When the drugs don’t work

Animal studies explore the random fluctuations in individual responses to anesthetic that are lost in the population-level data used to determine anesthetic doses in humans.

An anesthetist brings a patient out from under anesthesia. Image credit: Public domain

Every year, millions of patients undergo general anesthesia for complex or life-saving surgeries. In the vast majority of cases, the drugs work as intended. But a minority of patients take longer than expected to regain consciousness after anesthetic, and a few wake up during the surgery itself. It is unclear what causes these unintended events.

When choosing an anesthetic dose for each patient, physicians rely on data from large clinical studies. These studies expose many patients to different doses of an anesthetic drug. At higher doses, fewer and fewer patients remain conscious. This enables physicians to identify the dose at which an average person will lose consciousness. But this approach ignores the difference between the response of an individual and that of the population as a whole. At the population level, the likelihood of a patient being awake decreases smoothly as the concentration of anesthetic increases. But within that population, each individual patient can only ever show a binary response: awake or not awake.

To compare anesthetic effects on individuals versus populations, McKinstry-Wu, Wasilczuk et al. exposed mice to a commonly used anesthetic called isoflurane. During prolonged exposure to a constant dose of the drug, each mouse was sometimes unconscious and sometimes awake. These fluctuations in responsiveness seemed to occur at random. Exposing zebrafish to propofol, an anesthetic that works via a different mechanism, had a similar effect.

Notably, the responses of both species to anesthesia showed a phenomenon known as inertia. If an individual was unresponsive at one point in time, they were likely to still be unresponsive when assessed again after three minutes. The amount of inertia was similar in mice and zebrafish. This suggests that the mechanism responsible for inertia has remained unchanged over more than 400 million years of evolution.

The results reveal similarities between how individuals respond to anesthetics and how individual anesthetic molecules act on cells. When a molecule binds to its receptor protein on a cell, the receptor fluctuates spontaneously between active and inactive states. Studying how individuals respond to drugs could thus provide clues to how the drugs themselves work. Future studies should explore the biological basis of fluctuations in anesthetic responses. Understanding how these arise will help us tailor anesthetics to individual patients.