1. SUMMARY OF THE PROPOSAL :
Post-Operative Sore Throat (POST) is a common complication of airway instrumentation in General Anaesthesia that can lead to discomfort and dissatisfaction. The overall incidence of postoperative sore throat in various studies range from 51-100% 1. Many factors can contribute to postoperative sore throat and the incidence varies with the method of airway management. Female gender and increased duration of anaesthesia have been found to be associated with increased Post-Operative Sore Throat (POST) rates in various studies2. Tracheal intubation without neuromuscular blockade, use of double-lumen tubes, as well as high tracheal tube cuff pressures may also increase the risk of Post-Operative Sore Throat2. Several studies have showed a number of factors contributing to the development of POST in patients, like female gender, smoking, intubation difficulty and Suxamethonium use, high endotracheal cuff pressures, airway suctioning, long duration of surgery, Laryngeal Mask Airways, mucosal injury during laryngoscopy, or use of Pharyngeal Airway and use of large size Endotracheal tubes3. Post-Operative Sore Throat consists of pain, dysphagia, and in extreme cases, hoarseness of voice. It may also be associated with coughing. Although largely self-limiting, several remedial and preventive approaches have been studied, including topical and systemic Lidocaine therapy, Steroids such as IV Dexamethasone, Pre-operative inhaled Fluticasone, Non-steroidal Anti-inflammatory Drugs (NSAIDs) such as Benzydamine, N-Methyl-D-Aspartate (NMDA) receptor antagonists such as Magnesium and Ketamine, but none was found to be truly effective. This study will look into changes in incidence and severity of Post- Operative Sore Throat (POST) in the immediate post-operative period, with respect to administration of oral Zinc tablets in the pre-operative period.
2. TITLE:
“The Effectiveness of Pre-Operative Oral Zinc Tablets as a Pharmacological Intervention in Preventing Post-Operative Sore Throat: A Prospective Study in Adult Patients Undergoing Elective Surgery Under General Anaesthesia in KPC Medical College, Jadavpur, Kolkataâ€
3. BACKGROUND:
a. Justification and relevance of the proposed research work :
When patients undergo surgery under General Anaesthesia, they have to undergo Endotracheal Intubation, an invasive process, wherein a flexible tube is placed through the nose or mouth into their trachea facilitating mechanical ventilation, delivery of inhalational anesthetics and provide definitive airway protection from aspiration. Endotracheal Intubation is invasive and uncomfortable, leading to inflammation, giving rise to sore throat. This is called Post-Operative Sore Throat (POST). This is one of the commonest post operative complications following General Anaesthesia. Although it commonly resolves spontaneously in 72 hours, it can cause significant distress and dissatisfaction among patients.
Zinc therapy has been shown in several studies to upregulate the immune system and have anti-inflammatory properties. It helps in maintaining the integrity of skin and mucous membrane; and has been shown to reduce symptoms of inflammation.
This study aims at evaluating the effects of administering Zinc tablets orally before placement of endotracheal tubes on Post-Operative Sore Throat (POST).
b. Brief account of the present knowledge/understanding :
Post-Operative Sore Throat (POST) is a minor complication, but it can pose an immense deal of uneasiness in patientsundergoing surgery under General Anaesthesia with endotracheal intubation. The incidence of POST ranges from 21% to 100% after tracheal intubation,4 and it is one of the most common side effects in the postoperative period.Various pharmacological and nonpharmacological methods with variable success rate have been used for attenuating POST. Nonpharmacological methods tried were the use of a smaller sized tube, lubrication with water-soluble jelly, and minimizing intracuff pressure4. Pharmacological methods used include the application of steroids over the tracheal tube, lozenges, Lignocaine and Ketamine gargles etc. However, there are only a few randomized controlled trials done to compare these pharmacological methods to establish their efficacy and utility.
In this study, we will assess if preoperative oral administration of Zinc tablets can be effective in reducing the incidence of POST. To evaluate this, we will analyze the effects of oral Zinc administration on the incidence and severity of POST, cough, and hoarseness of voice, after endotracheal intubation in patients undergoing General Anaesthesia.
c. State the research question/hypothesis:
Research hypothesis seeks to compare the incidence of Post-Operative Sore Throat (POST), amongst patients undergoing elective endotracheal intubation during surgery under General Anaesthesia (GA) by anti-inflammatory effect of preoperative administration of oral Zinc.
4. REVIEW OF LITERATURE:
The highest incidence of sore throat and other airway-related symptoms tends to occur in patients who have undergone endotracheal intubation during surgery under GA. In a series of 1325 patients, there was an incidence of sore throat of 14.4% 5. In various studies it has been reported in upto 50% cases6, with 50% of patients being hoarse, 18.5% with cough and 70.5% with complaints of dryness of the throat6. Routine endotracheal intubation for elective surgical procedures can result in pathological changes, trauma and nerve damage which may also account for post-operative throat symptoms.7
The expression “Post-Operative Sore Throat†represents a broad constellation of signs and symptoms. Sore throat may also include a variety of symptoms including laryngitis, tracheitis, hoarseness, cough, or dysphagia. Post-operatively, it seems most plausible that the symptoms are the result of mucosal injury with resulting inflammation caused by the process of airway instrumentation (i.e., laryngoscopy and suctioning) or the irritating effects of a foreign object (i.e., Endotracheal Tube, Laryngeal Mask Airway, or oral airway)8. The reported incidence of POST after Laryngeal Mask Airway (LMA) insertion is remarkably similar to that seen with endotracheal intubation8. The mechanism and location of injury must also be similar. However, reducing the size of Endotracheal Tubes result in a significant decrease in the incidence of POST5. The size, pressure/volume characteristics, and shape of cuff have all been implicated in tracheal mucosal injury and resultant POST. It has been suggested that cuff inflation pressure has less of a role in POST when an LMA is used7. Both airway devices are clearly capable of inducing mucosal irritation and both can cause POST in patients at rates that are not strikingly different. Yet, anatomically, the site or sites of injury cannot be the same for both, leading to the conclusion that mechanism of inflammation if interfered with, may help to reduce the phenomena of POST8.
In experimental human Zinc-deficiency models, it has been found that even a mild deficiency increased ex vivo generation of IL-1β by Monocytes, suggesting that Zinc deficiency per se may activate Monocytes and Macrophages to generate inflammatory Cytokines and increase oxidative stress9. Zinc supplementation resulted in improved Th1 cells’ Cytokine production, decreased generation of inflammatory Cytokines, and decreased oxidative stress9.
Zinc functions as an antioxidant by different mechanisms. Firstly, Zinc competes with Iron (Fe) and Copper (Cu) ions for binding to cell membranes and proteins, displacing these redox active metals, which catalyze the production of â‹…OH- from H2O2. Secondly, Zinc binds to Sulfhydryl (SH) groups of bio-molecules, protecting them from oxidation. Thirdly, Zinc increases the activation of antioxidant proteins, molecules, and enzymes such as Glutathione (GSH), Catalase, and Super-Oxide Dismutase (SOD), and also reduces the activities of oxidant-promoting enzymes such as inducible Nitric Oxide Synthase (iNOS) and Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and inhibits the generation of lipid peroxidation products10. Zinc induces the expression of a metal-binding protein Metallothionein (MT), which is very rich in Cysteine and is an excellent excavanger of â‹…OH- ions10.
Zinc is a molecular signal for immune cells. It is required for differentiation and generation of T-Helper cells. Generation of mRNAs of IL-2 and IFN-γ, by Th1 cells, are Zinc-dependent and Zinc-dependent transcription factors are involved in this process10.
In the past, various interventional studies have resulted in only marginal reduction in incidence of POST. But the search for an effective remedy to this nagging problem continues.
5. OBJECTIVE:
To assess the effectiveness of oral Zinc tablets as a pharmacological intervention for prevention of Sore Throat in the post-operative period in patients undergoing surgery under General Anaesthsia with Endotracheal Intubation.
6. MATERIALS and METHODS:
This study would be carried out after getting approval by the Institutional Ethical Board of our tertiary care hospital. Written informed consent prior to participation will be obtained from all patients. Patients undergoing endotracheal intubation under General Anaesthesia with the American Society of Anesthesiologists (ASA) Score I~II status, aged >18 years, with a duration of surgery <4 hours and scheduled between the time-period of 2022 to 2023, for elective surgery, are to be included in the study. Patients with oral, neck, and thyroid surgeries, anticipated difficult airway, more than one attempt at intubation, preoperative steroid use, and lateral or prone position of surgery, are going to be excluded.
Patients will be divided into TWO groups by Systematic Random Sampling technique. On an average, 5~6 patients undergo General Anaesthesia in our Operation Theatres, every day. The patients would be selected alternatively, per day, till the required sample size is obtained. Group A – Zinc group, Group B – control group. Group A to be given Zinc tablets (2 tablets of Zia 20TM dispersible tablets)12 orally before intubation. While standard procedure would be followed in Group B patients during endotracheal intubation. Intraoperatively, monitoring would be done with the help of Electrocardiography (ECG), Pulse Oximetry (spO2), Non-invasive Blood Pressure (NIBP) measurements and End-tidal Carbon Dioxide (EtCO2) monitoring. Anaesthesia to be induced with Propofol (2 mg/kg) along with Morphine (0.1 mg/kg) and muscle relaxation to be achieved with Atracurium (0.6 mg/kg). After 3 min of administration of muscle relaxant, endotracheal intubation to be done with Polyvinyl Chloride (PVC) high-volume, low-pressure, cuffed Endotracheal Tube of size 7.5 mm Internal Diameter in female patients and 8.5 mm Internal Diameter in male patients. The tracheal cuff to be inflated with room air till no air leak is heard over the trachea with a peak Inspiratory Pressure of 20 cm of water. Cuff pressure to be monitored every hour and maintained between 18 and 22 cm of water. Propofol and Nitrous Oxide will be used for maintenance of anesthesia. After reversal of neuromuscular block by Neostigmine (0.05 mg/kg) and Glycopyrrolate (0.01 mg/kg); ensuring adequate reversal, the patients would be extubated and shifted to the Post Anesthesia Care Unit. The patients would be interviewed for POST, cough, and hoarseness of voice postoperatively at 1, 4, 12 & 24 h after extubation using subjective grading. The grading to be based on 4-point scale (0–3), where Grade 0 = No sore throat; Grade 1 = Mild sore throat (complaints of sore throat only on asking); Grade 2 = Moderate sore throat (complaints of sore throat on his/her own); and Grade 3 = Severe sore throat (change of voice or hoarseness, associated with throat pain).
a) Study Design:
Hospital based Prospective Interventional Study
b) Study Setting:
Operation Theatres and Post Operative patient care areas in K.P.C. Medical College and Hospital, Jadavpur, Kolkata
c) Study Period:
18 Months, from November 2022 through to April 2024. Out of which, first 12 months will be used to collect data, while the last 6 months will be devoted to tabulating & coding the data, calculating the results, establishing statistical significance, and preparing the dissertation.
d) Study Population:
Patients undergoing elective surgery under General Anaesthesia, above the age of 18 years, as per inclusion criteria.
e) Sample Size:
Sample size was determined by taking the following assumption: the proportion of POST is 59.6% based on a previous study11. Confidence level of 95% and margin of error of 0.10. The sample size was determined using the following single population proportion formula:
n=Z2(P)(1-P)/d2
Where n = sample size, Z = value of the Standard Normal Curve, P = Prevalence (0.596), d = margin of sampling error to be tolerated (0.10).
To get the sample size with confidence level of 95% and margin of error 0.5% :
n = (1.96)2 0.596(1- 0.596) / (0.10)2 = 0.925/0.01 = 92.5 = 93
Since the selection of the patients will not be done by Simple Random Sampling Technique, rather by Systematic Sampling, a design effect of size 1.5 will be considered.
Hence, the modified sample size is 93 x 1.5 = 140.
On an average per day 5~6 patients attend the OPD. Patients will be selected alternatively per day & we will continue to select them till we get the required sample size.
f) Control Required or Not :
Control required as it will be an interventional study.
g) Inclusion Criteria :
â–ª Patients with American Society of Anesthesiologists (ASA) score ASA-I and ASA-II
â–ª Patients undergoing Elective Surgery under GA
â–ª Ages 18 years and above
â–ª Patients giving consent for the study
h) Exclusion Criteria :
â–ª Patients who have any Respiratory Tract Infection (both upper & lower)
â–ª Patients who will undergo neck, mouth or throat surgery
â–ª Patients undergoing emergency surgery
â–ª Patients below 18 years of age
â–ª Patients undergoing surgery under Spinal or Regional Anaesthesia
â–ª Patients who have not given consent for the study
i) Study Variable :
Age, gender, smoking history, comorbidities, medications used, type and duration of surgery, air-way management details in patients undergoing surgery under General Anaesthesia developing Post-Operative Sore Throat (POST).
j) Data collection and interpretation :
Subjects in this study will be included after proper, informed, written consent is obtained, and all queries of the patient is explained in lucid language. All patients would be followed up postoperatively, and development of Post-Operative Sore Throat (POST) noted. Peri-Anaesthetic procedural data would also be collected during the study and their contribution to development of POST assessed in this prospective study.
k) Statistical Analysis Plan :
Multivariable analysis using standard statistical tools is to be performed. Correlation to be sought between observed incidence of POST in patients given Zinc and patients given placebo.
l) Ethical Clearance :
To be attached herewith.
7. ADDITIONAL RESOURCES and SOURCE:
a) Human resource - Anesthesiologists in the operating rooms.
b) Financial resource - No financial help taken from any source for conduct of this study.
8. BIBLIOGRAPHY/REFERENCES:
1. Shrestha S, Maharjan B, Karmacharya RM. Incidence and Associated Risk Factors of Postoperative Sore Throat in Tertiary Care Hospital. Kathmandu Univ Med J (KUMJ). 2017;15(57):10-13.
2. Kariem El-Boghdadly, C. R. Bailey, Matthew D Wiles. Postoperative sore throat: A systematic review. Anaesthesia. 2016;71(6). doi:10.1111/anae.13438.
3. Fenta E, Teshome D, Melaku D, Tesfaw A. Incidence and factors associated with postoperative sore throat for patients undergoing surgery under general anesthesia with endotracheal intubation at Debre Tabor General Hospital, North central Ethiopia: A cross-sectional study. Int J Surg Open. 2020; 25:1-5. doi:10.1016/j.ijso.2020.06.003.
4. Christensen AM, Willemoes-Larsen H, Lundby L, Jakobsen KB. Postoperative throat complaints after tracheal intubation. Br J Anaesth. 1994;73(6):786-787. doi:10.1093/bja/73.6.786.
5. Herlevsen P, Bredahl C, Hindsholm K, Kruhoffer PK. Prophylactic laryngo-tracheal aerosolized lidocaine against postoperative sore throat. Acta Anaesthesiologica Scandinavica 1992; 36: 505– 7.
6. Jorgensen LN, Weber M, Pedersen A, Munster M. No increased incidence of postoperative sore throat after administration of Suxamethonium in endotracheal anaesthesia. Acta Anaesthesiologica Scandinavica 1987; 31: 768– 70.
7. McHardy FE, Chung F. Postoperative sore throat: cause, prevention and treatment: Postoperative sore throat. Anaesthesia. 1999;54(5):444-453. doi:10.1046/j.1365-2044.1999.00780.x.
8. Scuderi, Phillip E. MD. Postoperative Sore Throat: More Answers Than Questions. Anesthesia & Analgesia: October 2010 - Volume 111 - Issue 4 - p 831-832doi: 10.1213/ANE.0b013e3181ee85c7.
9. Prasad AS. Zinc is an antioxidant and anti-inflammatory agent: Its role in human health. Front Nutr. 2014;1:14. doi:10.3389/fnut.2014.00014.
10. Bao B, Ahmad A, Azmi A, Li Y, Prasad A, Sarkar FH. The biological significance of zinc in inflammation and aging. In: Inflammation, Advancing Age and Nutrition. Elsevier; 2014:15-27.cited on 28.09.2022.
11. Gemechu BM, Gebremedhn EG, Melkie TB. Risk factors for postoperative throat pain after general anaesthesia with endotracheal intubation at the University of Gondar Teaching Hospital, Northwest Ethiopia, 2014. Pan Afr Med J. 2017;27:127. Published 2017 Jun 16. doi:10.11604/pamj.2017.27.127.10566.
12. Educational book agency (India). Indianpharmacopoeia.in. Accessed November 8, 2022. https://www.indianpharmacopoeia.in/Salient_Features_of_IP_2022.pdf