Testing Two Doses of Nebulized Ketamine for Postoperative Sore Throat

Postoperative sore throat (POST) is a common complication following general anesthesia with endotracheal intubation, with reported incidences ranging from 20% to 90%, depending on patient characteristics, airway management techniques, endotracheal tube size, cuff pressure, duration of surgery, and methods of postoperative assessment. Although generally self-limiting, POST remains an important cause of postoperative discomfort, delayed recovery, and reduced patient satisfaction. Consequently, reducing the incidence and severity of POST has become an important quality indicator in perioperative care.

The pathophysiology of POST primarily involves mechanical trauma to the pharyngeal and laryngeal mucosa during laryngoscopy, endotracheal tube insertion, cuff inflation, and extubation. This mechanical injury triggers local inflammation, mucosal edema, and activation of peripheral nociceptors, resulting in postoperative pain and throat irritation.

Numerous pharmacological and non-pharmacological interventions have been investigated to prevent POST, including topical lidocaine, corticosteroids, magnesium sulfate, benzydamine hydrochloride, licorice, ketamine gargles, and nebulized ketamine. Among these strategies, nebulized ketamine has attracted increasing interest because it is non-invasive, easy to administer, inexpensive, and capable of delivering high local drug concentrations while minimizing systemic exposure.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with well-established analgesic, anti-inflammatory, and antihyperalgesic properties. In addition to central analgesic effects, ketamine exerts peripheral actions through NMDA receptors located on airway mucosa and inflammatory cells, reducing local inflammatory responses and peripheral sensitization. Nebulized administration enables topical deposition throughout the upper airway, potentially preventing mucosal inflammation caused by endotracheal intubation.

Several randomized controlled trials and systematic reviews have demonstrated that nebulized ketamine significantly reduces both the incidence and severity of postoperative sore throat compared with placebo without producing clinically significant systemic adverse effects. However, nearly all previous clinical studies have evaluated a single dose of 50 mg. Whether a lower dose can provide equivalent clinical efficacy while further reducing the potential for dose-related adverse effects remains uncertain.

Determining the minimum effective dose has important clinical implications. If a lower dose provides similar protection against POST, it may improve the benefit-risk profile of nebulized ketamine, reduce drug exposure, decrease treatment costs, and facilitate wider implementation as part of routine perioperative care.

This study is designed as a prospective, randomized, placebo-controlled, double-blind clinical trial conducted at Aswan University Hospital. Adult patients aged 18-65 years with American Society of Anesthesiologists (ASA) physical status I or II who are scheduled for elective surgery under general anesthesia with endotracheal intubation will be enrolled after providing written informed consent.

Eligible participants will be randomly assigned in a 1:1:1 ratio to receive one of three interventions approximately 15 minutes before induction of anesthesia:

Group A: Nebulized ketamine 50 mg diluted to 5 mL. Group B: Nebulized ketamine 25 mg diluted to 5 mL. Group C: Nebulized 0.9% normal saline (5 mL placebo).

Randomization will be performed using a computer-generated sequence with allocation concealment through sequentially numbered, opaque, sealed envelopes. The study medication will be prepared by an anesthesiologist not involved in patient management or outcome assessment. Participants, anesthesia providers, postoperative assessors, and data analysts will remain blinded to treatment allocation throughout the study.

A standardized anesthesia protocol will be used for all participants, including induction with propofol, fentanyl, and atracurium, followed by maintenance with sevoflurane in an oxygen-air mixture. Endotracheal intubation will be performed using standard techniques, and cuff pressure will be maintained between 20 and 25 cmH₂O to minimize airway mucosal injury.

The primary outcome is the incidence of postoperative sore throat assessed at 2, 4, 6, 12, and 24 hours after extubation using a standardized four-point grading scale.

Secondary outcomes include:

Severity of postoperative sore throat. Postoperative pain intensity measured using the Visual Analog Scale (VAS). Patient satisfaction. Time to first rescue analgesic request. Total rescue analgesic consumption. Sedation assessed using the Ramsay Sedation Scale. Incidence of adverse events including nausea, dizziness, hallucinations, excessive sedation, and allergic reactions.

Safety monitoring will be performed throughout the perioperative period. Any adverse event will be documented, appropriately managed, and analyzed according to study protocol.

The study hypothesis is that preoperative nebulized ketamine reduces postoperative sore throat compared with placebo and that a 25-mg dose is non-inferior to the conventional 50-mg dose while maintaining a more favorable safety profile. The findings are expected to provide high-quality evidence regarding dose optimization of nebulized ketamine for prevention of postoperative sore throat and may contribute to future evidence-based perioperative airway management guidelines.