Reply to: Comment on: Variation in propofol induction doses administered to surgical patients over 65

Response to letter to the editor text:

We thank Pal and Butterworth for their interest in our article¹ and for providing an important anesthesia primer for non-anesthesiologist about the principles and challenges of providing appropriate levels of anesthesia (i.e. amnesia, unconsciousness, muscle relaxation, and blunting of the autonomic response to painful stimuli) for patients undergoing surgery. Furthermore, we appreciate their elegant outline of neuro-anatomical correlates and the neuro-connectivity model of achieving anesthesia. We agree that the state of anesthesia is a dynamic process and that the complexity of understanding anesthetic requirements cannot be captured based on an analysis of dosing practices for a single hypnotic agent such as propofol.

In particular, studying drug dosing behaviors throughout the course of a surgical encounter – including anesthetic induction, maintenance, and extubation - becomes extraordinarily complex, with a multiplicity of sources of variability and unclear implications for influencing practice. It is for this reason that we chose to focus solely on the induction phase of general anesthesia, which while no doubt also complex, is more likely to provide insight specifically into anesthesia provider dosing behaviors independent from the numerous factors that are at interplay during the period of surgical manipulation.

Induction practices in the time prior to surgical incision are predominantly determined by the anesthesiology team, and an understanding of what occurs during this period is critical in order to develop pertinent questions regarding what induction behaviors may benefit from further study and modification. We focused on propofol bolus inductions in particular, because propofol is presently the dominant induction agent used in approximately 90% of general anesthetic inductions throughout the United States. Furthermore, propofol is also commonly used an induction agent by other practitioners, such as emergency physicians and critical care teams.

Variation in drug dosing is ubiquitous² and in the anesthesiology world has been most commonly attributed ‘titration’. But in the case of propofol bolus inductions, what are anesthesiologists titrating to? The endpoint in common practice remains a poorly differentiated goal of amnesia, unconsciousness, muscle relaxation and hemodynamic stability, but we know that one of the challenges of anesthesiology is that these goals are often in stark competition with each other (i.e. the dose of drug that allows for adequate relaxation may not provide hemodynamic stability). One significant suggestion of our paper is that anesthesiologists demonstrate an enormous degree of unexplained variation in the way we titrate among these competing endpoints.³

Along with the unexplained variation in weight-adjusted dosing is an interesting lack of variation in absolute doses. Our data demonstrate a multi-modal distribution of absolute propofol doses that would suggest our titration is often ‘to the closest 50mg.’ To any practitioner familiar with the use of propofol in fragile patients, 50mg bolus increments would be recognized – to put it kindly – as somewhat lacking in nuance.

In this context, perhaps the simplicity of our paper is its virtue. Having empiric data describing actual practice patterns of ‘real world’ general anesthetic propofol inductions in older adults and the relationship of those prevalent practices to our current understanding of typical propofol dose requirements allows for the generation of empirically responsive, and somewhat urgent research questions. A recent PK-PD modeling study supports the published recommendation for propofol general anesthetic induction dosing in older adults of 1-1.5mg/kg as stated by the FDA-approved package insert,⁴ giving physiologic justification to the practice of reducing induction doses by 25 - 50% in healthy older adults as compared to younger patients. These same older patients often have reduced physiologic reserve to bounce back from hemodynamic perturbations brought on by anesthesia. Our study’s documentation of the common practice of administering above the recommended induction dose of propofol (in approximately 65% of cases) leads naturally to questions about potential overdose.

A simple question arises - is the FDA approved label correct, or are anesthesiologists correct? The two are clearly at odds, and both would benefit from more research to understand what doses of propofol are most likely to produce the safest possible anesthetic inductions in our patients. Such information will aid our specialty to make more nuanced efforts toward true titration during induction of general anesthesia, a period of time that remains among the most dynamic and challenging of clinical encounters.