibrated agent analyzer. An additional indirect confirmation of equilibration was the steady Bispectral Index® (BIS®; Aspect Medical Systems, Norwood, MA) and Auditory Evoked Potential ARX Index (AAI; Alaris Medical Systems, San Diego, CA) measurements in unstimulated volunteers. This is similar to the methodology used by Katoh et al.  2Although the “average” BIS values of 1.0% and 1.5% sevoflurane reported by Katoh et al.  2are different than those that we reported, we believe that both studies had achieved adequate equilibration because the observed and average values of the BIS at each of the modified Observer's Assessment of Alertness/Sedation scores were similar. In addition, the range of BIS values observed by Katoh et al.  2when the end-tidal sevoflurane was 1.0% (50–75) and 1.5% (30–55) are similar to what we observed.

The discrepancies between the predictions made by Katoh et al.  2and those made by our model are most likely due to the differences in the raw observed data range and the mathematical models used to fit the raw data. We believe that fitting a third-order polynomial to a smaller range of measured concentrations (0–2.5%) compared with generating a response surface for a wider range of measured sevoflurane concentrations (0–6%) resulted in the different predictions of the average BIS values at the various sevoflurane concentrations.

Preventing explicit recall is a vital goal of general anesthesia. Multiple investigators have demonstrated that opioids consistently reduce both the minimum alveolar concentration (MAC)2,3and the MAC required to follow commands (MACawake)2in addition to decreasing the effect site concentration of anesthetics required to produce loss of consciousness. There should be no reason why the observed pharmacodynamic interactions we observed in our human volunteer laboratory should not be evident during maintenance of anesthesia. Therefore, moderate to high doses of opioid should allow a persistent decrease in the anesthetic required to prevent explicit recall throughout the perioperative period.

We also agree with Dr. Hagihira et al.  that the importance of implicit recall of intraoperative events is less clear. Unfortunately, implicit recall is much more difficult to evaluate, and therefore, the literature is full of conflicting data on the anesthetic requirements necessary to abolish implicit memory. The data from Iselin-Chaves et al.  4are thought provoking, but the large variety of anesthetic techniques used does not allow conclusions to be made on the efficacy of moderate to high opioid concentrations to block implicit memory. However, if implicit recall can be prevented by diminishing noxious stimulation-induced activation of the auditory centers5or the arousal centers,6then moderate- or high-opioid anesthetic techniques may be useful alternatives to hypnotic-based anesthetics. In addition, if “too deep” anesthesia is indeed associated with a worsening in 1-yr survival,7the use of low or moderate doses of hypnotic with a balance of analgesia (via  regional anesthesia, systemic opioids, or a combination) may be desirable.

It is important to reemphasize that our data were derived from volunteers where the electroencephalogram-based assessments of depth of anesthesia were performed independent of response to painful stimuli. This is in contrast to what typically occurs in the operating room, where clinicians make electroencephalogram-based and subjective assessments of sedation in the presence of continuous surgical stimuli. It is conceivable that patients may require more sevoflurane and remifentanil than volunteers to achieve the same degree of electroencephalogram-based sedation. However, based on the current data and the available literature, our recommended anesthetic regimen should prevent explicit recall and may inhibit the formation of implicit memories.

*Northwestern University Feinberg School of Medicine, Chicago, Illinois. dhanesh-gupta@northwestern.edu

Manyam SC, Gupta DK, Johnson KB, White JL, Pace NL, Westenskow DR, Egan TD: When is a Bispectral Index of 60 too low? Rational processed electroencephalographic targets are dependent on the sedative–opioid ratio. Anesthesiology 2007; 106:472–83
Katoh T, Ikeda K: The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998; 88:18–24
Katoh T, Kobayashi S, Suzuki A, Iwamoto T, Bito H, Ikeda K: The effect of fentanyl on sevoflurane requirements for somatic and sympathetic responses to surgical incision. Anesthesiology 1999; 90:398–405
Iselin-Chaves IA, Willems SJ, Jermann FC, Forster A, Adam SR, Van der Linden M: Investigation of implicit memory during isoflurane anesthesia for elective surgery using the process dissociation procedure. Anesthesiology 2005; 103:925–33
Wright DR, Thornton C, Hasan K, Vaughan DJA, Dore CJ, Brunner MD: The effect of remifentanil on the middle latency auditory evoked response and haemodynamic measurements with and without the stimulus of orotracheal intubation. Eur J Anaesthesiol 2004; 21:509–16
Chortkoff BS, Gonsowski CT, Bennett HL, Levinson B, Crankshaw DP, Dutton RC, Ionescu P, Block RI, Eger EI II: Subanesthetic concentrations of desflurane and propofol suppress recall of emotionally charged information. Anesth Analg 1995; 81: 728–36
Monk TG, Saini V, Weldon BC, Sigl JC: Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005; 100:4–10