Skip Navigation LinksHome > July 2002 - Volume 97 - Issue 1 > Anesthesia-induced Alterations in Plasma Tracer Concentratio...
Anesthesiology:
Correspondence

Anesthesia-induced Alterations in Plasma Tracer Concentrations May Have Relevance for Brain Imaging Studies

Alkire, Michael T. M.D.*; Krejcie, Tom C. M.D.; Avram, Michael J. Ph.D.

Free Access
Article Outline
Collapse Box

Author Information

To the Editor:—
We read with great interest the recent report by Gyulai et al.1 regarding the ability of isoflurane to enhance the in vivo binding of 11C-flumazenil to the GABAA–benzodiazepine receptors in the human brain. This work demonstrates the feasibility of using brain imaging technology to help bridge the gap in knowledge that exists between the in vitro and the in vivo worlds of anesthesia research. This effort complements our finding that propofol's in vivo regional cerebral metabolic depressant effects correlate well with the reported regional ex vivo receptor density data of human benzodiazepine binding sites. 2 In contrast, however, we also found that the regional cerebral metabolic depressant effects of isoflurane did not appear to correlate with the benzodiazepine receptor density data. 2 The present work by Gyulai et al. suggests that the regional cerebral metabolic depression caused by isoflurane may indeed involve the GABA receptor, but perhaps in a less regionally specific manner than that of propofol.
However, before accepting this idea, a technical issue relevant to the emerging field of brain imaging applied to anesthesia research needs consideration. An issue that may play a role in the results presented by Gyulai et al. is the anesthetic-induced alteration of the arterial plasma drug concentration-versus-time relationship in the minutes after rapid intravenous administration of the tracer (the front-end kinetics). 3 The experimental group in the study of Gyulai et al. was anesthetized with isoflurane, and the subjects’ arterial blood pressures were maintained at control values by infusing phenylephrine. Isoflurane and phenylephrine, by the combined effect of depressing cardiac output, may have increased the fraction of the dose of tracer to which the brain was exposed. 4
One measure of tissue drug exposure is the area under the arterial plasma concentration-versus-time curve (AUC) for the time during which the concentration of the drug remains above some threshold value. We have previously demonstrated that in dogs anesthetized with isoflurane (1.7 MAC), the AUC0–3min for antipyrine, a marker of lipophilic drug disposition, more than doubled compared to the same animals while awake. 5 Likewise, when awake dogs were treated with an infusion of phenylephrine in a dose sufficient to double the baseline calculated systemic vascular resistance, the AUC0–3min increased by 75% relative to placebo-treated awake animals. 6 We discovered that the increased arterial concentrations of this lipophilic marker were due to a relative increase in the proportion of cardiac output not involved in the distribution of drug to peripheral tissues. The nondistributive blood flow acts as a “pharmacokinetic shunt.” This pharmacokinetic shunt could have significantly increased the amount of tracer delivered to the brain in the isoflurane–phenylephrine condition in the study of Gyulai et al., making it appear as if the isoflurane had done something in the brain to increase tracer binding.
Gyulai et al. did, however, report regional differences in apparent binding and that “no significant differences were observed in nonreceptor ligand binding between the two experimental conditions in either experimental group. This would indicate that the observed changes in binding were not confounded by altered ligand delivery.”1 Nevertheless, perhaps the authors could have included a control condition in which a few subjects would have received only a phenylephrine infusion. The increased nondistributive blood flow caused by phenylephrine results in an increase in AUC similar to that seen with isoflurane. 6 Thus, if such an active control experiment were to reveal increased tracer binding relative to the saline-treated controls, then perhaps one might conclude that some of the published isoflurane effect should be attributed to an anesthetic-induced change in tracer kinetics, rather than to a central GABAergic effect of isoflurane itself.
In any event, the work by Gyulai et al. provides further evidence that functional brain imaging technology has a role to play in helping us elucidate mechanisms of anesthetic action, and we suggest that some of the work left to be done might involve obtaining a better understanding of how our anesthetic agents interact with the techniques being used to study them.
Michael T. Alkire, M.D.*
Tom C. Krejcie, M.D.
Michael J. Avram, Ph.D.
Back to Top | Article Outline

References

1. Gyulai FE, Mintun MA, Firestone LL: Dose-dependent enhancement of in vivo GABAA-benzodiazepine receptor binding by isoflurane. A nesthesiology 2001; 95: 585–93

2. Alkire MT, Haier RJ: Correlating in vivo anaesthetic effects with ex-vivo receptor density data supports a GABAergic mechanism of action for propofol, but not for isoflurane. Br J Anaesth 2001; 86: 1–9

3. Krejcie TC, Avram MJ: What determines anesthetic induction dose? It's the front-end kinetics, doctor! Anesth Analg 1999; 89: 541–4

4. Price HL: A dynamic concept of the distribution of thiopental in the human body. A nesthesiology 1960; 21: 40–5

5. Avram MJ, Krejcie TC, Niemann CU, Enders-Klein C, Shanks CA, Henthorn TK: Isoflurane alters the recirculatory pharmacokinetics of physiologic markers. A nesthesiology 2000; 92: 1757–68

6. Krejcie TC, Wang Z, Avram MJ: Drug-induced hemodynamic perturbations alter the disposition of markers of blood volume, extracellular fluid, and total body water. J Pharmacol Exp Ther 2001; 296: 922–30

© 2002 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Share