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Correspondence  |   December 2001
What Are “Relevant” Concentrations?
Author Affiliations & Notes
  • Edmond I Eger, M.D.
    *
  • *University of California, San Francisco, California. egere@anesthesia.ucsf.edu
Article Information
Correspondence
Correspondence   |   December 2001
What Are “Relevant” Concentrations?
Anesthesiology 12 2001, Vol.95, 1538-1539. doi:
Anesthesiology 12 2001, Vol.95, 1538-1539. doi:
In Reply:—
Our article 1 dealt with mechanisms underlying the immobility produced by inhaled anesthetics. We analyzed the possible connections between the population concentration–effect relations applied in the determination of MAC (the minimum alveolar concentration required to eliminate movement in 50% of patients in response to a noxious stimulus) and the receptor concentration–effect relations that might underlie MAC.
From simple, mathematically consistent models, we concluded that an additive effect of several receptors could not explain either the steepness of the population concentration–effect relation underlying MAC or the position of that relation relative to the concentration–effect relations for receptors mediating anesthesia. Assuming a finite variability in individual responses to anesthesia, our analysis concluded that the steepness of the concentration–effect relation underlying MAC results from effects on only one or a few receptors and that the anesthetic concentration depressing or exciting such receptors cannot radically differ from MAC. Eckenhoff and Johansson 2 disagree with the assumptions underlying the proposed model and, therefore, any conclusions resulting from it. However, if one accepts those assumptions, our analysis and conclusions are sound. They differ diametrically from the analysis and conclusions originally offered by Eckenhoff and Johansson, 2 a simpler analysis flawed by truncating the sum of several dose–response curves and improperly fitting curves to the resulting data. Eckenhoff and Johansson 2 found that the combined effects of several receptors could produce the steep population–effect curves found for MAC determinations (Hill coefficients of 6–20), whereas we found that the combined effects of several receptors produced a maximum Hill coefficient of 1.5.
Gottschalk, Eckenhoff, and Johansson argue that our simplistic models may not mirror the complex results that flow from an organ such as the brain, or the spinal cord—which mediates MAC. Perhaps this is true, but our simplistic models lead to conclusions that square with the comment of Eckenhoff and Johansson that “we, too, believe that the likelihood of a target being an important contributor diminishes with increasing EC50.” Eckenhoff and Johansson argue that our use of simple models that assume linearity or additivity “invalidates” those models because nonlinearities may  govern the relations that we have analyzed. However, neither they nor we know that nonlinearities govern the relations between multiple receptors sites. Therefore, it seems premature to dismiss the simple models and presumptuous to use the term invalidate. Similarly, in our article, we provided more than “intuition” in defining the probable limits to the threshold. Whether more complex models will lead to different conclusions awaits further efforts.
Eckenhoff and Johansson argue that the “remarkably conserved response (across the whole animal kingdom) to inhaled anesthetics arises from multiple interacting targets—the normal heterogeneity in any one of which will only have a small effect on the final integrated behavioral response. This interpretation is consistent with knockout and inhibitor experiments to date: the effects on inhaled anesthetic potency is consistently small and incomplete.” We agree that many knockout experiments provide small or no effects, 3 but, in contrast to Eckenhoff and Johansson, we propose the simpler view that no or little effect means no or little effect. The comment regarding inhibitor experiments is incorrect. Some of these produce profound effects on anesthetic requirement, 4,5 and inhibitor studies that do not affect MAC indicate that the inhibited receptor does not mediate MAC. Therefore, not every receptor affected by anesthetics must mediate anesthesia.
The notion that a single receptor might govern a given effect of inhaled anesthetics is consistent with findings for many injected anesthetics. Only one receptor seems to underlie the effects of anesthetics such as propofol, etomidate, and ketamine (γ-aminobutyric acid type A receptor for propofol and etomidate;N  -methyl-d-aspartate for ketamine), and the concentrations materially affecting each receptor lie within the range producing clinical effects. That is, a single target is probably responsible for the action of these agents. The fact that inhaled anesthetics affect diverse receptors makes it tempting to argue (as do Eckenhoff and Johansson) that each contributes to the anesthesia they produce. Indeed, an effect on a given receptor may only apply to a specific action (e.g.  , immobility or amnesia). However, such a conclusion may be as incorrect as it would be for the actions of propofol, an anesthetic that can cause amnesia and immobility during noxious stimulation, all through enhancement of the response of the γ-aminobutyric acid type A receptor to γ-aminobutyric acid. And the population dose–effect relation defining the propofol EC50for immobility has a Hill coefficient 6 of 6 or 7, a value similar to that for inhaled anesthetics.
All of us agree that a population threshold explains the steepness of the in vivo  concentration–effect curves for MAC and, further, that individual variability (and measurement error) explains, at least in part, why in vivo  concentration–effect curves are not infinitely steep. We believe all agree that receptors with EC50values that deviate from the population EC50value are less likely to be mediators of the in vivo  effect, but we may disagree on the extent of the deviation required to dismiss a given receptor as relevant.
Our position continues to be that relevant concentrations for studies of anesthetic effects on the receptors (or interneuronal pathways) that mediate anesthesia (MAC) probably do not differ markedly from concentrations required to produce anesthesia, and that only one or a few receptors mediate the anesthetic effect underlying MAC.
References
Eger El II, Fisher DM, Dilger JP, Sonner JM, Evers A, Franks NP, Harris RA, Kendig JJ, Lieb WR, Yamakura T: Relevant concentrations of inhaled anesthetics for in vitro  studies of anesthetic mechanisms. A nesthesiology 2001; 94: 915–21Eger, El Fisher, DM Dilger, JP Sonner, JM Evers, A Franks, NP Harris, RA Kendig, JJ Lieb, WR Yamakura, T
Eckenhoff RG, Johansson JS: On the relevance of “clinically relevant concentrations” of inhaled anesthetics in in vitro  experiments. A nesthesiology 1999; 91: 856–60Eckenhoff, RG Johansson, JS
Quinlan JJ, Homanics GE, Firestone LL: Anesthesia sensitivity in mice that lack the β3 subunit of the γ-aminobutyric acid type A receptor. A nesthesiology 1998; 88: 775–80Quinlan, JJ Homanics, GE Firestone, LL
Kuroda Y, Strebel S, Rafferty C, Bullock R: Neuroprotective doses of N-methyl-D-aspartate receptor antagonists profoundly reduce the minimum alveolar anesthetic concentration (MAC) for isoflurane in rats. Anesth Analg 1993; 77: 795–800Kuroda, Y Strebel, S Rafferty, C Bullock, R
Zhang Y, Wu S, Eger El II, Sonner JM: Neither GABA(A) nor strychnine-sensitive glycine receptors are the sole mediators of MAC for isoflurane. Anesth Analg 2001; 92: 123–7Zhang, Y Wu, S Eger, El Sonner, JM
Andrews DT, Leslie K, Sessler DI, Bjorksten AR: The arterial blood propofol concentration preventing movement in 50% of healthy women after skin incision. Anesth Analg 1997; 85: 414–9Andrews, DT Leslie, K Sessler, DI Bjorksten, AR