Remifentanil Without Muscle Relaxant for Thoracotomy
Condition: Elective Open Thoracotomy
MeSH terms: Muscle Hypotonia
Study type: Interventional
Phase: Phase 2

Summary: 
      Although the administration of muscle relaxation is essential standard of care for thoracic
      procedures, it could cause long-reversal times and postoperative residual curarization (PORC)
      increasing length of post-anesthesia care unit (PACU) stay and hospital costs. Sugammadex
      offers new perspectives to reduce the incidence of PORC. Unfortunately it is not available in
      many countries because of its significantly high cost. We hypothesized that the use of
      target-controlled remifentanil infusion (TCI) with the non-muscle relaxant (NMR) would be
      associated with comparable surgical conditions and reduced total costs compared with the use
      of neuromuscular blockers during thoracotomy.

      After ethical approval, 66 patients scheduled for elective thoracotomy under sevoflurane
      anesthesia with TCI remifentanil will be included in this prospective, randomized,
      single-blind, controlled study.

      Patients will be randomly assigned to receive cisatracurium or saline (n = 33 for each group)
      throughout the procedure. Laryngoscopy and intubating conditions, intraoperative modified
      thoracic surgery rating scale (Table below), incidence of light anesthesia, and use of
      vasopressors and anesthetics, clinical recovery, incidence of PORC, PACU and hospital stays,
      and total costs will be recorded.
    

Detailed description: 
      Administration of muscle relaxation is essential standard of care in thoracic surgery as it
      causes an improvement of surgical conditions. The concept of "Fast-track thoracic anesthesia"
      requires the use of either short or intermediate-acting nondepolarising neuromuscular
      blocking drugs, to provide a sufficient neuromuscular blockade during surgery and to restore
      the normal neuromuscular transmission immediately at the end of surgery.1

      However, long-reversal times and postoperative residual curarization (PORC) are still a
      problem in 30%-60% of the anesthetized patients even with the use of new intermediate-acting
      neuromuscular blockers.2-3 PORC could cause aspiration of the lungs and respiratory failure4
      after thoracic surgery that may prolong the post anesthesia care unit (PACU) and hospital
      stays.

      Although, sugammadex, a modified gamma-cyclodextrin, offers new perspectives to reduce the
      incidence of PORC,4 it is not available in many countries because of its significantly high
      cost.5

      Therefore, in fast-track cardiac surgery, it seems unnecessary to maintain paralysis by
      repetitive bolus injection or continuous infusion of neuromuscular blockers with overall
      surgeons' satisfaction.6

      The use of remifentanil without muscle relaxants provides excellent intubating conditions and
      short recovery duration.7 The effective concentration range of remifentanil for tracheal
      intubation without muscle relaxant is 4.5-5.5 ng/ml.8 The use of non-muscle relaxant (NMR)
      anesthetic techniques using remifentanil with either propofol or sevoflurane allows early
      extubation after trans-sternal or video-assisted thymectomy in myasthenic patients.9-10

      The use of NMR technique on the surgical conditions during thoracotomy in patients without
      neuromuscular diseases has not yet been studied.

      We hypothesizes that the use of NMR technique during thoracotomy will be associated with
      comparable surgical conditions with the standard use of neuromuscular blockers.

      The attending anesthesiologist is not blinded. All patients will be premedicated with 1-2 mg
      oral lorazepam the night before surgery.

      In all patients, standard monitors, and state and response entropy (SE and RE, respectively)
      will be applied. Neuromuscular blockade is measured with a train-of-four (TOF) (Datex-Ohmeda
      Division, Instrumentarium Corporation, Helsinki, Finland). The forearm is immobilized to
      prevent interfering movements. The ulnar nerve will be stimulated supramaximally at the wrist
      with a TOF stimuli (60 mA for 200 μsec) at 15-sec intervals. Baseline twitch amplitude is
      established after induction of anesthesia. TOF ratio is recorded as ratio between the fourth
      and the first twitch (T4/T1).

      The radial artery is catheterized. Normothermia is maintained by using forced-air warming
      blankets. A thoracic epidural or paravertebral catheter is inserted but no local anesthetics
      are infused during the study to avoid their effects on the study outcomes.

      Anesthetic technique is standardized in all studied patients. Anesthesiologists who give the
      anesthetic will not be involved in the collection of outcome data.

      After preoxygenation, anesthesia is induced using propofol 1.5-3 mg/kg and target-controlled
      infusion (TCI) of remifentanil at an effect-site concentration (Ce) of 4 ng/mL using the TCI
      system (Injectomat® TIVA Agilia, Fresenius Kabi, France), to achieve the SE values below 50
      and the difference between RE and SE below 10 and the mean arterial blood pressure (MAP) and
      heart rate are <20% of the baseline values. When the SE is >50 and the RE-SE difference is
      >10, and the MAP and heart rate are >20%, propofol 0.5 mg/kg is administered followed with
      gradual increases in remifentanil Ce by 0.5 ng/mL with a maximum Ce of 6 ng/ml.

      Anesthesia is maintained with 0.7-1.5 minimum alveolar concentration (MAC) of sevoflurane to
      maintain the SE values below 50 and the difference between RE and SE below 10.

      Remifentanil Ce will be increased by 0.5 ng/mL when the SE values are > 50, the difference
      between RE and SE >10, and the MAP and heart rate are >20% of the baseline values despite a
      target sevoflurane MAC ≥ 1.5.

      When the SE is <50 and the RE-SE difference is <10, the sevoflurane MAC will be gradually
      decreased to a minimum of 0.7, followed with gradual decreases in remifentanil Ce by 0.5
      ng/mL with a minimum Ce of 1.5 ng/ml.

      Light anesthesia is defined as an episode with SE values that exceeds 50 and/or MAP and HR
      values that exceeds the baseline by 20% and that lasted for more than 3 consecutive min.

      Patients' two lungs (TLV) are mechanically ventilated with fraction of inspired oxygen (FiO2)
      of 0.4 in air, tidal volume (VT) of 8 mL/kg, inspiratory to expiratory (I: E) ratio of 1:2.5
      and PEEP of 5 cm H2O, fresh gas flow (FGF) of 1.5-1.7 l/min, and respiratory rate adjusted to
      achieve a PaCO2 of 35-45 mm Hg.

      After pleurotomy, the patient's dependent lung is ventilated with a TV of 6 mL/kg and FiO2,
      I: E ratio, PEEP, FGF, and respiratory rate, are maintained as during TLV and the lumen of
      the nondependent lung is left open to air.

      Hemodynamic control is standardized according to the authors' protocol.

      During surgery, the authors will administer Lactated Ringer's solution at a rate of 2
      mL/kg/h. If MAP drops down to 60 mmHg, 250 mL of plasma protein fraction 5% will be
      administered, and, if this is not enough, repeated doses of intravenous of ephedrine 5 mg or
      norepinephrine 5 µg, will be administered to maintain urine output to be equal or greater
      than 0.5 ml/kg/hour. A hemoglobin concentration of 8 g/dL or greater is compensated with red
      blood cell concentrates.

      All surgical procedures will be performed by the same surgeons who are blinded for the study.

      In the case of clinically unacceptable laryngoscopy and intubating conditions, poor or
      extremely poor surgical conditions, or a sudden deterioration of surgical conditions despite
      the SE values below 50, the difference between RE and SE < 10, the MAP and heart rate are
      <20% of the baseline values, cisatracurium is administered in a bolus dose of 0.1 mg/kg.

      At the end of surgery, the nondependent lung is re-expanded, TLV is resumed as before
      surgery. The remifentanil and sevoflurane will be discontinued after chest closure and skin
      closure (T0), respectively. In the Muscle Relaxant group, during skin closure, when the TOF
      ratio ranged between 0.3 and 0.5, the neuromuscular blockade is antagonized with 50 µg/kg
      neostigmine and 10 µg/kg glycopyrrolate.

      Tracheal extubation will be performed immediately when all extubation criteria were achieved
      (TOF ratio ≥ 0.9, spontaneous ventilation, the ability to follow verbal commands, eyes
      opening, head lift ≥ 5 s, and hand grip).

      A pilot study showed that the proportion of the surgeons who rated their satisfaction with
      surgical conditions as an excellent (Score 4) in anesthetized patients with cisatracurium was
      92.5%. A priori power analysis indicated that a sample size of 30 patients was sufficiently
      large to detect a 30% difference in the proportion of the excellent operative conditions,
      during the use of NMRT, a type-I error of 0.05 and a power of 90%. We added more patients
      (10%) for a final sample size of 33 patients to compensate patients dropping out during the
      study.
    

Intervention name(s): Muscle Relaxants (MR) group; Non- Muscle Relaxants (NMR) group
Intervention type(s): Drug; Drug
Intervention description(s): patients received 0.2 mL/kg cisatracurium® (Nimbex) 0.2%, and a left-sided endobronchial double-lumen tube was placed when the TOF revealed one or two twitches; No cisatracurium® (Nimbex) will be administered
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Thoracic surgery; non-muscle relaxant; target-controlled infusion; remifentanil; surgical conditions