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

Characterization of the Temporal Profile of the Anti- Nociceptive Effect of an Intravenous Ketamine Bolus Using the Nociception Analgesia Index (ANI)

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.

Study Overview

• Status: Completed
• Conditions: Analgesia; Ketamine; Pharmacokinetic
• Intervention / Treatment: Drug: Ketamine

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 450881
      • Pontificia Universidad Catolica de Chile

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing elective surgery with general anaesthesia.

Description

Inclusion Criteria:

• Elective surgery with general anaesthesia
• Without premedication
• ASA I, II or III

Exclusion Criteria:

• Body weight greater than 120% of ideal weight
• Ingestion of sedatives of short or long action in the 48 hours before surgery
• People with a history of adverse effects to the drug under study

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Ketamine; In the preoperative room a vein of the forearm with preriferic access #18 will be established for the administration of general intravenous anesthesia and intraoperative fluids. In the operating room, after routine monitoring (Heart Rate, Non-Invasive Blood Pressure, Oxygen Saturometry), the sensor of the Nociception Analgesia Index (ANI) monitor will be installed from the right chest to the left 5th intercostal space. Wait XX time for calibration and capture of the electrocardiographic signal. The ANI value shall initially be measured and shall be considered as the reference value. Inject 0.1 mg/kg of ketamine (1 mg/ml) once, then inject 5 ml of physiological saline at the same rate. The time from ketamine administration until the ANI index rose above 50 (minimum appropriate nociception value) shall be recorded every 6 seconds.

Drug: Ketamine; One bolus of ketammine; Other Names: Analgesia using ketamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To measure ANI values after ketamine bolus dose administration.	The observed effect of ketamine is measured with the ANI monitor index in each patient (outcome is ANI values [ANI Units])	Every 6 seconds for 5 minutes after ketamine bolus
To determine the time maximum predicted concentrations in each patient	The time from the start of ketamine administration until the maximum predicted ketamine plasma concentrations value will be determined in each patient (mg/L).	Every 6 seconds for 5 minutes after ketamine bolus
To determine the time to maximum effect of a bolus dose of ketamine	The time from the start of ketamine administration until the maximum ANI index value will be determined in each patient (ANI Values/minutes)	Every 6 seconds for 5 minutes after ketamine bolus
To predict ketamine plasma concentrations values after ketamine bolus	The expected maximum plasma concentrations mg/L. Wil be estimated using the pharmacokinetic parameters of Domino knowing the administered dose (0.1 mg/Kg).	Every 6 seconds for 5 minutes after ketamine bolus
To calculate the difference between the time of maximum ANI effect	With the time (minutes) maximum predicted concentrations and the ketamine plasma concentrations (mg/mL)	At the minute of maximum effect

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient weight	The patient's weight will be measured prior to the administration of the ketamine bolus, which will be described in kg.	Once before the procedure

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile
• Investigators: Principal Investigator: Luis I Cortinez, MD, Pontificia Universidad Catolica de Chile

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2024
• Primary Completion (Actual): August 1, 2024
• Study Completion (Actual): August 1, 2024

Study Registration Dates

• First Submitted: February 5, 2024
• First Submitted That Met QC Criteria: March 27, 2024
• First Posted (Actual): April 3, 2024

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 20, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Analgesia; Ketamine; Target controlled infusion
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Agnosia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 124/2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No