Effect of Selenium on Succinylcholine-Induced POM
Condition: Postoperative Myalgia
MeSH terms: Myalgia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      For more than 60 years, succinylcholine is still being administered as the selective relaxant
      for rapid sequence intubation by anesthesiologists in many countries. It has been shown to
      possess unique features such as low cost, fast-acting, short half-life, safe metabolites, and
      causing excellent muscle relaxation for intubation. However, it has many side effects as
      well.

      Postoperative myalgia (POM), with an incidence rate of about 41%-92%, is one of the most
      common side effects of this drug and can take several days to cause significant discomfort in
      patients. However, its effect is felt more in the throat, neck, shoulder, and abdominal
      muscles and is common among patients with outpatient surgery. Due to its unknown real context
      of pathogenesis and in an effort to reduce the incidence and severity of
      succinylcholine-induced myalgia, various medications including non-depolarizing muscle
      relaxants, benzodiazepines, magnesium sulfate, opioids, gabapentin, pregabalin and
      nonsteroidal anti-inflammatory drugs have been tested, with varying degrees of success.

      Free radicals are created as a consequence of ATP (adenosine triphosphate) production by the
      mitochondria. These by-products are generally reactive oxygen species (ROS) as well as
      reactive nitrogen species (RNS) that result from the cellular redox process. These species
      play a dual role as both toxic and beneficial compounds. The delicate balance between their
      two antagonistic effects is clearly an important aspect of life. At low or moderate levels,
      ROS and RNS exert beneficial effects on cellular responses and immune function. At high
      concentrations, they generate oxidative stress, a deleterious process that can damage all
      cell structures. Muscle injuries might lead to the production of free radicals and further
      cellular damage, triggered by lipid peroxidation and protein oxidation. Peroxidation of
      membrane lipids leads to loss of membrane fluidity and elasticity, impaired cellular
      functioning, and even cell rupture. The various direct products of lipid peroxidation, such
      as malondialdehyde (MDA), isoprostanes, and 4-hydroxynonenal are considered among the most
      important biomarkers of oxidative stress in tissues. Malondialdehyde is a reactive carbonyl
      compound and is both mutagenic and carcinogenic. It reacts with DNA to form DNA adducts that
      are believed to contribute significantly to cancers linked to lifestyle and dietary factors.
      Protein oxidation can cause fragmentation at amino acid residues, formation of
      protein-protein cross-linkages, and oxidation of the protein backbone which ultimately leads
      to loss of function. Damaged proteins affect intracellular pathways and are contributing
      factors to different disorders and diseases. Protein carbonyl (CO) groups are produced on
      protein side chains during oxidation. High levels of protein CO groups have been observed in
      rheumatoid arthritis, Alzheimer's disease, diabetes, sepsis and chronic renal failure.

      Selenium is a well-recognized antioxidant which act s as a cofactor of antioxidant enzymes.
      This essential element helps protect the body against free radicals causing damage to the
      cells. Substantial evidence suggests that free radical production leads to increased oxygen
      uptake over time. The indirect though significant impact of selenium supplements is to
      protect the cells against oxidative stress and free radical production. Nature-made selenium
      contains 200 mg of this element with a natural origin, high absorption capacity, and
      prolonged retention. Selenium exerts its antioxidant effects through glutathione peroxidase.
      Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyze the
      breakdown of hydrogen peroxide and organic hydroperoxides. There are at least four different
      glutathione peroxidase isozymes in animals. Glutathione peroxidase 1 is the most abundant and
      is a very efficient scavenger of hydrogen peroxide, while glutathione peroxidase 4 is most
      active with lipid hydroperoxides. The glutathione S-transferases show high activity with
      lipid peroxides. These enzymes are at particularly high levels in the liver and serve in
      detoxification metabolism.
    

Detailed description: 
      Eligibility and type of the study: This prospective randomized placebo-controlled
      double-blind study will be conducted after approval from the Institutional Ethics Committee
      and obtaining written informed consent from patients scheduled for elective adult sinuscopic
      procedures under general anesthesia. This study will be conducted at Assiut University
      Hospital from April 2018 until April 2019.

      Sample size: Sample size calculation is based on the pilot study, where the incidence of POM
      in outpatient cases is found to be more than 70% and intervention that can cause 25-50%
      reduction in incidence of POM will be interesting. With a power of 90% and type I error of
      5%, 37 patients will be required in each group (α=0.05 and β=90%). But to avoid possible loss
      of samples (dropouts) during the study, the number of patients in each group will be
      increased to 40 to be a total of 80 patients.

      Drugs coding and Randomization: Patients will be randomly allocated to two equal groups with
      the help of a computer-generated table of random numbers to receive the study drugs. All
      capsules will be removed from their strips and will be stored in envelopes numbered from 1 to
      80. The envelopes will be numbered and randomized according to the computer-generated
      randomization tables to ensure an equal number of patients in each arm. Access to the
      envelopes codes will be only available to one anesthesiologist who will pack the envelopes.
      The anesthetic technique and outcome data will be collected by an anesthesiologist not
      included in giving study drugs or envelops coding.

      Patients: Eighty patients will be enrolled in this study. They will be equally divided into
      two groups:

        -  Group C (control group): 40 patients will receive starch capsules orally with sips of
           water 2 hours before induction of anesthesia.

        -  Group S (Selenium group): 40 patients will receive Selenium (selenium NATURE'S BOUNTY,
           INC. Bohemia) 200 mcg orally with sips of water 2 hours before induction of general
           anesthesia.

      Anesthetic Technique and Data Collection: Two days before surgery, patients will visit the
      outpatient clinic for history taken, clinical assessment and explanation about the study
      protocol. Laboratory investigations will be performed and patients will be informed that they
      can stop participation in the study at any time without any loss of service.

      With no pre-medications and 2 hours before sinuscopies, the study drug will be given to all
      patients by another anesthesiologist blinded to the envelops coding. No IM injections will be
      administered during the perioperative period.

      Inside the operating room, standard monitoring (electrocardiogram, non-invasive blood
      pressure, heart rate, peripheral oxygen saturation) will be attached and the preliminary
      values will be recorded. An intravenous cannula 18G will be inserted and secured in the
      dorsum of the non-dominant hand and intravenous fluids (NaCl 0.9%) was started at the
      calculated volume and rate. After 3 minutes of 100% pre-oxygenation via facemask, anesthesia
      will be induced with fentanyl 1 mcg/kg, propofol 2.0 mg/kg (diluted with normal saline 0.9%)
      and succinylcholine 1.5 mg/kg.

      Fasciculations Assessment:

      The intensity of fasciculations will be assessed by an anesthesiologist blinded to the
      patient's group allotment based on a four-point scale.

      After end of fasciculations, the values of heart rate, non-invasive blood pressure and oxygen
      saturation will be measured and recorded.

      Patients will be intubated with an appropriate size cuffed endotracheal tube under direct
      laryngoscopy after complete muscular relaxation. The endotracheal tube then will be fixed at
      the appropriate length, by adhesive tape at the angle of the mouth. After 5 minutes of
      tracheal intubation, the previous values in addition to the EtCO2 will be recorded.
      Subsequent values will be recorded every 5 minutes throughout the surgical procedure.
      Anesthesia will be maintained with oxygen 100% and sevoflurane (2-4% MAC). The respiratory
      tidal volume will be adjusted to keep end-tidal CO2 at 35-40 mmHg. The same surgical team
      will complete all surgical procedures. Atend of surgery and before extubation, all patients
      will receive infraorbital block by bupivacaine 0.25% 1 ml each side.

      At the end of the procedure, sevoflurane inhalation will be discontinued and all patients
      will be ventilated by 100% oxygen until full consciousness regains and following verbal
      commands. At that point, endotracheal tubes will be removed after gentle suction of
      secretions through the tube and the oropharyngeal cavity. After the desired spontaneous
      ventilation, the patients will be transferred to post-anesthesia care unit (PACU).

      In PACU, postoperative care will be standardized for all patients. Pain related to POM will
      be treated with paracetamol 1g intravenously (Perfalgan; Bristol-Myers Squibb, New York, USA)
      when NRS more than or equal 4. The total dose of analgesic requirement in the first 24 hours
      will be recorded. After meeting the discharge criteria, the patients will be discharged to be
      taken home and cared for, by a responsible adult.

      Myalgia Assessment:The incidence and severity of myalgia in all patients will be determined
      24 hours after surgery by an anesthesiologist who is unaware of the grouping. Myalgia is
      defined as "a pain with no surgical interference" and is graded based on a four-point scale.

      Pain Assessment:

      All pain scores will be obtained during rest. To assess postoperative pain, Numeric rating
      scale (NRS) will be used. The NRS is a segmented numeric version of the visual analog scale
      (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the
      intensity of their pain. The common format is a horizontal bar or line. An 11-point numeric
      scale (NRS 11) with 0 representing one pain extreme (e.g., "no pain") and 10 representing the
      other pain extreme (e.g., "pain as bad as you can imagine" and "worst pain imaginable"). NRS
      will be used immediately at the recovery room, 1, 2, 4, 6, 12 and 24 hours postoperatively

      Laboratory Study:

      Glutathione peroxidase measurement in plasma will be assessed in venous blood sample of all
      included patients (4 ml) under complete aseptic conditions at two events; baseline before
      induction of anesthesia (in the holding area after IV canula insertion) and 6, 24 hours after
      induction of anesthesia.

      Assessment of possible complications:

      Any complications like postoperative nausea, vomiting, headache, dizziness, somnolence,
      vertigo, confusion will be recorded and managed accordingly. Nausea will be treated by 10 mg
      metoclopramide intravenously, vomiting will be treated by 4 mg ondansetron intravenously.

      Statistical Analysis:

      Data will be performed using a standard SPSS software package version 21 (SPSS Inc., Chicago,
      Illinois, USA). Data will be expressed as mean ± SD, numbers (n), percentages (%) and median
      (range). The demographic data will be analyzed by Student t-test. Patient data will be
      analyzed with the Chi square test. The consumption of analgesia in groups will be analyzed by
      using Student t-test. The incidence and severity of fasciculation and POM will be analyzed
      using Fisher's exact test. Pearson's r correlation will be used to test the correlation
      between fasciculations and postoperative myalgia. A p-value of <0.05 will be considered
      statistically significant.

      Ethical Considerations:

        -  Patients will be informed about the nature and steps of the study.

        -  Any patient can stop participation in the study at any time without any loss of service.

        -  There is no risk affecting the patients participating in this study.

        -  Any data taken from all patient will be made confidential and available only to persons
           conducting the study.

        -  Written consent will be obtained from each patient after approval from our institutional
           ethical committee.

        -  All of the regulations of the local ethics committee of Faculty of Medicine, Assiut
           University will be followed.
    

Intervention name(s): Placebo; Selenium
Intervention type(s): Drug; Drug
Intervention description(s): 40 patients will receive starch capsules orally with sips of water 2 hours before induction of anesthesia; 40 patients will receive Selenium (selenium NATURE'S BOUNTY, INC. Bohemia) 200 mcg orally with sips of water 2 hours before induction of general anesthesia
Intervention MeSH terms: Selenium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention