Fade Upon TOF Stimulation Induced by Succinylcholine
Condition: Muscle Relaxants
MeSH terms: Muscle Hypotonia
Study type: Interventional
Phase: Phase 4

Summary: 
      Muscle relaxants are medications used during surgery to facilitate surgical access. The
      effect of the muscle relaxant medications is measured by stimulation a motor nerve and
      measuring the force of the resultant muscle contraction. Based on the mechanism of action,
      two kinds of muscle relaxants are described. First a nondepolarizing muscle relaxant and the
      second kind is the depolarizing muscle relaxant. These two kinds of muscle relaxants can be
      distinguished by rapidly stimulating the nerve 4 times over 2 seconds (Train of four or TOF).
      The nondepolarizing muscle relaxants produce fade ie successive muscle contractions are less
      forceful than the preceding ones. Whereas the depolarizing muscle relaxants are generally
      believed to produce four contractions of equal strength. However, there is some indication
      that this may not be entirely correct. There is evidence that depolarizing muscle relaxants
      also may produce fade. The investigators are conducting the following study to determine if
      indeed depolarizing muscle relaxants produce fade. The investigators would also like to
      characterize the fade ie differences during onset and offset of the block and the effect of
      the dose on the degree on the fade.
    

Detailed description: 
      Muscle relaxants are frequently employed during anesthesia. These medications may be employed
      to facilitate tracheal intubation, mechanical ventilation or to allow better surgical access.
      All muscle relaxants act at the neuromuscular junction. Based on the mechanism of action, two
      kinds of muscle relaxants have been defined1. Nondepolarizing muscle relaxants are
      competitive antagonists of the neurotransmitter acetylcholine (Ach) at the neuromuscular
      junction. The second kind of muscle relaxant is the depolarizing muscle relaxant and
      succinylcholine is the only muscle relaxant in this class that is clinically used. The
      mechanism of action of succinylcholine is less clear. Succinylcholine appears to mimic the
      actions of acetylcholine but results in a longer duration of depolarization of the post
      synaptic membrane1.

      The degree of muscle relaxation produced by these muscle relaxants is measured by stimulating
      a motor nerve and measuring either the force of the muscle contraction produced or its
      compound muscle action potential (CMAP). As the muscle relaxation increases, the force of
      muscle contraction or the amplitude of the electromyogram (EMG) is correspondingly reduced.

      On occasion, to measure the degree of muscle weakness or paralysis caused by a muscle
      relaxant, instead of a single stimulus, trains of stimuli are applied2. One method of
      repetitive stimulation is to apply four stimuli over a two second period. This method of
      nerve stimulation is called Train-of-Four (TOF). When this form nerve stimulation (TOF) is
      applied to patients who have been given nondepolarizing muscle relaxants -there is fade. Fade
      means that the force of successive muscle contractions is less than the preceding
      contraction3. The second contraction is less than the first, the third less than the second
      and so on. The degree of fade appears to have some reasonably well defined relationship to
      the degree of relaxation produced3.

      The classic teaching in the anesthetic literature is that depolarizing muscle relaxants do
      not produce fade upon repetitive stimulation. It means that upon repetitive stimulation, the
      successive contractions are similar. This is one of the defining features of a depolarizing
      block and is called a Phase I block. The traditional teaching is that when a depolarizing
      muscle relaxant is administered in large or repetitive doses, a Phase II block develops. The
      phase II block has characteristics similar to those of a nondepolarizing muscle relaxant (ie
      fade on repetitive or TOF stimulation). De Jong and Freund first proposed that this
      differentiation between deplolarizing and nondepolarizing block based upon fade may not be as
      clear cut. These investigators demonstrated that succinylcholine caused fade upon repetitive
      stimulation right from the outset of the neuromuscular block. Other investigators have also
      demonstrated that succinylcholine causes fade from the initiation of the neuromuscular block.
      If it can be conclusively demonstrated that succinylcholine causes fade, then fade would be
      less useful in differentiating a depolarizing from a nondepolarizing block. We have
      previously investigated and defined the fade caused by nondepolarizing muscle relaxants.
      Using the experience we have gained in studying fade with nondepolarizing muscle relaxants,
      we would like to now define the characteristics of fade (if any) caused by succinylcholine.

      Method: We intend to enroll fifty healthy adults, 18-60 years of age of either sex who are
      scheduled to undergo a surgical procedure under general anesthesia. Only subjects with a BMI
      <25 Kg/m2 will be enrolled. Only subjects free from any hepatic or renal disease will be
      included. We will exclude any subjects with known allergy to succinylcholine, family history
      of malignant hyperthermia or any history of skeletal myopathy. We will also exclude subjects
      that have recently sustained burns, or any illness resulting denervation injury (paraplegia
      or hemiplegia).

      The subjects will give an informed consent prior to the participation in the study. All
      patients will receive 2 mg of midazolam for premedication. Anesthesia will be induced with
      the intravenous administration of fentanyl 5-6 µg/kg and propofol 2-3 mg/kg. Following
      tracheal intubation, anesthesia will be maintained with 70% nitrous oxide in oxygen
      supplemented with an infusion of propofol (120 -150 µg/kg/min). Ventilation will be
      controlled to maintain normocapnia (end-tidal carbon di oxide 35-40 mmHg).

      After the commencement of the anesthesia monitoring of neuromuscular transmission will be
      commenced. Ulnar nerve at the wrist will be stimulated in a TOF sequence (2 Hz every 12
      seconds). The resultant force of contraction of the adductor pollicis will be recorded using
      a mechanomyograph. After obtaining a stable muscle contraction, succinylcholine will be
      administered. The subjects will be randomly allocated to one of five groups. Group 1 will
      receive 0.1 mg/kg, group 2 -0.15 mg/kg, group 3 -0.2 mg/kg, group 4 -0.25 mg/kg, group 5 -0.3
      mg/kg. Muscle contraction will be recorded until the force of muscle contraction returns to
      baseline (6-8 minutes). At this time the study will be concluded. Further conduct of the
      anesthetic will be at the discretion of the subject's primary anesthesiologist.

      Data Analysis: We intend to plot the force of all four muscle contractions from immediately
      preceding the injection succinylcholine to complete recovery of the muscle contraction. We
      would then plot the force of the first twitch (T1) against the ratio of the fourth to the
      first twitch (T4/T1 ratio) for each individual subject. This plot will allow us to determine
      if there is any difference in fade characteristics between onset and offset of muscle
      relaxant effect.
    

Intervention name(s): Succinylcholine
Intervention type(s): Drug
Intervention description(s): will be administered succinylcholine in a dose of 0.1 mg/kg in Arm 1, 0.15 mg/kg in Arm 2, 0.2 mg/kg in Arm 3, 0.25 mg/kgin Arm 4, 0.3 mg/kg in Arm 5.
Intervention MeSH terms: Succinylcholine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: succinylcholine; depolarizing muscle relaxants; pharmacologic effects