• General anesthesia with inhalational anesthetic agents is widely used in surgical procedures.
  • Total intravenous anesthesia is more common in Europe than in the United States.
  • Limited knowledge exists on the effects of inhalational anesthetics in older adults.
  • Clinical trials often lack age stratification, making it difficult to assess age-related differences.


  • Pharmacokinetics involves absorption, distribution, and metabolism of inhalational anesthetic drugs.
  • Age-related changes in pharmacokinetics are expected due to profound alterations in elderly patients.
  • Comprehensive studies on inhalational anesthetics have primarily focused on young adults.
  • Limited data exist on how pharmacokinetics change with age in the elderly.


The aging pulmonary system can influence the behavior of inhalational anesthetic agents in several ways:

  1. Changes in Ventilation-Perfusion (V/Q) Matching: As people age, there is an increased likelihood of V/Q mismatching in the lungs. V/Q mismatch occurs when there is an imbalance between the ventilation (airflow) and perfusion (blood flow) to different areas of the lungs. This mismatch can result in regions of the lung that are well-ventilated but poorly perfused. Inhalational agents may be absorbed more quickly in these areas, potentially affecting the rate at which the agent reaches the bloodstream and exerts its effects.
  2. Decreased Lung Elasticity: With age, there is a loss of lung elasticity and changes in the structure of the lung tissue. This reduced elasticity can impact the lung’s ability to expand and contract effectively during the breathing cycle. Inhalational agents may be affected by altered lung compliance, potentially influencing their distribution within the lung and how they are eliminated.
  3. Altered Ventilatory Responses: The sensitivity of the respiratory system to changes in carbon dioxide (CO2) and oxygen (O2) levels may decrease with age. This means that older individuals may have a reduced ability to increase their minute ventilation (the volume of air breathed in one minute) in response to elevated CO2 or decreased O2 levels. Inhalational agents, which can depress respiratory drive, may have a more pronounced effect on elderly patients who already exhibit reduced ventilatory responses.
  4. Risk of Hypoxia: The combination of reduced sensitivity to hypoxia, sedation from inhalational agents, and potential age-related lung changes increases the risk of hypoxia (low oxygen levels) during and after anesthesia. Hypoxia can lead to complications and may require supplemental oxygen to maintain adequate oxygenation.
  5. Slower Uptake and Elimination: Age-related changes in lung function may lead to slower uptake of inhalational agents into the bloodstream and slower elimination from the body. This can affect the time it takes for patients to emerge from anesthesia and recover fully after surgery.
  6. Impact on Choice of Inhalational Agents: Given the considerations mentioned above, anesthesiologists may choose inhalational agents with properties that are better suited for older patients. For example, less-soluble agents like sevoflurane and desflurane may be preferred over more-soluble agents like isoflurane or halothane, as they may offer a more predictable and faster recovery profile.


  1. Cardiovascular Changes with Age: Aging is associated with several cardiovascular changes, including impaired pump function and atherosclerotic alterations in the vasculature. These changes occur independently of specific cardiovascular diseases.
  2. Common Cardiovascular Problems in the Elderly: Hypertension, arteriosclerosis, atherosclerotic vascular disease, and coronary artery disease are prevalent in older adults. Cardiac arrhythmias, especially atrial fibrillation, also become more common with age.
  3. Heart Failure and Diastolic Dysfunction: Heart failure, including diastolic dysfunction, is a frequent issue in elderly patients. Diastolic dysfunction is often associated with coronary artery disease and ventricular hypertrophy, contributing to subendocardial myocardial ischemia.
  4. Decline in Cardiac Function: Cardiac performance during exercise, measured by maximum oxygen transport (VO2-max), decreases at a rate of approximately 1% per year after age 30. The decrease in VO2-max is primarily attributed to a reduced maximal heart rate.
  5. Peripheral Vascular Changes: In healthy older individuals, peripheral blood flow decreases, and peripheral vascular resistance increases compared to younger counterparts. These changes are not significantly affected by physical conditioning.
  6. Determinants of Cardiac Output: Cardiac output depends on multiple factors, including heart rate and stroke volume. Aging can lead to a decreased maximal heart rate response and changes in stroke volume due to factors like ventricular hypertrophy and altered ventricular function.

7. Effect on Inhalational Agents:

  • Slower Circulation and Uptake: In elderly patients with reduced cardiac output, the circulation of blood throughout the body occurs at a slower pace. This slower circulation affects the uptake of inhalational anesthetic agents. During general anesthesia, when these agents are administered via inhalation, they enter the bloodstream through the alveoli in the lungs. With slower circulation, there is more time for the volatile anesthetics to diffuse from the alveoli into the bloodstream.
  • Higher Partial Pressure in Arterial Blood: The consequence of slower circulation is that arterial blood can attain a higher partial pressure of the anesthetic gas than expected. This means that, despite lower concentrations of the inhalational agent administered, the blood carries a more significant amount of the agent.

8. Choice of Inhalational Agents:

  • Solubility Coefficients: Anesthesiologists consider the solubility coefficients of inhalational agents when selecting the most suitable agent for a particular patient. Solubility coefficients refer to how readily anesthetic agents dissolve in blood and tissues. Agents with lower blood/gas solubility coefficients, such as desflurane and sevoflurane, are favored in elderly patients with diminished cardiac output.
  • Faster Recovery with Low-Solubility Agents: The choice of low-solubility agents like desflurane and sevoflurane is beneficial because these agents are less influenced by the slower circulation seen in older patients. They are cleared more rapidly from the bloodstream during emergence from anesthesia, leading to faster recovery and reduced time spent in the post-anesthesia care unit (PACU).

9. Cardiac Depression and Contractility:

  • Depression of Myocardial Contractility: Some inhalational agents, notably halothane and enflurane, have a greater potential to depress the contractility (the ability of the heart muscle to contract effectively) of the heart. This depression can lead to a reduction in the force of each heart contraction.
  • Impact on Heart Function: When these agents are administered, especially in higher concentrations, they may lead to a decrease in the strength with which the heart pumps blood. This effect is particularly concerning in elderly patients with compromised cardiac function, as it can result in a further decline in cardiac output and blood pressure.
  • Consideration of Cardiac Function: Anesthesiologists must carefully consider the cardiac function of elderly patients when selecting inhalational agents and their concentrations. Agents that are less likely to cause significant cardiac depression may be preferred to ensure hemodynamic stability during surgery.

10. Induction and Emergence:

  • Slower Induction: Due to the cardiovascular changes associated with aging, elderly patients may experience slower induction into anesthesia. This means that it may take more time for the patient to reach the desired depth of anesthesia during the initial administration of inhalational agents.
  • Prolonged Emergence: Similarly, during the emergence from anesthesia, older patients may exhibit a more extended recovery period. This is because the slower circulation affects the elimination of the inhalational agents from the body. As a result, it takes more time for the patient to fully awaken and regain consciousness after surgery.


1. Increase in Body Fat Percentage:

  • Elderly Impact: In the elderly, there is a significant increase in body fat percentage due to age-related changes in metabolism, hormonal shifts, and decreased physical activity. This increase in body fat has a pronounced impact on the pharmacokinetics of inhalational agents.
  • Effect on Drug Distribution: With a higher percentage of body fat, elderly individuals have a larger reservoir for lipid-soluble drugs like inhalational agents. These drugs tend to accumulate in fat tissue more readily in the elderly, leading to prolonged drug effects during and after anesthesia.
  • Volume of Distribution: The volume of distribution for lipid-soluble inhalational agents is further increased in elderly individuals with a higher body fat percentage. This means that a larger proportion of the drug is distributed into fat tissue, contributing to delayed drug elimination and prolonged emergence.
  • Prolonged Emergence: The slow redistribution of lipid-soluble drugs from the increased fat tissue in elderly patients can result in extended recovery times from anesthesia. This can lead to a higher risk of excessive sedation, respiratory depression, and postanesthesia delirium in this population.

2. Loss of Skeletal Muscle Mass:

  • Elderly Impact: Aging is associated with sarcopenia, which is the age-related loss of skeletal muscle mass. Elderly individuals typically experience a decrease in muscle mass and strength.
  • Impact on Drug Pharmacokinetics: The reduction in skeletal muscle mass is particularly relevant for inhalational agents because muscle tissue receives a significant portion of the blood supply. With less muscle mass available for drug distribution, the volume of distribution for these agents may be diminished in the elderly.

3. Variability in Fat Stores:

  • Elderly Impact: While the overall body fat percentage increases in the elderly, there can be variability in how fat is distributed throughout the body. Some elderly individuals may have more centralized fat distribution, such as abdominal fat, while others may accumulate fat in subcutaneous stores.
  • Heterogeneous Fat Distribution: Variability in fat distribution within the elderly population can result in differences in drug uptake and retention. For example, those with more epicardial fat may have a different drug distribution profile compared to individuals with subcutaneous fat predominance.
  • Unexplored Effects: The potential impact of these variations in fat distribution on the pharmacokinetics of inhalational agents in the elderly population is an area that requires further investigation.

4. Differences in Volatile Agents:

  • Elderly Impact: The choice of inhalational agents can be particularly important in elderly patients due to changes in body composition and pharmacokinetics.
  • Variation in Volume of Distribution: Different inhalational agents have varying solubility coefficients and pharmacokinetic properties. Elderly individuals, with their increased body fat percentage, may experience a more significant volume of distribution for lipid-soluble agents like isoflurane compared to agents with lower lipid solubility, such as desflurane.
  • Rate of Movement: The rate at which volatile agents move from the central compartment to peripheral compartments may also be affected by age-related changes in circulation, potentially influencing the speed of drug distribution and elimination.

5. Impact on Emergence from Anesthesia:

  • Elderly Impact: The elderly population may be more susceptible to the prolonged effects of inhalational agents due to changes in body composition.
  • MAC-Awake Value: The MAC-awake value, which determines emergence from anesthesia, is influenced by age-related changes in drug distribution and metabolism. Elderly individuals may require more time to reach the MAC-awake threshold, resulting in delayed emergence.
  • Prolonged Drug Release: The slow and continued release of lipid-soluble inhalational agents from increased fat tissue in the elderly can contribute to prolonged sedation, respiratory depression, and an increased risk of postoperative complications, including postanesthesia delirium.


1. Renal Atrophy and Decreased Function:

  • Aging Effect: With age, individuals often experience renal atrophy, characterized by the loss of cortical nephrons. This results in a reduction in kidney mass, with the kidney losing approximately 20% of its mass by age 80. Functional changes accompany this atrophy, including a decrease in renal blood flow, glomerular filtration rate (GFR), and creatinine clearance.
  • Impact on Inhalational Agents: The reduction in renal blood flow and GFR can affect the clearance of drugs, including inhalational agents, from the body. Drugs that are primarily eliminated through renal excretion may have prolonged effects in elderly patients due to reduced renal function.

2. Creatinine Clearance and Age-Related Changes:

  • Aging Effect: Creatinine is a waste product produced by muscle metabolism, and its levels can vary with muscle mass. Age-related changes in body composition, including a decrease in muscle mass, can affect plasma creatinine levels in the elderly.
  • Cockroft–Gault Formula: To assess renal function in the elderly more accurately, healthcare providers often use formulas like the Cockroft–Gault formula, which takes into account factors such as age, weight, and creatinine levels. This formula provides a better estimation of renal function than solely relying on plasma creatinine levels.

3. Fluoride Toxicity Risk:

  • Aging Effect: The aging kidney may be less efficient at processing certain substances, including fluoride ions, which can result in an increased risk of fluoride toxicity.
  • Impact on Inhalational Agents: All volatile anesthetic agents used in clinical practice are fluorinated ether compounds. Metabolism of these agents can produce inorganic free fluoride ions, which, when present at toxic levels, can lead to acute renal failure.
  • Risk with Specific Agents: Enflurane, isoflurane, and sevoflurane are volatile agents that can produce enough fluoride ions to be of concern, especially in elderly patients who may have reduced renal function.

4. Sevoflurane and Compound A Production:

  • Aging Effect: Sevoflurane, a commonly used inhalational agent, can break down in the presence of carbon dioxide absorbers to form a nephrotoxic compound known as Compound A. This breakdown is influenced by factors such as absorber temperature and gas flow rates.
  • Impact on Inhalational Agents: While there is concern about the potential nephrotoxicity of Compound A, clinical studies have not consistently demonstrated renal injury associated with sevoflurane use, even in elderly patients.


1. Reduction in Hepatic Blood Flow:

  • Effect of Aging: With aging, there is a reduction in hepatic blood flow. This reduction can result in diminished metabolism of drugs that rely on hepatic clearance. Importantly, this decrease in hepatic blood flow is primarily responsible for the decreased hepatic metabolism of drugs, rather than changes in hepatic enzyme activity.
  • Inhalational Agents Metabolism: Among the volatile inhalational agents, halothane is the most extensively metabolized in the liver, with approximately 20% of it undergoing hepatic metabolism. In contrast, the other commonly used inhalational agents are metabolized to a much lesser extent. Sevoflurane is metabolized by about 5%, enflurane by 2.4%, isoflurane by 0.2%, and desflurane by only 0.02%.

2. Impact on Hepatic Function:

  • Effect of Aging: The hepatic-function changes associated with aging may be particularly relevant for halothane and sevoflurane, which undergo more significant hepatic metabolism compared to other agents. However, it’s not well-documented whether the loss of hepatic tissue with age directly leads to decreased metabolism of volatile agents.

3. Variable Effects of Volatile Agents on Liver Function:

  • Effect of Aging: Volatile anesthetic agents can have variable effects on liver function. For example, sevoflurane has been shown to decrease the production of certain proteins, such as fibrinogen, transferrin, and albumin, in cultured hepatocytes to a greater extent than halothane, isoflurane, or enflurane.
  • Inhalational Agents Metabolism: The effects of desflurane on hepatic synthesis are not well-studied, but it is anticipated to have less effect since very little of it is metabolized.

4. Protein Binding Considerations:

  • Effect of Aging: Many drugs, including some intravenous anesthetic agents, bind to plasma proteins, and elderly patients often have lower blood concentrations of albumin, which is a carrier for many drugs. This can result in a greater fraction of unbound (free) drug in the bloodstream, potentially leading to exaggerated drug effects.
  • Inhalational Agents Metabolism: Unlike some intravenous anesthetic drugs, there is no evidence to suggest that volatile inhalational agents rely on significant protein binding for transport. Therefore, the increased sensitivity to volatile anesthetics observed in elderly patients is unlikely to work through this mechanism.

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