Daily clinical practice indicates that elderly patients often require smaller doses of intravenous (i.v.) anaesthetics. Some investigations have demonstrated an increased sensitivity to several anaesthetics or analgesics in the elderly, e.g. for thiopental , etomidate  or remifentanil , which are best explained by age-dependent changes of pharmacokinetics and/or pharmacodynamics. For propofol pharmacokinetics, some investigators have shown age-dependent effects [4,5]; for propofol pharmacodynamics, Schnider and colleagues  reported that elderly patients in a laboratory setting were more sensitive to the hypnotic and EEG effects of propofol than were younger persons.
It was the aim of the present study to investigate possible age-dependent effects of EEG-guided propofol infusion rates during propofol-remifentanil anaesthesia under clinical conditions. For EEG guidance we used the Narcotrend EEG-monitor (MonitorTechnik, Bad Bramstedt, Germany), a system that performs an automatic EEG analysis based upon a multivariate statistical algorithm which has recently been described in detail . Narcotrend analysis (version 2.0 AF) results in a six-letter-classification from A (awake) to F (general anaesthesia with increasing burst suppression) including 14 substages (A, B0-2, C0-2, D0-2, E0,1, F0,1). Meanwhile, comparative studies between Narcotrend monitoring and bispectral index analysis have shown corresponding results of both monitors during propofol-remifentanil anaesthesia [8,9] and moreover, several studies indicate the favourable use of the Narcotrend to titrate anaesthesia in clinical practice [7,10].
Materials and methods
With institutional review board approval and written informed consent 200 Caucasian patients scheduled for minor orthopaedic surgery expected to last at least 1 h were prospectively studied. Patients had to be aged 16 yr or older and ASA I, II or III. Exclusion criteria were a history of substance abuse, any disabling central nervous or cerebrovascular disease, treatment with opioids or any psychoactive medication. Furthermore, renal and hepatic function had to be within normal limits according to the medical history and to laboratory analysis.
All patients were premedicated with diazepam 0.15 mg kg−1 orally on the day of surgery. In the operating room an i.v. catheter was inserted into a larger forearm vein and standard monitors were applied. For Narcotrend EEG analysis the skin of the forehead was degreased with 70% isopropanol and Narcotrend electrodes (Blue sensor™; Medicotest, Olstykke, Denmark) were positioned as recommended by the manufacturer: two electrodes were placed on the patient's forehead with a minimum distance of 8 cm, a third electrode was positioned laterally serving as a referential electrode. Finally, impedances were measured to ensure optimal electrode contact which is defined as ≤6 kΩ by the manufacturer.
Induction of anaesthesia was started with a remi-fentanil infusion at 0.4 μg kg−1 min−1; 5 min later 2 mg kg−1 propofol were given for hypnosis. After loss of consciousness oxygen was given by facemask ventilation, patients received 0.5 mg kg−1 of atra-curium, the trachea was intubated 3 min later, and the lungs were ventilated to an end-tidal carbon dioxide concentration of 35 mmHg. The propofol infusion rate was decreased or increased in steps of 0.5-2 mg kg−1 h−1 to reach the target Narcotrend stage as soon as possible; additional propofol bolus doses were not given. Immediately after intubation, remifentanil was reduced to a constant rate of 0.2 μg kg−1 min−1 and, concomitantly, the propofol infusion was started with 3 mg kg−1 h−1 and then adjusted according to a target Narcotrend stages of D0-2. The propofol infusion rate was decreased or increased in steps of 0.5 mg kg−1 h−1. Further propofol boluses were not planned. During maintenance of anaesthesia all patients were ventilated with 50% oxygen in air.
Twenty minutes before the expected end of surgery neuromuscular blockade was studied by train-of-four and double burst stimulation monitoring, and neuromuscular recovery was judged sufficient when both stimulation patterns indicated no fade. At the same time, all patients received a 100 mL infusion of normal saline containing metamizol 25 mg kg−1 for postoperative pain relief (metamizol is a pyrazolone non-steroidal anti-inflammatory agent).
The end of surgery was defined as the last surgical suture when propofol and remifentanil delivery was stopped without tapering, and the time to unstimulated opening of eyes was determined. All patients were visited in the postanaesthesia care unit and on the first and third postoperative day and interviewed about intraoperative recall.
End-points and statistical analysis
The primary end-point of this study was defined as the propofol consumption given in mg kg−1 h−1. The propofol consumption was calculated from the total amount of infused propofol but without the induction bolus, from the actual body weight and the duration of propofol infusion. Primarily, age dependency of propofol consumption and recovery time was analysed by linear regression analysis. For further analysis, the patients were divided into four groups according to their age of ≤30, 31-50, 51-70 and >70 yr, and propofol consumption as well as recovery time were calculated accordingly. In addition, at different time points during anaesthesia, propofol infusion rates were calculated in mg kg−1 h−1 from the actual infusion rate and the actual body weight. Furthermore, we have analysed the fractions of time that the Narcotrend values were within or without the target values. For nominal data, statistical analysis was performed by means of a Χ2-test, for numerical data by one-way analysis of variance (ANOVA) with Student-Newman-Keuls test for multiple comparisons. All tests were two-tailed with statistical significance defined as P < 0.05; data are presented as mean and standard deviation (SD). For statistical calculations and figures SigmaStat™ 2.03 and SigmaPlot™ 2000 computer software (SPSS GmbH, Erkrath, Germany) were used.
Two hundred patients were enrolled in this study. Patient characteristics data and the duration of surgery are displayed in Table 1. The participants of the study were 46.6 ± 18.5 (range: 16-83) yr old. Problems with skin adherence of the electrodes were not observed; none of the electrodes fell off. In all patients the propofol bolus dose of 2 mg kg−1 was sufficient to obtain a Narcotrend stage of D0 or lower so that an additional bolus dose of propofol was not necessary in any patient. No patient complained of intraoperative recall, neither during intubation nor during the further course of anaesthesia.
Narcotrend target values
The time fractions of actual (vs. targeted) Narcotrend values obtained during maintenance of anaesthesia were analysed: Narcotrend data were within a range of D0-2 during more than 85% of the study period. During 0.4% of the time Narcotrend stage C2 was found whereas during 13.4% of the time Narcotrend stages E0,1 and F0 were observed. The time fractions of the different Narcotrend stages were comparable for all age groups (Table 2).
A comparison of the average actual propofol infusion rates at predefined time points during anaesthesia showed lower infusion rates with increasing age (Fig. 1). Concomitantly, the average normalized propofol consumption calculated from the maintenance doses decreased with patient age. Mean propofol consumption was significantly lower for patients aged 51-70 yr (4.5 ± 1.7 mg kg−1 h−1) when compared to younger patients aged ≤30 yr (5.9 ± 1.7 mg kg−1 h−1) or 31-50 yr (5.4 ± 1.8 mg kg−1 h−1, P < 0.05). The propofol consumption of the patients >70 yr (3.5 ± 1.4 mg kg−1 h−1, P < 0.05) was significantly lower than for the three younger groups. When applying a linear regression analysis, mean propofol consumption decreased with increasing age with:
However, there was a substantial inter-individual variability of propofol consumption values for all age groups.
With Narcotrend monitoring male patients received 6.7 ± 2.2 mg kg−1 h−1 and female patients 5.9 ± 2.1 mg kg−1 h−1 of propofol but the difference was not significant. Furthermore, the propofol amount significantly decreased with the ASA classification (i.e. for ASA I, II and III, 7.2 ± 2.2, 6.3 ± 2.1 and 5.3 ± 1.9 mg kg−1 h−1, respectively). However, it must be noted that ASA physical status and age are not independent from each other, e.g. all ASA III patients were older than 60 yr.
Recovery time, defined as the time from stopping the propofol infusion to spontaneous opening of eyes, increased with patient age. The recovery time was significantly shorter for patients aged ≤30 yr with 7.4 ± 3.7 min when compared to older patients of 31-50 yr (9.5 ± 4.0 min) or 51-70 yr (9.8 ± 4.1 min, P < 0.05). Patients >70 yr needed significantly more time to open eyes (14.9 ± 12.1 min, P < 0.05) than all younger patient groups. With linear regression analysis age dependency of the recovery time was described as:
However, as already observed for propofol consumption, the recovery time showed a marked inter-individual variability for all age groups.
This study was designed to investigate the impact of patient age on propofol consumption and recovery time during a propofol-remifentanil anaesthetic. We investigated a total of 200 patients undergoing minor orthopaedic surgical procedures. Remifentanil was infused at a constant rate of 0.2 μg kg−1 min−1 whereas propofol was titrated to EEG effect, i.e. to a target Narcotrend stages of D0-2. We could show that average normalized propofol consumption decreases with increasing patient age. However, as a result of large inter-individual variability, age per se does not allow a prediction of the individual propofol need. The latter is also true for the recovery time after propofol infusion while the mean time to opening of eyes increased with increasing patient age.
Propofol titration guided to clinical end-points
Our results compare well with the results of different clinical studies in which the individual propofol dosage was solely titrated according to clinical needs. Scheepstra and colleagues  investigated 20 young patients aged 25-40 yr and 20 old patients aged 65-85 yr, both groups receiving a propofol-fentanyl anaesthetic. The propofol maintenance doses were significantly different with 10.0 ± 1.3 mg kg−1 h−1 for the younger and 8.6 ± 1.1 mg kg−1 h−1 for the older patients. This was also true for the time to opening of eyes with 7.8 ± 3.0 vs. 14.3 ± 9.9 min. In a study by Doze and colleagues  60 patients received a propofol-N2O anaesthetic, and propofol infusion rates were controlled using haemodynamic end-points. Applying a linear regression analysis, these authors reported a relationship between patient age and the mean propofol infusion rate as propofol (mg min−1) = 12.5 − 0.10 × age (yr) (R = 0.61).
Narcotrend-guided propofol titration
In contrast to these investigations purely based on clinical criteria we used an EEG monitor designed to measure the depth of anaesthesia for individual titration of the propofol infusion rate. The Narcotrend monitor uses a multivariate statistical algorithm based on the recognition of EEG patterns, and both the algorithm as well its clinical applicability have recently been described in detail . The Narcotrend stages D0-2 are assigned to increasing delta activity, i.e. 30%, 50% and 80%, indicating general anaesthesia. Age-related changes in the EEG are incorporated in the Narcotrend algorithm . In another study we were able to demonstrate that increasing depth of anaesthesia as indicated by BIS monitoring is accompanied by corresponding effects displayed by the Narcotrend monitor with the Narcotrend stages D0-2 being equivalent to a bispectral index of 45-50 . Meanwhile, Schmidt and colleagues  have also reported comparative results of bispectral index and Narcotrend monitoring during propofol-remifentanil anaesthesia.
Pharmacokinetics and pharmacodynamics
For an explanation of the presently observed results, both pharmacokinetic and pharmacodynamic mechanisms must be considered, i.e. that a defined dose of propofol produces higher drug concentrations in an elderly patient and that the same propofol concentration produces a more profound anaesthetic effect . When comparing the pharmacokinetics of a propofol bolus, Kirkpatrick and colleagues  could demonstrate that mean propofol blood concentrations tended to be higher in elderly (65-80 yr) than in younger (18-35 yr) patients, best explained by a significantly lower metabolic propofol clearance and a smaller volume of the central compartment. Furthermore, Schüttler and Ihmsen found a linear decrease of the propofol elimination clearance in patients older than 60 yr . These findings may be explained by a reduction of liver function or liver blood flow in elderly patients , as the propofol clearance has been characterized as liver blood flow dependent .
For propofol pharmacodynamics, age-related changes of brain function must be considered. Comparing a 20- and a 90-yr-old individual, brain undergoes an age-dependent weight reduction of approximately 10%, while the gray matter decreases more than the white matter . Concomitantly, the cell number of the frontal cortex decreases by approximately 40% . Our clinically obtained data are supported by results of Schnider and colleagues  who, in a laboratory setting, reported that elderly patients were more sensitive to hypnotic and EEG effects of propofol than were younger persons. However, it must be taken into consideration that EEG itself as an indicator of brain function undergoes age-dependent changes. These changes may include slowing of the dominating rhythm, especially of the alpha frequency, a reduction of the amplitude including passages of curve flattening and an increased occurrence of theta waves . Thereby, these age-dependent changes of the raw EEG might hypothetically interfere with its interpretation as a measure of anaesthetic drug effect.
In conclusion, we could show that if Narcotrend guidance is used for titration of propofol effect, aging leads to a reduction of mean propofol consumption while recovery times increase. However, because of large inter-individual variability, age per se does not allow a prediction of the individual propofol need or the time span until awakening.
The Narcotrend monitor was provided by AstraZeneca, Wedel, Germany. The study itself was solely supported by departmental funding.
Results of this investigation were presented in part at the Euroanaesthesia 2003 meeting, Glasgow, UK.
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