Context-Sensitive Half-Time and Anesthetic Implications

Definition

• CSHT is defined as the time required for the plasma concentration of an intravenous drug to decrease by 50% after discontinuation of a continuous infusion.¹
• CSHT differs from elimination half-life, which is the time required for the concentration of a single dose of a drug to decrease by 50%.
• The CSHT of a drug is a dynamic parameter largely determined by the drug’s distribution between the central and peripheral compartments, its elimination, and patient-specific factors.

Multicompartment Model of Drug Distribution

• The distribution of an intravenous drug is commonly described using the multicompartment model.¹
• After a drug is administered into the plasma (central compartment), it moves into various tissues (peripheral compartments).
• After discontinuation of drug administration, the drug follows concentration gradients and moves out of its peripheral compartments, back into the plasma, and is ultimately cleared from the body.

Multicompartment model where substances can move freely between compartments depending on concentration gradients

Drug Infusion Initiation

Intravenous drug enters the plasma and then travels to the peripheral tissues following concentration gradients (shown in blue arrows)

Drug Infusion Termination

Intravenous drug exits the peripheral tissues following concentration gradients into the plasma and is then cleared (shown in blue arrows)

Although fentanyl may have a short elimination half-life, once it is accumulated in peripheral tissues, its redistribution back into the plasma is slow.

Factors Affecting CSHT

CSHT varies across drugs due to differences in intrinsic properties and patient factors.^2,3

Pharmacologic Factors

• Lipophilicity and tissue uptake: Lipid-soluble drugs (e.g., fentanyl, thiopental, midazolam) accumulate in peripheral compartments, prolonging CSHT.
• Intercompartmental distribution: Agents that move slowly to peripheral tissues at infusion onset later return slowly to the central compartment after infusion termination, prolonging CSHT.
• Metabolic clearance: Drugs metabolized quickly (e.g., remifentanil via plasma esterase) have a short and stable CSHT.

Patient Factors

• Obesity: Obesity leads to increased peripheral compartment size, often prolonging CSHT.
• Organ dysfunction: Impaired function of the kidneys or liver (e.g., in elderly patients) will prolong CSHT for renally or hepatically cleared drugs.

Anesthetic Implications

• If administered over time via an infusion, some anesthetic drugs (e.g., fentanyl, midazolam) have the potential to accumulate in peripheral tissues. As a result, these drugs exhibit increased CSHT after prolonged infusion periods, because larger accumulations of drug in peripheral tissues require more time to be cleared from the plasma.
• Other drugs (e.g., remifentanil) do not accumulate in the tissues to the same degree. They move quickly between compartments and can be cleared from the body quickly. Therefore, the CSHT of these drugs remains nearly constant across infusion durations.⁴

Intraoperative Considerations

• The CSHT of a drug infusion should be accounted for when determining when to terminate the infusion.
• Infusions of drugs with a long CSHT would need to be stopped a substantial amount of time before the desired end of the drug effect, especially for infusions of long durations.