Propofol pharmacokinetic/dynamic changes with age
PD Dr. med. Thomas W. Schnider; Institut für Anästhesiologie; 3010 Bern; Switzerland
It is clinically obvious that the dose of propofol
must be reduced in older patients. Age can influence induction, maintenance
and recovery from anesthesia with propofol. Changes in the propofol dose versus
effect relationship are due to age related changes in pharmacokinetics and/or
pharmacodynamics. As always, the goal of optimal dosing hypnotics, is to
reduce the hemodynamic side effects and to decrease the recovery time.
Clinical observations
Early investigators observed that anesthesia could
be satisfactorily induced with 1 mg/kg in very old patients although the
recommended induction dose was 2.5 mg/kg.1,2 However, Scheepstra et al.3 also reported lower induction doses in the elderly
(66-80 year old) compared to younger patients (25-39 year old), but the dose
reduction was only 20%. The difference in the changes in arterial pressure from
baseline was pronounced. McCleane et al.4 investigated factors that influence the induction
dose of propofol in 1000 patients. They defined a minimal induction dose (MID).
This induction dose was correlated with age but even more strongly with ASA
grade. Their findings emphasize the disparity between chronological age and
physical health. The quantitative difference in the induction dose might be due
to different dosing schemes in the different studies.
It is also well know that the maintenance dose of
propofol in the elderly can be reduced. Hilton et al.5 found a negative correlation between age and dose
requirements during propofol-alfentanil anesthesia. Although the elderly
received less drug, there was a significant correlation between age and the
magnitude of blood pressure decrease. Doze et al.6 observed major blood pressure reduction in the
elderly following induction with 2 mg/kg. The propofol was dosed during surgery
according to hemodynamic changes and the requirements correlated negatively
with age. Dunnet et al.7 investigated 84 patients to determine the dose
response relationship for infusions of propofol alone to suppress consciousness
under conditions of stable anesthesia. They found a significantly lower ED50
for suppression of consciousness in the older compared to the younger patients.
Age related changes of recovery times are not as
well documented. A recent publication with the title “Aging prolongs recovery
of psychomotor functions at emergence from propofol-alfentanil anesthesia”
suggests that recovery is slower in old than in young patients. However, in
this investigation time to eye opening and extubation was not significantly
prolonged in the elderly. In another study 3 recovery from propofol-fentanyl anesthesia, measured
as time to awakening and time to orientation, was more variable in younger than
in older patients. The time to eye opening was 1.63 minutes in the young and
2.56 minutes in the older patients. In an investigation where propofol and
alfentanil were administered with the use of an objective measure of
hypnosis/sedation based on the electro-encephalogramm (BIS), no correlation
between age and recovery times were reported.8 This study included 274 patients aged 18 to 80 years.
Pharmacokinetic/Pharmacodynamic studies
To explain the clinical observations, investigation
of the relationship between dose or infusion rate and plasma concentration is
the obvious first step. Although many studies have shown a difference in the
pharmacokinetics between elderly and adults and children only few
pharmacokinetic parameter sets have formally included age as a covariate.9,10. The pharmacokinetic parameters of Schnider et al.
predict a more rapid increase in concentration at the beginning of an infusion
and a more rapid decrease in concentration
after the end of an infusion.(figure 1). In a bolus dose study of
Kirkpatrick et al.11 differences in the central volume and the metabolic
clearance were found which would explain the initially higher concentrations in
the elderly, but not a faster decrease of the concentration after cessation of
the infusion in this patient group. From pharmacokinetic studies, it can be
concluded that fast infusions and bolus doses lead to higher concentrations in
older patients.
Figure 1: Time course of concentrations during and
after a 60 minute infusion starting at time 60 min. In the elderly the concentration
increases faster during the infusion but also decreases more rapidly.
A more rapid onset of effect and a more pronounced
effect could also be due to faster equilibration between blood and plasma. None
of the published blood-brain equilibration parameters (ke0) for the hypnotic
effect (measured with the EEG) are age adjusted.12-15 For the hemodynamic side effect, Kazama et al.15 found that the onset is more delayed in the elderly
than in the younger patients.
For describing age related changes in the
sensitivity either investigation of binary response data (i.e., sleep or awake)
or of a continuous objective measure of the drug effect can be used. In one
investigation based on the EEG it was found that the sensitivity to propofol is
increased in the elderly, 14 in another study no difference was found between
young and old patients.15 Two investigations in rats would suggest that
propofol sensitivity decreases with aging.16,17 Kazama et al.15 reported that the elderly are more sensitive to the
hemodynamic effects of propofol.
Summary
In can be concluded that the induction dose (be it a
bolus or rapid infusion) must be reduced in the elderly because of a
pharmacokinetic reason. Since age is correlated with ASA status, careful
titration of the induction dose is mandatory because of the profound
hemodynamic effects in this population. Generally, the dose can be reduced for
maintenance because older patients wake up at lower concentrations. Recovery
from pure propofol anesthesia seems not to be prolonged in the elderly.