Anesth Analg 1999;88:667
© 1999 International Anesthesia Research Society
GENERAL ARTICLES
Isobolographic Analysis of Propofol-Thiopental Hypnotic Interaction in Surgical Patients
H. Ronald Vinik, MD*,
Edwin L. Bradley, Jr., PhD , and
Igor Kissin, MD, PhD
Departments of
*Anesthesiology and
Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; and
Department of Anesthesia, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
Address correspondence and reprint requests to H. Ronald Vinik, MD, Eye Foundation Hospital, Department of Anesthesia, 1720 University Blvd., Birmingham, AL 35233. Address e-mail to ronald.vinik{at}ccc.uab.edu
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Abstract
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Drugs acting via the same mechanism interact additively, whereas a supraadditive effect can result from an interaction of drugs with different mechanisms of action. Hypnotic midazolam-propofol and midazolam-thiopental interactions are supraadditive. In contrast to midazolam, the mechanisms of actions of propofol and thiopental are quite similar. The aim of this study was to test the hypothesis that similarity in the mechanisms of action of propofol and thiopental results in the additive hypnotic interaction. We studied the hypnotic effects of thiopental, propofol, and their combinations in 150 unpremedicated patients in a randomized, double-blind fashion. The ability to open eyes on command was used as an end point. Dose-response curves for the drugs given separately and in combinations at three different dose ratios between the drugs were determined by using a probit procedure, and the 50% effective dose values were compared by using isobolographic and algebraic (fractional) analysis. The hypnotic propofol-thiopental combination was additive with all dose ratios between components of the combination. The absence of propofol-thiopental synergy, as demonstrated with midazolam-thiopental or propofol-midazolam combinations, suggests that the mechanisms underlying the hypnotic effects of propofol and thiopental, in contrast to the above combinations with midazolam, are very similar and could be identical.
Implications: The propofol-thiopental hypnotic interaction is additive.
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Introduction
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Acommon feature of general anesthetic action is facilitation of the inhibitory neurotransmission mediated by  -aminobutyric acid (GABA) (1,2). Actions as the GABAA receptor/chloride channel complex are the dominant effect for a number of IV drugs, including barbiturates, benzodiazepines, and propofol. The enhancement of GABAergic inhibition can be provided via different mechanisms (1). For example, benzodiazepines, barbiturates, and propofol potentiate GABA-induced changes in the GABAA receptor/chloride channel complex; however, benzodiazepines—in contrast to barbiturates or propofol—cannot directly activate the chloride channel coupled to the GABAA receptor (3–5).
Drugs acting via the same mechanisms interact additively, whereas synergy can result from interactions of drugs with different mechanisms of action. Therefore, pronounced synergistic midazolam-thiopental (6,7) or midazolam-propofol (8–10) hypnotic interactions observed in surgical patients could be regarded as a confirmation of differences in the mechanisms of actions at the GABAA complex by the respective components of the combinations. Although both barbiturates and propofol enhance GABAergic inhibition by similar mechanisms, these drugs may, in principle, interact with the GABAA complex at distinct recognition sites (11). Naguib and Sari-Kouzel (12) reported that the propofol-thiopental hypnotic interaction is synergistic. However, the deviation of the interaction outcome from simple addition observed in their study was very small, and its statistical significance is questionable. The aim of this study was to test the hypothesis that similarity in the mechanisms of action of propofol and thiopental results in an additive hypnotic interaction.
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Methods
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One hundred fifty unpremedicated ASA physical status I or II adult (18–60 yr old) patients weighing 45–90 kg and scheduled for eye surgery participated in this randomized, double-blind study. Those who had received benzodiazepines or opioids within 1 wk of the investigation were excluded. As an end point of hypnotic effect, the abolition of the ability to open the eyes on command was used.
The drugs were injected in an upper extremity over 10 s into a rapidly flowing IV infusion. When drugs were given in combination, propofol was injected first, followed by thiopental. When only one of the drugs was given, the missing drug injection was substituted with the injection of saline. The end point was determined 2–3 min after the last injection by an investigator who was unaware of which drug or dose had been used. Patients who did not respond to two consecutive verbal commands with a 5-s interval were assumed to be unconscious. After determination of the end point, the patient received an additional dose of propofol, if necessary, to obtain an adequate depth of anesthesia to continue regular anesthetic management.
Patients were randomly (blocked randomization) assigned to one of the subgroups of five patients indicated in Table 1. Each subgroup received one predetermined dose of a drug or a drug combination. In the combined subgroups, dose ratios based on hypnotic equipotency were used. The doses in the subgroups for the combined groups (B, C, D) were increased in proportionate dose steps, maintaining the dose ratio constant. The selection of the doses and the dose ratios between the components was based on the data obtained in our previous studies (10,13,14).
The percentages of patients who reached the end point were converted into probit values and plotted against logarithmic values for the respective dose (15). The 50% effective dose (ED50) values determined by using probit analysis in all groups (A–E) of patients were used for algebraic (fractional) and isobolographic analyses of the drug interaction (16,17). With isobolographic analysis, a straight line joining the single-drug ED50 points is the additive line (Fig. 1); the deviation of a combined ED50 point to the left of the additive line indicates a supraadditive effect (synergy); to the right, an infraadditive effect. With algebraic (fractional) analysis, the component doses of the drug combinations are expressed as fractions of the doses that produce the same effect when given alone. The sum of fractional doses of a combination equals 1.0 in additive effect; in supraadditive effect, the sum is <1.0.
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Figure 1. Fifty percent effective dose (ED50) isobologram for the hypnotic interaction of thiopental and propofol. ED50 values generated by probit analysis indicate the dose level that provides the effect in 50% of the patients. A and E are ED50 values for thiopental and propofol given alone. B–D are ED50 values for the thiopental-propofol combinations with different dose ratios. The dashed straight line connecting the single-drug ED50 points, A and E, is an additive line. In the small box are numerical ED50 values with 95% confidence limits (in parentheses) for thiopental (T) and propofol (P). The deviation of Point D from the additive line was statistically insignificant (P > 0.50). With all three dose ratios, isobolographic analysis demonstrated an additive interaction.
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Statistical significance of the deviation of the combined ED50 point from additivity was determined as described previously (10,18) by using a propagation of error method (19) (sometimes called statistical differential) using error estimates from a combined ED50 point, as well as single-drug ED50 points, in the calculations. The statistical differential technique is a standard method for computing standard errors of nonlinear functions of random variates (20), which occurs in the present case because our statistic is a sum of ratios of ED50 values. An approximate t-test used to test the assumption of additivity was obtained as the difference of the sum of fractions minus unity all divided by the standard error (21).
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Results
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The study groups were comparable with respect to age, weight, and gender. Figure 1 presents the results in the form of an isobologram. The single-drug ED50 values were (mg/kg): 2.17 (95% confidence limits 1.93, 2.44) for thiopental and 1.01 (0.86, 1.17) for propofol. For thiopental-propofol combinations, the ED50 values were (1.79 (1.35, 2.37) for thiopental and 0.18 (0.14, 0.23) for propofol given in the 1:0.1 dose ratio; 1.04 (0.89, 1.22) for thiopental and 0.52 (0.45, 0.61) for propofol given in the 1:0.5 dose ratio; and 0.31 (0.26, 0.38) for thiopental and 0.78 (0.64, 0.96) for propofol given in the 1:2.5 dose ratio. None of the combined ED50 points had any significant deviations from the additive line. The fractional analysis of thiopental-propofol interaction indicates that, with two dose-ratios, the sums of fractional doses were 1.00 (Table 2). With the third dose-ratio (high propofol-low thiopental group), the sum of fractional doses was 0.92; however, the difference from the unity (indicating additive interaction) was too small to provide a possibility for statistical significance (P > 0.50).
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Discussion
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The single-drug ED50 values for thiopental and propofol were very close to those obtained in previous studies (6–10,13,14). Our results indicate that hypnotic interaction of propofol and thiopental is additive with all three ratios of propofol-thiopental combinations. This outcome is different from those for propofol-midazolam or thiopental-midazolam hypnotic interactions that demonstrated a profound synergism (6–10). The disparity may be explained by the significant differences in the mechanism of the hypnotic action of midazolam compared with that of propofol or thiopental. Midazolam acts on the GABAA complex via specific benzodiazepine receptors that can be blocked by selective antagonists. In contrast to thiopental or propofol, benzodiazepines did not activate the GABAA channel directly; they only potentiate the effect of GABAA agonists (5). In mice without the ß3 subunit of the GABAA receptor, the hypnotic effect of midazolam, but not that of the barbiturate pentobarbital, is attenuated, which suggests that these two drugs produce hypnosis via different specific molecular mechanisms (22).
The discrepancy between our results and those of Naguib and Sari-Kouzel (12) is most likely due to the problem associated with the determination of statistical significance of the deviation of interaction outcome from additivity in their study.
In conclusion, our data indicate that the hypnotic propofol-thiopental interaction is additive. The absence of synergy (as demonstrated for midazolam-thiopental or propofol-midazolam combination) suggests that the mechanisms underlying the hypnotic effects of propofol and thiopental, in contrast to the two above combinations, are very similar and could be identical. The additive interactions simplify the calculations for the combined use of thiopental and propofol for the induction of anesthesia. Such use may be accepted because of cost-containment considerations.
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Acknowledgments
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This study was supported in part by National Institutes of Health Grant GM-35135.
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Accepted for publication November 30, 1998.
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Abstract
Introduction
