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*Servicio de Anestesiología y Reanimación,
Unidad de Investigación, Hospital de Basurto, Bilbao, Spain
Address correspondence and reprint requests to Dr. M. Olmos Rodríguez, Servicio de Anestesiología y Reanimación, Hospital de Basurto, Avenida de Montevideo 18, Bilbao 48013, Spain.
Abstract
In this prospective study, we evaluated the combined influence of age and premedication on propofol requirements for the induction of anesthesia and their hemodynamic effects using a target-controlled infusion. We studied 180 patients separated into three age groups: 20–39 yr, 40–59 yr, and more than 59 yr. In each age group, patients were randomly allocated to receive either no premedication (n = 20), fentanyl (2 µg/kg) (n = 20), or midazolam (0.03 mg/kg) plus fentanyl (2 µg/kg) (n = 20). The concentration of propofol targeted for the induction was 5 µg/mL, to be reached in 2 min. The dose, time, and predicted plasma concentration of propofol at hypnosis were measured. Baseline and postinduction heart rate and arterial blood pressure were registered. Computer simulation was used to calculate the effect site propofol concentration at hypnosis. The concentration of propofol, effect site propofol concentration, time, and induction dose and their hemodynamic effect were significantly different among groups with respect to age and premedication. The combined effect of the two factors was additive, but without significant interaction. The propofol requirements were significantly less in the midazolam-fentanyl groups, regardless of age, and among the premedicated patients older than 60 yr compared with the other age groups. We conclude that the combined effect of age and premedication on the requirements of propofol for the induction of anesthesia should be considered when the concentration is targeted with a target-controlled infusion system.
Implications: Induction of anesthesia by using a target-controlled infusion system is influenced by both age and premedication. We define the effect site propofol concentration required for hypnosis with an alternative system to that of plasma-effect site equilibration. These findings may have an impact on the induction with pumps targeting an effect site concentration.
Propofol requirements to achieve loss of consciousness depend on the interindividual variability and on the interaction with other drugs administered at the same time. Marked sensitivity to propofol in elder patients with respect to both the induction dose and hemodynamic effects has been described (1–4). The induction dose of propofol is up to 40% smaller in elderly patients than in younger patients (1–3). The influence of age on the pharmacokinetics and pharmacodynamics of propofol has been recently confirmed (4,5).
The characteristics of the induction of anesthesia with propofol alone or in combination with fentanyl or benzodiazepines have been reported (6–9). The hypnotic synergism between propofol and opiates is moderate and shows a ceiling effect (7). In contrast, the synergism with benzodiazepines is stronger than with opioids, resulting in an important reduction in the dose of propofol required to produce anesthesia (8,9). When given with propofol, fentanyl, but not midazolam, can increase postinduction hypotension (8–10).
To date, studies have focused mainly on the individual effects of age or premedication for the induction of anesthesia. We are not aware of published data combining these factors. The objectives of our study were: 1) to determinate the combined effect of age and premedication on propofol induction requirements by using a target-controlled infusion system, 2) to predict the propofol concentration in the biophase at induction in these patients, and 3) to evaluate the influence of those two factors on the hemodynamic effect of propofol induction.
Method
This prospective study was approved by our institutional review board, and written informed consent was obtained from each patient. We studied 180 patients, ASA physical status I or II, scheduled for surgery under general anesthesia. We excluded patients with a history of cardiac, hepatic, or renal pathology, obesity (body mass index of >30 kg/m2), abuse of alcohol or drugs, and habitual treatment with benzodiazepines, opiate, or psychotropic drugs. The patients were stratified according to age into three groups of 60 persons each: 20–39 yr (Group I), 40–59 yr (Group II), and more than 59 yr (Group III). In each age group, patients were randomly allocated to receive no premedication (Group A), 2 µg/kg fentanyl (Group B), or 0.03 mg/kg midazolam and 2 µg/kg of fentanyl (Group C). Nine parallel groups, with 20 patients in each, were established.
After premedication, we waited for 5 min before beginning the induction of anesthesia. Propofol was administered by a Pilot perfusion pump (Becton Dickinson Infusion Systems, St Etienne de St Geoirs, France) incorporating the Diprifusor subsystem (Zeneca Ltd, Macclesfield, Cheshire, UK). Prefilled syringes of propofol 1% were used, and a target blood concentration of 5 µg/mL propofol was programmed to be reached in 2 min. A blinded investigator evaluated the hypnosis defined by both the loss of response to verbal commands and the absence of eyelid reflex. Response to call was assessed every 10 s, and the eyelid reflex was evaluated at 5-s intervals from the loss of verbal response. If hypnosis was achieved before the predetermined 2-min period, the target concentration was reduced to the new hypnosis concentration. If hypnosis was not achieved within the 2 min, the target concentration was increased by 1 µg/mL, at 1-min intervals, until the induction of anesthesia was completed. No other anesthetic drugs were administered during the study period.
Induction time was measured by the other investigator, and the predicted plasma concentration and the propofol dose for successful induction registered from the display of the infusion pump. To evaluate the hemodynamic response, the heart rate (HR), systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) were recorded on arrival to the operating room (baseline value) and immediately after the induction. The hemodynamic response to the induction was defined for each patient as the percentage change of baseline value. To determine the predicted effect site concentration of propofol at the time of hypnosis (Ce), we used the simulation software Stanpump (S. Shafer, Stanford University, Stanford, CA). The computer simulation was programmed to predict the effect site concentration based on the time to achieve the hypnosis and by using the same pharmacokinetic variables and identical target concentration incorporated in the Diprifusor.
The inclusion of 20 patients in each group was calculated to enable detection of a 25% reduction in propofol requirements with a Type I error of 0.05 and a statistical power of approximately 80%. Data were analyzed by using the statistical program SPSS 6.0 (SPSS Inc., Chicago, IL). All results were expressed as mean ± SD and absolute values. We studied the influence of age and premedication on the quantitative variables by using two-way analysis of variance (ANOVA) and the Tukey test for post hoc contrasts. Multiple regression analysis was used to evaluate the relationship among patient age, considered as a continuous variable, premedication, and Ce. In each age-premedication group, we compared the hemodynamic postinduction values with baseline by using the Student’s t-test for paired data. The qualitative variables were compared by means of 
2. A statistical significance level of P < 0.05 was established for all tests.
Results
There were no significant differences in body weight and gender distribution among the nine groups. Height was significantly lower in the patients over 60 yr (ANOVA P < 0.001) (Table 1).
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We confirmed the additive effect of age and premedication on propofol induction, but we could not demonstrate significant interaction. We found a 37% reduction in the Ce for hypnosis in the patients over 60 years compared with those under 40 years. The propofol requirements for the induction of anesthesia decreased approximately 8% for each 10-year increase in age in unpremedicated patients, 10% in fentanyl premedicated, and 17% in midazolam-fentanyl group. These results agree with previous reports on the effect of age on propofol requirements (1–4,7). The documented pharmacokinetic changes in the elderly (5,11) could explain in part this increased sensitivity, but the effects of aging on propofol pharmacodynamics are probably more important. Using electroencephalogram measures and responsiveness to verbal command, Schnider et al. (4) showed that age increases the sensitivity of the brain to propofol. The observed age effect on propofol Ce in our patients is consistent with those findings. The interindividual variability in the ke0, which characterizes the equilibrium of the drug with the effect site, could also contribute to this reduction of propofol requirements (12,13).
As in previous studies, we found a small reduction by fentanyl in the propofol requirements for hypnosis (7,14). In contrast, the premedication with midazolam decreased the Ce by 55%. The hypnotic synergism between propofol and benzodiazepines has been described in several studies, and it depends on the administered dose (8,9). The association of opiates with benzodiazepines produces a larger decrease in the 50% effective dose of propofol, but no further synergism among the three drugs occurred that were observed for the pairwise combinations (15,16). Although a pharmacokinetic mechanism is possible, the interaction between propofol and midazolam can be attributed more to increased pharmacodynamic sensitivity (8,9,15).
When we analyzed the combined effect of age and premedication, we did not find a significant interaction. Smith et al. (7) observed a reduction of the plasma concentration of propofol required to prevent a response in 50% of patients to verbal commands with increasing age, which was increased after fentanyl by an additive effect. Some studies have demonstrated that elderly patients are more sensitive to the sedative action of midazolam or fentanyl (17–19). We expected that the effect of the premedication was greater in the patients over 40 years, and some age-premedication interaction was proved. However, the reduction of propofol requirements caused by the premedication was similar in all age groups. The reasons for this discrepancy are not clear.
Reductions in arterial blood pressure and HR usually occur during the induction of anesthesia with propofol and are influenced by the dose and rate of administration (3,20,21). The mechanism of the blood pressure decrease after propofol is still debated, but it is mainly the result of a decrease in pre- and afterload without compensatory increases in heart rate or cardiac output (20,22). This cardiovascular depression is more pronounced in elderly than in younger patients (1,2,23). In our study, patients over 60 years showed reductions in SAP close to 20%, but less than those referred by other authors with conventional systems of administration (1,2). The use of target-controlled infusion could justify this smaller hemodynamic effect (21). Like Kazama et al. (23), we found more severe hypotension in elderly patients despite smaller propofol concentrations, which suggests a pharmacodynamic mechanism.
When given with propofol, fentanyl can increase the postinduction hypotension (10,21). Billard et al. (10) recorded a decrease in systolic blood pressures of 40% during the induction with bolus doses of propofol and fentanyl 2 µg/kg. We found a smaller decrease in SAP, probably because we did not use a fixed dose of propofol but titrated the induction infusion against clinical effect, resulting in a smaller dose of propofol. When we added midazolam, hypotension did not increase significantly in comparison with the groups premedicated with fentanyl only, in accordance with previous studies (8,9,24).
In conclusion, we confirmed the influence of age and premedication on the propofol requirements to induction with target-controlled infusion and on their hemodynamic effect. The combined effect of both factors is additive, but we found no significant interaction between them. The choice of a target plasma concentration of propofol should include these factors, especially in patients over 60 years and when benzodiazepines are used as premedication.
References
This article has been cited by other articles:
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  E. Gurses, H. Sungurtekin, E. Tomatir, and H. Dogan Assessing Propofol Induction of Anesthesia Dose Using Bispectral Index Analysis Anesth. Analg., January 1, 2004; 98(1): 128 - 131. [Abstract] [Full Text] [PDF]
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 D. J. Casarett, S. K. Inouye, and for the American College of Physicians-American So Diagnosis and Management of Delirium near the End of Life Ann Intern Med, July 3, 2001; 135(1): 32 - 40. [Abstract] [Full Text] [PDF]
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