Interest of a Tetanus Test at a Fixed Remifentanil Concentration Before Laryngoscopy and Skin Incision
Condition: Intravenous Anesthetic Agent Overdose
MeSH terms: Tetanus
Study type: Interventional
Phase: Phase 4

Summary: 
      Individually-tailored administration of the opioid analgesic component during general
      anaesthesia is still a challenge for the anesthesiologist. The aim of this protocol is to
      look if the gradient response of a nociception index to a calibrated tetanic stimulus during
      standard anesthetic conditions, could help to titrate remifentanil analgesia before tracheal
      intubation and before skin incision. The studied parameters are the SPI index developed by
      General Electric, the "Analgesia Nociception Index" and the pupil dilation using the pupil
      scan algometer.
    

Detailed description: 
      Two randomized groups of patients scheduled for general surgery under Target Controlled
      remifentanil propofol anaesthesia are compared.

      All patients receive two standard calibration tests (Tetanic stimulus at the ulnar nerve: 100
      Hertz, 60 milliamperes, 30 seconds) before tracheal intubation and skin incision at a stable
      remifentanil level of 3 ng/ml. Propofol concentration is targeted to maintain the BIS value
      as close as possible to 50. Patients are mechanically ventilated at an inspired O2
      concentration of 50% and using tidal volumes of 8 to 10 mL/kg and respiratory rates of 12 to
      15/min. Patients receive an induction dose of neuromuscular blocking agent.

      In the treated group, the importance of the Surgical Plethysmogram Index (SPI) gradient after
      the tetanic stimulus will guide the subsequent administration of remifentanil to cover
      tracheal intubation and surgical incision. As compared to SPI value before the calibration
      test, a less than 10 unit increase in SPI will not prompt any change in remifentanil
      concentration before tracheal intubation and surgical incision. An increase in SPI between 10
      and 20 units will prompt a remifentanil effect-site target concentration of 4 ng/ml, between
      20 and 30 of 5 ng/ml, and above 30 of 6 ng/ml for tracheal intubation. Once the trachea is
      intubated, remifentanil concentration will be lowered to 3 ng /ml. It will be adjusted again
      before surgical incision according to the same criteria. Ten minutes after surgical incision
      until the end of the surgical procedure, the remifentanil concentration will be targeted to
      maintain SPI between 20 and 50.

      In the control group, conditions will be the same as those of first group, except that
      remifentanil concentration will be adjusted according to heart rate and blood pressure. The
      anesthesiologist in charge is blinded to the results of the SPI gradient after the two
      calibration tests at 3 ng/ml remifentanil concentration and also blinded to the 2 other
      nociception indexes at all times. Remifentanil concentration is targeted at 4 ng/ml before
      tracheal intubation and surgical incision. Ten minutes after skin incision until the end of
      surgery, remifentanil concentrations will be adjusted according to the hemodynamic
      parameters.

      Data acquisition and analysis will lead to the following statistical comparisons between the
      two groups:

        -  Hemodynamic reactivity to tracheal intubation and surgical incision.

        -  Concordance between SPI, Analgesia Nociception Index (ANI), and pupil diameter
           variations in response to the calibration test and during maintenance of anesthesia.

        -  Reliability of the prediction of hemodynamic reactivity to intubation and incision by
           the SPI, ANI, pupil diameter and hemodynamic response to the calibration test, and
           improvement of the prediction when combining the information given by those parameters.

      2.2. Monitoring The monitoring will correspond to the classical monitoring of any general
      anesthesia procedures (Electrocardiogram, peripheral saturation in O2, Non-Invasive Blood
      Pressure, respiratory gases, pressure and flows in the airway, muscle relaxation).

      The following parameters will be continuously recorded and saved for subsequent analysis :

        -  Heart rate

        -  Inspired and expired gases : O2, Carbon dioxide (CO2)

        -  Spirometry : peak, plateau, and end-expiratory pressures

        -  EKG : heart rate

        -  Non-invasive blood pressure : automatic measured every 5 minutes

        -  SPI

      Additional monitoring :

        -  Bispectral Index (BIS)

        -  ANI

        -  Pupil dilation measurement

      2.3. Anesthetic medications

      2.3.1. Premedication The premedication will consist of 0.5 mg oral alprazolam (XANAX) one
      hour before induction of anesthesia.

      2.3.2. Anesthesia General anesthesia will be induced and maintained using Target Controlled
      Infusions (TCI) of propofol and remifentanil, and using a single cisatracurium bolus.

      2.3.2.1. Induction of anesthesia In the experimental group, the initial target effect-site
      concentration (Ce) of remifentanil will be 3 ng/ml and 3 µg/ml for propofol. The propofol Ce
      will be increased by steps of 1 µg/ml until loss of consciousness (6.0 µg/ml maximum). A 0.2
      mg/kg bolus of cisatracurium will be given immediately after loss of consciousness. The
      tetanic calibration test will be performed once all responses to train of four (TOF)
      stimulation have disappeared. The BIS target before the tetanic stimulation will be 50 (range
      40-60).

      Pupil dilation and the ANI response to the tetanic stimulation will also be measured.

      After tracheal intubation, remifentanil concentration will be reduced to 3 ng/ml, and
      propofol concentration adjusted to keep the BIS value as close to 50 as possible.

      In the control group, the induction of anesthesia will occur the same way as in the
      experimental group, except that the initial concentration of remifentanil will be 3 ng/ml,
      and 4 ng/ml for tracheal intubation and incision. It will be changed according to hemodynamic
      parameters thereafter. Propofol concentration will be targeted to maintain stable BIS values
      around 50. The tetanic calibration test will be performed blindly once all responses to TOF
      stimulation have disappeared, and once propofol and remifentanil concentrations have been
      stable for more than 5 minutes. SPI, ANI, and pupil diameter values will be blindly recorded.

      2.3.2.2. Maintenance of anesthesia The upper and lower limits of propofol concentrations will
      be 2.0 and 6.0 µg/ml, respectively. It will be targeted to maintain a stable BIS value around
      50. During surgery, remifentanil concentrations will range between 2.0 and 10 ng/ml. In the
      experimental group (SPI), the calibration test-defined remifentanil concentration and the
      pre-incision propofol concentration will be kept intact for 10 minutes after the surgical
      incision. Thereafter, they will be modified according to the below-defined criteria.

      In the control group, remifentanil concentration will be maintained at 4 ng/ml during 10
      minutes after the surgical incision. Thereafter, propofol and remifentanil concentrations
      will be modified according to hemodynamic reactivity, and according to BIS, which will be
      kept at 50 (see tables below). SPI, and the other nociception indexes will be blindly
      recorded in that group.

      2.3.2.3. Propofol concentration adaptations in both groups Propofol concentrations will be
      adapted to maintain BIS as close to 50 as possible. Changes in propofol concentration will be
      allowed every 5 minutes after having reached the new target, if necessary, as a function of
      criteria defined in Table 2.

      Table 2 Propofol concentration adaptation as a function of BIS BIS Change in propofol
      concentration >70 +2 µg/ml > 55 +1 µg/ml < 45 -0.5 µg/ml < 35 -1 µg/ml

      2.3.2.4. Remifentanil concentration adaptations

      2.3.2.4.1. In the experimental group The goal in the experimental group will be to maintain a
      SPI value between 20 and 40 during surgery, from 10 minutes after incision to the end.

      After incision, remifentanil concentration will be adapted according to criteria defined in
      Table 3.

      Table 3 Remifentanil concentration adaptation during surgery (range 2 to 10 ng/ml) Event
      Change in remifentanil concentration SPI<20 -1 ng/ml SPI>50 +1 ng/ml SPI>80 +2 ng/ml

      In case of hemodynamic reactivity (increase or decrease of more than 20 % as compared to
      reference values), despite adequate adaptation of remifentanil concentration as a function of
      SPI, it will be corrected according to criteria defined in paragraph 2.5 for hypotension or
      bradycardia episodes. In case of hypertension, (more than 20% as compared to reference
      value), despite adequate remifentanil concentration adaptation as a function of SPI, 0.5 mg
      intravenous boluses of nicardipine (Nicardipine) will be administered intravenously until
      return to acceptable values. Similarly, in case of tachycardia despite adequate adaptation of
      remifentanil adaptation as a function of SPI values, it will be corrected by 1 mg intravenous
      boluses of metoprolol (Seloken) until return to pre-defined values. In the event of both
      cases, exclusion of the patient's data from statistical analysis should be considered.

      2.3.2.4.2. In the control group Before surgical incision, in the absence of hemodynamic
      reactivity, remifentanil concentration will be 4 ng/ml, and will not change for 10 minutes
      after incision.

      Ten minutes after incision, remifentanil concentration will be adapted according to
      hemodynamic reactivity

      Table 4 Remifentanil concentration adaptation in the Control group Hemodynamic Reactivity (>
      20% as compared to reference values or Mean Arterial Pressure (MAP) > 90 mmHg and/or Heart
      Rate (HR) > 100/min): -1 ng/ml Hypotension/bradycardia (<20% as compared to reference values
      or MAP < 60 mmHg and/or HR < 45/min): +1 ng/ml

      Remifentanil concentration will always be kept between 2 and 10 ng/ml. In case of hemodynamic
      changes at those concentrations, they will be corrected according to the criteria defined
      above for the SPI group.
    

Intervention name(s): Remifentanil adapted to SPI; Remifentanil fixed
Intervention type(s): Drug; Drug
Intervention MeSH terms: Remifentanil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Remifentanil; Heart Rate Variability; Pupil dilation; SPI