Remifentanil Effect-site Prediction by Algometry
Condition: Conscious Sedation Failure During Procedure
Study type: Observational

Summary: 
      This study validates the pharmacodynamic analgesic predictions (effect) given by Minto's
      remifentanil pharmacokinetic and dynamic model in conscious sedation. This standard model is
      based on the electroencephalogram (EEG) changes induced by this opioid as a proxy for
      describing the remifentanil analgesic effect, which might be only valid for high
      concentrations. Validation of the standard remifentanil model for low concentrations under
      sedation is needed for safer remifentanil administration.
    

Detailed description: 
      According to pharmacokinetic and-dynamic (PK/PD) models, the proper use of anesthetics
      depends on the effect-sites mechanisms and the time-courses of action. This aspect is crucial
      for the practitioners to target the desired effect-site concentrations of the drugs (drug
      concentration at brain) by optimizing the drug administration using target control infusion
      (TCI) systems operating under these model predictions.

      For more than two decades, the pharmacodynamic properties of remifentanil relied on Minto's
      model, which is based on processed EEG as the reference to quantify the analgesic effect and
      effect-site concentration estimate. This remifentanil pharmacodynamic was modeled under
      conditions administered to volunteers rapidly and at very high doses to induce substantial
      changes in the spontaneous processed EEG. The experimental concentrations and infusion rates
      are far from sedative levels, where the EEG has shown a clear response to hypnosis but not to
      analgesia or nociception.

      Under the hypothesis that pharmacological models should predict equally well the effects
      induced by drugs at different concentrations levels, the purpose of this study is to evaluate
      and validate the pharmacodynamic predictions given by Minto's model in patients under
      conscious sedation using the algometry as a reference of nociception.

      The study recruits 100 female patients scheduled for benign gynecological surgery divided
      into three groups. A group of 35 patients receives a constant TCI effect-site target infusion
      of 1.5 ng/ml of remifentanil for 25 min. The second group of 35 follow the same protocol with
      a bolus of 1 mg of midazolam before the remifentanil infusion. The rest configures the
      control group under saline solution.

      Experimental data consist of basal algometry (pressure pain threshold) aside from BIS index,
      blood pressure, and heart rate values and at time-points of 1.5, 5, 10, 15, 18, 20, and 25
      minutes after induction.

      Minto's remifentanil pharmacodynamic model validation relies on comparing the levels and
      temporal evolution of the algometry measurements during the whole experiment concerning the
      effect-site estimations provided by the TCI-pump Minto's model.
    

Intervention name(s): Remifentanil 1 MG Injection [Ultiva]; Midazolam 1 MG/ML Prefilled Syringe; Saline solution; Algometry
Intervention type(s): Drug; Drug; Drug; Device
Intervention description(s): Group I TCI effect-site target infusion of 1.5 ng/ml of remifentanil.; Group II TCI effect-site target infusion of 1.5 ng/ml of remifentanil + 1 mg Midazolam iv; Group III Control; The algometry technique is used to assess the pain pressure threshold as an analgesic effect of remifentanil concerning Minto's model prediction.
Other intervention name(s): Opioid; Benzodiazepine; 0.9% Sodium Chloride Injection; Somedic Type II®, Sweden
Intervention MeSH terms: Midazolam; Remifentanil
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        We enrolled 100 female patients scheduled for benign gynaecological surgery. A group of 35
        patients received a constant TCI effect-site target infusion of 1.5 ng/ml of remifentanil
        for 25 min. The second group of 35 followed the same protocol with a bolus of 1 mg of
        midazolam previous to the remifentanil infusion to evaluate potential anxiolysis effects.
        The rest configured to the control group.

        Algometry was used to quantify pressure pain thresholds regarding basal measurements at
        time-points of 1.5, 5, 10, 15, 18, 20, and 25 min after induction began beside the blood
        pressure and heart rate.
      
Keywords: Remifentanil; Algometry; Pharmacodynamics; TCI Infusion system; Conscious Sedation