Age and intravenous anesthetic pharmacology: developing rational dosing strategies.

Talmage D. Egan, M.D.

Introduction

Clinicians have long recognized that elderly patients usually require a smaller dose of most intravenous anesthetics to produce the desired therapeutic effect while minimizing adverse effects.  Is there an "evidence-based” rationale for this practice?  Is the reduced dosage requirement a function of pharmacokinetic or pharmacodynamic factors?

Data gathered over the last twenty years from pharmacokinetic-pharmacodynamic modeling studies have provided part of the necessary scientific foundation to characterize the impact of patient covariates on drug behavior.  Of the frequently considered patient covariates (e.g., gender, age, body weight, kidney function, hepatic function, etc.), age is perhaps one of the most valuable in terms of developing a therapeutic, non-toxic dosage strategy for many intravenous anesthetics.  Age is easily measured (i.e., just ask the patient) and its influence on the pharmacokinetics and pharmacodynamics of many intravenous anesthetics has been described in some detail.

Clinical Relevance of Age in Anesthesia Pharmacology

Considering the aging of the world’s population, the clinical significance of age in the practice of anesthesia is obvious.  Anesthesiologists are frequently faced with the clinical challenge of anesthetizing older adults, sometimes even patients in their 9th or 10th decade.

The progressive “graying” of the western world’s population in recent years is well known.  The elderly (i.e., 65 years and older) represent the most rapidly growing subset of the United States population and will constitute nearly 20% of the population by the year 2030.(1)  Similar trends are evident in Europe.  A recent European study suggests that increased surgical activity in the elderly represents the biggest source of growth in the demand for anesthesia services.(2)

Remifentanil as a Prototype Example for Other Intravenous Anesthetics

The new short acting opioid remifentanil can serve as a prototype to examine the impact of age on anesthetic pharmacology.  In part because of its relatively recent introduction, remifentanil has been exhaustively studied using sophisticated pharmacologic modeling techniques.(3)  Studies specifically designed to assess the influence of age on remifentanil pharmacokinetics and pharmacodynamics have been conducted and non-linear “mixed-effects” models have been constructed that characterize the influence of age in quantitative terms.(4, 5)  Using the pharmacokinetic-pharmacodynamic parameters from these age adjusted pharmacologic models it is possible to perform computer simulations to explore the suitability of various dosage schemes.  Thus, remifentanil can be used as a model to discuss the effect of age on intravenous anesthetic pharmacology.

Age Related Changes in Remifentanil Kinetics and Dynamics

It is clear that the elderly do indeed require less remifentanil to produce the desired spectrum of opioid effects.  The reduced dosage requirement is a function of both pharmacokinetic and pharmacodynamic mechanisms, although pharmacodynamic factors dominate.(5)  Remifentanil’s EC50, the concentration necessary for 50% of maximal effect as measured by the electroencephalogram (EEG), is markedly decreased in the elderly;  in addition, remifentanil’s central clearance and central distribution volume are also decreased.(4)  Interestingly, a slower equilibration between plasma and effect site concentrations in the elderly mitigates the clinical impact of the decreased central volume of distribution.  All in all, these age related changes translate clinically into the need for a very substantial dosage reduction in the elderly (i.e., as much as 50-70%) that is based largely on the increased potency of remifentanil in older patients (i.e., a pharmacodynamic difference).

The Role of Cardiac Output in Age Related Pharmacokinetic Changes

While the physiologic mechanism of the pharmacodynamic changes remains largely unexplored, the pharmacokinetic changes may be due at least in part to alterations in drug distribution secondary to decreased cardiac output.  The lower cardiac output associated with advanced age(6) presumably results in slower drug mixing and therefore higher peak concentrations after a bolus dose.(7)  Lower cardiac output may also decrease drug delivery to metabolic organs resulting in lower clearance for some drugs (it is unclear what this may mean in the case of remifentanil).

The importance of cardiac output as it relates to the initial mixing of a drug and the achievement of its peak concentration is well known and is particularly relevant to anesthetics because they exert their effect in the first few minutes after injection.(8)  Recirculatory pharmacokinetic models plainly demonstrate the impact of circulatory changes on initial drug distribution.(9)  For example, it has been shown using alfentanil in human volunteers that intercompartmental clearance (i.e., tissue distribution) is largely determined by cardiac output.(10)  More recent data generated through the use of a sheep model demonstrates the importance of cardiac output as a critical determinant of initial propofol concentrations.(11)  Similar conclusions emerge for thiopental based on a detailed rat “physiologic” model that was scaled to humans.(12)

Although it is unknown whether reduced cardiac output is the primary underlying mechanism responsible for the pharmacokinetic changes observed in the elderly, it certainly is a plausible explanation supported by a plethora of experimental data.  This assertion is also consistent with the observation that many intravenous anesthetics appear to have a smaller central distribution volume or slower intercompartmental clearance in the elderly.(13-15)  Similar findings were recently reported for propofol in humans.(16)

It is important to emphasize that some evidence fails to support the hypothesis that reduced cardiac output is a primary mechanism responsible for the age associated changes in intravenous anesthetic pharmacokinetics.  For example, while it is frequently lower in the elderly,(6) reduced cardiac output is not a ubiquitous finding in the elderly, particularly in the absence of heart disease in well conditioned individuals.(17)  Recognizing this has perhaps led to the common clinical notion of identifying a patient’s “physiological” age instead of relying on chronological age alone.(18, 19)  Significant reductions in dosage may not therefore be necessary for physically robust elderly patients with normal body habitus and without substantial coexisting disease (e.g., for some drugs such as thiopental).  It is conceivable, of course, that some intravenous anesthetics may rapidly cause a reduction in cardiac output after injection and thereby produce the pharmacokinetic changes observed in the elderly (rather than a baseline reduction in cardiac output causing the changes).(12, 20)

Age Related Pharmacodynamic Changes for Other Intravenous Anesthetics

It is more difficult to generalize with regard to age induced pharmacodynamic changes for intravenous anesthetics.  Although the elderly clearly have a “left-shifted” concentration-effect relationship for opioids (i.e., the opioids are more potent in the elderly),(4, 21) a good deal of data suggests that they are not more pharmacodynamically sensitive to the sedative-hypnotics.  For example, there is no difference between old and young in terms of the EEG EC50 for etomidate or thiopental.(13-15)  On the other hand, recently published data suggests that both propofol and midazolam are more potent in the elderly.(22, 23)  Thus, while there is certainly general consensus that the elderly require less medication than younger patients, whether this reduced dosage requirement can be attributed to pharmacokinetic or pharmacodynamic mechanisms remains unclear for some individual agents.

Impact of Other Factors that may Correlate with Age

It is important to recognize that patient age must be viewed in concert with other covariates that are known to influence the pharmacokinetics or pharmacodynamics of intravenous anesthetics.  In the elderly, perhaps chief among these factors is body weight.  Older adults typically have a higher incidence of obesity and body weight is often an important covariate influencing the pharmacokinetics of intravenous anesthetics.

In the case of remifentanil, for example, the impact of obesity has been well described.  Remifentanil’s pharmacokinetic parameters are more closely related to lean body mass (LBM) than to total body weight (TBW).(4, 24)  To the clinician in everyday practice, this simply means that remifentanil dosing regimens should be calculated based on LBM and not TBW.  Even substantially overweight and morbidly obese patients should receive remifentanil based on LBM.  Although the obese do indeed require somewhat more medication than lean patients, the dosage increase is significantly less than what would be indicated by TBW.  For practical purposes, because the estimation of LBM requires a somewhat cumbersome calculation that is not well suited to the clinical environment, ideal body weight (IBW), a parameter closely related to LBM and one that is perhaps more easily “guestimated” by the clinician is probably an acceptable alternative.(24, 25)

This recommendation for remifentanil is consistent with knowledge gathered over many years regarding the effect of body weight on the pharmacokinetics and clinical response of other intravenous anesthetics.(26)  Scaling dosage to LBM instead of TBW has been recommended for thiopental, methohexital, muscle relaxants and propofol, among others.(27-32)

The Importance of Pharmacokinetic Simulations

Computer simulations of various dosing strategies are perhaps the most clinically meaningful way of understanding the effect of age (and weight) on intravenous anesthetic behavior.  Pharmacokinetic simulations of remifentanil and propofol administration using pharmacokinetic models that account for age and weight (4, 16, 22) can be combined with knowledge about the concentration-effect relationship to develop rational dosing strategies.

References

 

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