Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03476044 |
| Other study ID # |
Selenium and POM |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2018 |
| Est. completion date |
March 31, 2020 |
Study information
| Verified date |
October 2020 |
| Source |
Assiut University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
