Characterization of the Temporal Profile of the Anti-nociceptive Effect of Ketamine Bolus Measured With ANI

Overview

Ketamine, an intravenous anesthetic, and analgesic agent has experienced a resurgence in its clinical application, particularly in subanesthetic doses. The aim of this observational study is to characterize the changes in the Nociception Analgesia Index (ANI) associated with the administration of an intravenous ketamine bolus using a Pharmacokinetic-Pharmacodynamic (PKPD) modeling approach. The pharmacokinetic parameters of the Domino model will be used to predict ketamine plasma concentrations after the bolus dose. An Emax model and a link model assuming a first order rate constant (ke0) will be used to fit the data. Modeling analysis will use the program NONMEM. It is expected to recruit a total of 20 patients between 40 and 80 years, ASA I, II or III, programmed for elective surgery with general anesthesia. ANI values will be recorded every 6 seconds for 5 minutes from the bolus dose.

Ketamine was introduced into clinical practice in 1965 and has been widely used as an intravenous anesthetic and analgesic. In recent years there has been a resurgence in its use mainly using low intravenous doses as a multimodal analgesia strategy and attenuation of postoperative hyperalgesia. Its use in low doses as an analgesic has also grown in other areas such as in emergency medicine and in patients with chronic pain and neuropathic pain. While optimal analgesic doses are not well defined in general the recommended regimens range from 0.15 to 0.3 mg/kg bolus and infusions from 0.1 to 0.3 mg/kg/h. Target-controlled infusion (TCI) is an intravenous anesthesia delivery technique that incorporates pharmacokinetic models in pump infusion algorithms to allow obtaining objective-stable concentrations of the drug in the plasma or effect site. The TCI mode effect site presents advantages over plasma-to-plasma TCI since plasma concentrations do not have a good correlation with the drug's effect in nonequilibrium scenarios. This modality is based on that TCI systems can be instructed to exceed the desired plasma concentration to accelerate the rate at which the drug's effect is achieved. For the pharmacokinetic model to perform this the parameter set has to have the ke0 which is the equilibrium constant between the plasma and the effect site. This parameter provides the necessary information of the time profile of the drug's effect to the model. These models are known as on-site effect models or PKPD models. The potential benefit of TCI to site effect is the most accurate titration of the desired effect. Moreover, these models allow us to better understand the temporal profile of the drug effect. TCI has been used for ketamine administration in various settings, including critical care. The operating room, and studies in neuroscience. In routine practice, ketamine TCI is performed using the model described by Domino with plasma target concentrations lower than 1.2 ng/ml to obtain its anti-nociceptive effect. Currently ketamine TCI can only be used in plasma mode since ke0 for its analgesic effect has not been determined. The analgesic monitor PhysioDolorisTM (MDoloris Medical Systems SAS, Lille, France) was developed to quantitatively evaluate the effects of nociceptive stimuli on analgesic/nociceptive balance (the balance between the sympathetic/parasympathetic nervous system) in the anesthetized patient. ANI monitoring provides information on physiological coding and processing of nociceptive stimuli by analyzing the high-frequency component of heart rate variation in relation to respiratory rate. During anesthesia, the nociception index values reflect whether analgesia is adequate and whether analgesia allows the maintenance of nociception-antinociception balance, in which parasympathetic activity predominates over sympathetic. This monitoring provides a promising and objective evaluation of nociception. The aim of this observational study was to describe changes in the ANI value associated with the administration of an intravenous ketamine bolus in a group of patients scheduled for elective surgery under general anesthesia. The hypothesis is that the anti-nociceptive effect of the drug can be characterized by changes in ANI associated with the administration of a ketamine bolus. Effect-site TCI will be possible by incorporating this information into the available ketamine pharmacokinetic models.