The aim of the present study is to investigate the effect of chronic treatment with
      β1-adrenergic antagonist on the NOL index variation, the heart rate variation and the mean
      blood pressure variation after a standardized noxious stimulus.

Impact of Chronic Treatment by β1-adrenergic Antagonists on Nociceptive-Level (NOL) Index Variation After a Standardized Noxious Stimulus Under General Anesthesia

Nociception During Anesthesia in Patients Taking β1-adrenergic Antagonist Chronic Treatment

Hypothesis: We hypothesize that the NOL values variations obtained in response to a
      standardized noxious stimulus under general anesthesia in a group of patients chronically
      treated with β1-adrenergic antagonists, will be similar to the NOL values variations
      previously obtained in response to a similar standardized noxious stimulus and previously
      reported in a group of patients without any β1-adrenergic antagonist.

      Background: The Pain Monitoring Device (PMD200TM) monitor (Medasense Biometrics Ltd., Ramat
      Gan, Israel) uses the Nociception Level (NOL) index, a multiple parameter-derived index that
      has recently shown a good sensitivity and specificity to detect noxious stimuli. The NOL
      index variations of the latest version of the PMD200TM has shown better sensitivity and
      specificity to detect standardized noxious stimulus than heart rate or blood pressure
      variation in a population without any β1-adrenergic antagonist treatment. β1-adrenergic
      antagonist treatment was so far a limitation to the use of the NOL index. Indeed,
      β1-adrenergic antagonists have a depressive action on the heart rate, including limitation of
      the heart rate variability after a noxious stimulus. Because heart rate and its variability
      are parameters which are part of the parameters combined to build the NOL index, chronic
      treatment with β1-adrenergic antagonist could alter the ability of the NOL index to detect
      noxious stimulus. However, Edry R. (Edry R, 2017) assessed the impact of chronic treatment
      with β1-adrenergic antagonist on NOL index variation after noxious stimuli in a pilot study
      (9 patients under chronic treatment with β1-adrenergic antagonist and under general
      anesthesia) and didn't show any influence of this treatment on the NOL index variation. But
      this study was not large enough and did not fully answered the question whether chronic
      treatment with β1-adrenergic antagonist might impact NOL ability to detect precise and
      standardized stimulus and to compare the results to those in patients without this type of
      chronic medication.

      Objectives:

      Primary objective:

      To explore the NOL variation in a group of patients under chronic treatment with
      β1-adrenergic antagonists submitted to standardized noxious stimulus under general
      anesthesia.

      Secondary objectives:

      Secondary outcome [1] To explore the heart rate variation and the mean blood pressure
      variation in a group of patients under chronic treatment with β1-adrenergic antagonists
      submitted to standardized noxious stimulus under general anesthesia.

      Secondary outcome [2] To compare the heart rate variation and the mean blood pressure
      variation in a group of patients under chronic treatment with β1-adrenergic antagonists
      submitted to standardized noxious stimulus under general anesthesia to a control group of
      patients without any β1-adrenergic antagonist chronic treatment; results gathered from a
      previous study (Renaud-Roy E, 2019), exposed to the same noxious stimulus and under the same
      anesthesia conditions.

      Secondary outcome [3] To explore the ability of the NOL index, the heart rate and the mean
      blood pressure to discriminate between noxious and non-noxious states in a group of patients
      with β1-adrenergic antagonist chronic treatment submitted to standardized noxious stimulus
      under general anesthesia. To determine sensitivity and specificity (ROC curve and AUC of ROC)
      for each parameter: HR, MAP, NOL index.

      Secondary outcome [4] To evaluate the NOL index, the heart rate and the mean blood pressure
      variations after tracheal intubation in patients with β1-adrenergic antagonist chronic
      treatment.

      Methods:

      Adult patients undergoing general anesthesia for any types of surgery and who have been
      chronically treated with β1-adrenergic antagonists for at least three months prior to surgery
      will be enrolled to reach a total of patients with full analysis of data of n=25. All
      patients will be consented prior to the surgery. Induction of anesthesia will be standardized
      for all patients and based on their adjusted body weight calculated before induction, with:
      IV midazolam (0.02mg/kg), IV propofol (1.5-2mg.kg-1), IV remifentanil (1mcg.kg-1 followed by
      a continuous infusion of 0.05 µg.kg-1.min-1), IV rocuronium (0.6 to 1mg.kg-1). Depth of
      anesthesia with desflurane will be maintained and monitored with the BIS index kept between
      40 and 60. Intubation will be performed 3 minutes after the intravenous administration of the
      propofol, remifentanil and rocuronium boluses. The end of the bolus of remifentanil (given
      1mcg/kg; adjusted body weight) will be the start of the 3 min period to wait before
      proceeding with the tracheal intubation. Three minutes after intubation, the remifentanil
      infusion will be decreased to 0.005 µg.kg-1.min-1 to reduce the risk of developing
      hypotensive events and to prepare the patient for the standardized noxious stimulus of the
      study protocol realized under very low doses of opioids under desflurane hypnosis with BIS
      40-60.

      At least 10 min after the post-intubation decrease of the remifentanil infusion rate, the OR
      team will stop any physical contact/stimulation of the patient allowing at least a 3-minutes
      rest period under stable anesthesia. Baseline mean arterial blood pressure (MAP) and heart
      rate (HR) will be defined for the rest of the study as the mean of 3 measures in the 3
      minutes during this "no pain - no touching" evaluation period to get baselines values of all
      the study parameters. If necessary, phenylephrine will be given to keep a MAP > 65 mmHg.

      At this point, the standardized electrical (tetanic) stimulation will be applied on the area
      of the ulnar nerve at the wrist level, at a frequency of 100 Hz and a current of 70 mA for a
      duration of 30 seconds, followed by 3 minutes of observation period without any other
      stimulation of the patient by the anesthesia or the surgical team (EZstimII, Model ES400,
      Life-Tech, Stafford, Tx, USA). At the end of the observation period, the study is
      discontinued and the anesthesia will be conducted at the discretion of the anesthesiologist
      in charge of the patient.

standardized noxious stimulus under general anesthesia.

Impact of Chronic Treatment by β1-adrenergic Antagonists on Nociceptive-Level (NOL) Index Variation After a Standardized Noxious Stimulus Under General Anesthesia: An Observational Study

To explore the NOL variation between NOL average values before tetanic stimulation at the forearm level, and peak of NOL after stimulation (peak will be considered as an average values of 5 values around the maximal value of NOL, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to standardized noxious stimulus under general anesthesia.

Professor Anesthesiology and Pain Medicine

To explore the NOL variation between NOL average values before tracheal intubation, and peak of NOL after intubation (peak will be considered as an average values of 5 values around the maximal value of NOL, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to intubation under general anesthesia.

To explore the Heart Rate variation between heart rate average values before tetanic stimulation at the forearm level, and peak of heart rate after stimulation (peak will be considered as an average values of 5 values around the maximal value of heart rate, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to standardized noxious stimulus under general anesthesia.

To explore the Heart Rate variation between heart rate average values before tracheal intubation, and peak of heart rate after tracheal intubation (peak will be considered as an average values of 5 values around the maximal value of heart rate, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to intubation under general anesthesia.

To explore the Mean Blood Pressure variation between Mean Blood Pressure average values before tetanic stimulation at the forearm level, and peak of Mean Blood Pressure after stimulation (peak will be considered as an average values of 5 values around the maximal value of Mean Blood Pressure, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to standardized noxious stimulus under general anesthesia.

To explore the Mean Blood Pressure variation between Mean Blood Pressure average values before tracheal intubation, and peak of Mean Blood Pressure after tracheal intubation (peak will be considered as an average values of 5 values around the maximal value of Mean Blood Pressure, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to tracheal intubation under general anesthesia.

To explore the BIS index variation between BIS average values before tetanic stimulation at the forearm level, and peak of BIS after stimulation (peak will be considered as an average values of 5 values around the maximal value of BIS, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to standardized noxious stimulus under general anesthesia.

To explore the BIS index variation between BIS average values before tracheal intubation, and peak of BIS after intubation (peak will be considered as an average values of 5 values around the maximal value of BIS, as the definition already used in previous studies) in a group of patients under chronic treatment with β1-adrenergic antagonists submitted to intubation under general anesthesia.

Patients who have been treated for more than 3 months with β1-adrenergic antagonists

Impact of Chronic Treatment by β1-adrenergic Antagonists on Nociceptive-Level (NOL) Index Variation After a Standardized Noxious Stimulus Under General Anesthesia

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