Probability Ramp Control of Propofol for EGD

Administration of propofol to achieve a target of moderate sedation is a challenging task for
which anesthesia providers receive minimal training. Undersedation results in a noncompliant
patient, while oversedation results in airway obstruction, respiratory depression, and
hypotension. Considerable variability in patient pharmacokinetics (the distribution of drug
within the body) and pharmacodynamics (the translation of drug concentration to clinical
effect) has been demonstrated. The skill of titrating propofol to the desired target and
maintaining this state is slowly acquired in the clinical environment of the endoscopy center
with frequent reliance on rescue skills. An automated system that facilitates this process
would be useful.

Pharmacokinetic models allow us to make predictions of the results of drug administration. If
we know the age and size of the patient, we can determine a quantity of propofol that will
attain a desired concentration at some point in the future (within the predictive accuracy of
the model). If they are old, this is less than if they are young. If they are obese, this is
more than if they are thin. By adjusting the dosing, we can achieve similar concentrations at
a specified time in a wide range of patients.

Pharmacodynamic models allow us to relate drug concentration to a probability of response.
Sensitivity is a randomly distributed variable, and the cumulative probability of response to
propofol is well represented by a sigmoid curve. While we do not know the concentration that
will suffice for a given individual, we can determine the probability that this individual
will lose responsiveness within an interval of concentrations. For example, the probability
of loss of responsiveness between 1 µg/ml and 6 µg/ml is around 99%. For any given age and
size, an infusion sequence can be determined so that we traverse this interval smoothly. The
infusion sequence is determined by minimization of the difference between the simulated
probability and the target (1). We predict that 90% of 50 year old 70 kg patients will lose
responsiveness between one minute and three minutes after initiating the infusion, and 99% by
five minutes. The infusion sequence for this patient is comprised of a bolus of 287 µg/kg
followed by an initial infusion of 216 µg/kg/min, with an increase to 550 µg/kg/min after 147
seconds. By selecting the infusion sequence based on the age and size of the patient, all
patients will track the same target line. These infusion rates are determined prior to
initiation of sedation, and the clinician can verify that they are appropriate for the
patient before beginning sedation.

Once the endpoint of adequate sedation is observed, the effect site concentration associated
with this endpoint is inferred, and the infusion that will maintain this concentration can be
determined. This allows the clinical observation to be translated into an infusion rate, much
as a driver accelerates to a desired speed and then engages the cruise control to maintain
that speed.

The intent of this study is to demonstrate equivalent safety and efficacy of PRC to control
by a skilled clinician.

References

1. Mandel JE, Sarraf E. The Variability of Response to Propofol Is Reduced When a Clinical
Observation Is Incorporated in the Control: A Simulation Study. Anesthesia & Analgesia.
2012;114:1221-9.

Inclusion Criteria:

- scheduled for elective EGD

Exclusion Criteria:

- Unable to provide informed consent