In the past several decades, there has been a dramatic increase in the percentage of the world’s population that is elderly, defined as people 65 years or older. This trend is projected to continue to increase in the future.1 Understanding core principles of perioperative care of the elderly, particularly in the context of clinical pharmacology, will become increasingly more important for clinicians.
As people age, there are important changes in physiology and response to pharmacologic interventions. Aging consists of the deterioration or loss of functional units (eg, neurons, nephrons, or alveoli) at the cellular, tissue, or organ level, as well as disruption of regulatory processes at the molecular level.2 Basal organ function, in the otherwise healthy individual, is relatively preserved with aging,3 but functional reserves and the ability to tolerate stress, such as occurs with anesthesia and surgery, declines significantly with age. However, with regard to organ function, wide intraindividual and interindividual variability does exist.4 That is, biologic age does not linearly correlate with physiologic or medical age. The geriatric population is unique in its physical and medical heterogeneity, which only increases with advancing age. Acute or chronic disease states, genetics, environmental, socioeconomic and likely countless other factors play into the rate or degree of organ function decline. Advanced age, nevertheless, has been shown by many studies to be an independent predictor of perioperative outcome (Table 25–1).
| Physiologic Changes With Age | Consequences of Changes | |
|---|---|---|
| Cardiovascular | Increased: systolic blood pressure, pulse pressure, sinoatrial node conduction time5 Decreased: LV compliance, β1-receptor response, heart rate,6 VO2 max (10% per decade between age 20 and 80),7 compliance of aorta and great arteries8 | Increased: LV wall thickness, LV chamber size, LV mass, oxygen demand9 Decreased: chronotropic responses to noxious stimulus or β agonist, ability to compensatorily increase cardiac output |
| Pulmonary | Increased: work of breathing, physiologic shunt, ventilation/perfusion mismatch, residual volume, closing capacity Decreased: FEV1 (8%–10% per decade), chest wall compliance, vital capacity, respiratory muscle strength, maximal minute ventilation | Increased: propensity for hypoxemia, atelectasis Decreased: functional reserve to deal with stresses of anesthesia/surgery, gas exchange, arterial oxygenation, respiratory mechanics |
| Neurologic | Increased: enzymatic activity that leads to neuronal degradation Decreased: brain mass, neurotransmitter synthesis, hypoxic drive, hypercarbic ventilatory drive | Increased: propensity for postoperative delirium, cognitive dysfunction (41% and 13% at 3 months)9 Additional risk factors include anticholinergics, opioids, preexisting cognitive impairment, blood urea nitrogen–to–creatine ration greater than 18, fever, blood loss, infections) |
| Renal | Maintained: acid–base balance Decreased: number of nephrons, renal mass, glomerular filtration rate and renal blood flow (30%–50% by age 70) | Decreased: clearance of certain drugs, urine concentrating ability during water deprivation10 |
| Hepatic | Decreased: hepatic blood flow and volume, first-pass metabolism, mass (decreased 40% by age 80) | Increased: bioavailability of drugs that undergo significant first-pass metabolism (eg, labetalol, propranolol)11 Decreased: onset/effectiveness of prodrugs (eg, ACE inhibitors) |
Blood albumin concentration is decreased by approximately 10% in the elderly. This decrease has been associated with an increase in unbound fraction of many drugs. Acidic compounds (eg, salicylic acid, phenytoin, warfarin) bind primarily to albumin, while basic compounds (eg, lidocaine, propranolol) bind to α1-acid glycoprotein.5 Drugs that are highly extracted by the liver or highly protein bound are more affected, including fentanyl, propofol, midazolam, and lidocaine.6 Volume of distribution is affected by aging, related to age-related changes in body composition. Body fat increases by 20% to 40% and body water percentage decreases by 10% to 15%.7 Polar drugs that are mainly water soluble will have higher serum levels in the elderly due to their smaller volume of distribution.8 Nonpolar drugs, on the other hand, tend to be lipid soluble and therefore tend to have an increased volume of distribution and longer half-life in the elderly.
Altered drug absorption, distribution, metabolism, and excretion lead to different drug concentrations in the body for a given dose in the elderly compared with younger people (pharmacokinetics). Evidence also exists for a pharmacodynamic explanation for decreased anesthetic requirements in the elderly, with increased sensitivity for any given plasma concentration of certain drugs.
Propofol sensitivity is increased by about 30% to 50% in the elderly compared with younger patients, independently of the decrease in drug clearance. This is due to age-related changes of the central nervous system.9 Studies have shown this increased sensitivity using electroencephalographic (EEG) measures, probability of responsiveness to verbal stimulus, and insertion of an endoscope. When 75-year-old volunteers were compared with 25-year-old subjects, effect-site concentrations of propofol needed to achieve a similar state of unconsciousness were about half in the older individuals.10
Age does not affect brain sensitivity to thiopental using EEG as a measure of effect, but there is slower intercompartment clearance in the elderly, leading to higher serum concentrations, for longer period of time, in the elderly versus young patients. This leads to a greater, longer lasting, clinical effect, following an intravenous bolus of thiopental in the elderly.11
One study examining etomidate, however, showed no significant increased brain sensitivity with aging, based on no observed age-related changes in the IC50 for etomidate, where the IC50 is the blood concentration (ng/mL) that produces 50% of the maximal median frequency depression on EEG. The administered dose needed to reach a uniform EEG end point, however, was decreased significantly in the elderly. This indicates pharmacokinetic differences, such as a decreased volume of distribution in the elderly; thus, higher initial blood concentrations for a given dose may be responsible for the observed clinical difference.
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