Postoperative sore throat (POST) represents one of the most frequent complications following general anesthesia with endotracheal intubation, affecting 12.1% to 70.3% of patients undergoing surgical procedures[1]. Although traditionally classified as a minor complication, POST significantly impacts patient satisfaction, extends hospital stays in outpatient and day-care surgical settings, and can lead to serious sequelae including voice hoarseness, difficulty swallowing, aspiration pneumonia, and laryngeal damage[1,2,3]. The mechanisms underlying POST are multifactorial, involving direct mucosal trauma during laryngoscopy and intubation, sustained pressure from the endotracheal tube cuff causing ischemic injury to the tracheal mucosa, epithelial erosion, and airway inflammation[1,4]. Excessive cuff pressure exceeding 30 cm of water diminishes capillary perfusion to the tracheal mucosa, rendering tissue vulnerable to ischemic injury[1].

Despite decades of clinical experience, POST remains an inadequately managed complication, particularly in extended surgical procedures exceeding two hours in duration. Multiple pharmacological and non-pharmacological interventions have been investigated to mitigate POST incidence and severity[5,6,7]. Non-pharmacological approaches include meticulous airway handling, use of appropriately sized endotracheal tubes, maintenance of cuff pressure at or below 20 cm H₂O, single-attempt intubation, gentle oropharyngeal suctioning under direct visualization, and careful cuff deflation during extubation[7,8]. Pharmacological strategies encompassing topical or systemic administration of analgesic and anti-inflammatory agents have also demonstrated efficacy in reducing POST[6,8,9].

N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine and magnesium, represent a promising pharmacological approach to POST prevention[10]. These agents possess analgesic and anti-inflammatory properties mediated through blockade of NMDA receptors present in both central and peripheral nervous systems[10,11]. The analgesic mechanisms include reduction of nuclear factor-kappa B (NF-κB) activity, tumor necrosis factor-alpha (TNF-α) production, inducible nitric oxide synthase expression, and circulating levels of serum C-reactive protein, interleukin-6 (IL-6), and interleukin-10 (IL-10)[10].

Amongst various delivery modalities, nebulization has emerged as the preferred method for administering these agents. Compared to gargling, nebulization offers uniform distribution across all airway regions affected by instrumentation-induced injury, eliminates aspiration risk associated with ingested gargle solutions, requires smaller drug volumes, demonstrates superior patient acceptability, and enables medication delivery to deeper airway structures[12,13]. Previous comparative studies have yielded conflicting results regarding the relative efficacy of ketamine and magnesium sulfate in POST prevention[13,14,15,16,17]. Some investigations favored magnesium sulfate[15], while others demonstrated superior outcomes with ketamine[13,16]. These inconsistencies necessitate further investigation to establish which agent provides optimal prophylaxis.

Objective: To compare the efficacy of nebulized ketamine and magnesium sulfate in reducing the incidence and severity of postoperative sore throat in patients undergoing general anesthesia with endotracheal intubation.

This comparative observational study was conducted in the Department of Anaesthesiology. The research protocol received approval from the institutional ethics committee. Written informed consent was obtained from all patients or their legal representatives in their preferred language, in accordance with the tenets of the Helsinki Declaration. Sample size was calculated using web-based software from the University of British Columbia. Calculations were based on comparisons of means between two independent samples. A pilot study of 10 subjects revealed a mean reduction in Visual Analogue Scale (VAS) pain score of 3.0 in the ketamine group and 2.4 in the magnesium sulfate group (common standard deviation = 1.0). With alpha set at 0.05 and power at 80%, the estimated sample size was 44 patients per group, yielding a total sample size of 88 patients. Patients were randomly allocated to study groups using computerized randomization with sealed, opaque envelope assignment. Odd numbers were assigned to Group 1 (magnesium sulfate), and even numbers to Group 2 (ketamine). Inclusion criteria: (1) patients who consented to study participation; (2) age 20–65 years of either gender; (3) American Society of Anesthesiologists (ASA) physical status I or II; (4) elective surgery under general anesthesia with endotracheal intubation; (5) surgery duration between 30–90 minutes. Exclusion criteria: (1) patient refusal to participate; (2) documented allergy to study medications; (3) pregnancy or lactating status; (4) intubation difficulty requiring >2 laryngoscopic attempts or traumatic intubation; (5) excessive perioperative bucking requiring IV lidocaine rescue during extubation. Study Interventions: All patients received standardized monitoring including continuous pulse oximetry, electrocardiography, and capnography, with non-invasive blood pressure measured at 5-minute intervals. Baseline hemodynamic parameters (heart rate, systolic and diastolic blood pressure, oxygen saturation) were recorded. Group 1 (n=44): Received nebulization with 250 mg magnesium sulfate in 5 mL normal saline. Group 2 (n=44): Received nebulization with 50 mg ketamine in 5 mL normal saline. Study drugs were prepared by an anesthetist not involved in patient assessment or data collection. Nebulization was administered using a wall-mounted oxygen source at 10 L/minute for 15 minutes, beginning 5 minutes prior to induction of general anesthesia. Anesthesia Protocol: Fifteen minutes post-nebulization, general anesthesia was induced with IV midazolam 0.02 mg/kg, IV fentanyl 2.0 μg/kg, and IV propofol 2–2.5 mg/kg, following 3-minute pre-oxygenation with 100% oxygen via hand-held face mask. Tracheal intubation was facilitated by IV vecuronium 0.1 mg/kg. Male patients received endotracheal tubes sized 8.0–8.5 mm inner diameter; female patients received 7.0–7.5 mm inner diameter tubes. Cuff pressure was maintained at 20 cm H₂O immediately after intubation and monitored every 30 minutes throughout surgery. Anesthesia was maintained with a 50:50 mixture of nitrous oxide and oxygen, isoflurane 1–2%, and intermittent doses of fentanyl and vecuronium as required. Duration of laryngoscopy and time to successful intubation were recorded. Thirty minutes before surgery completion, all patients received IV ondansetron 4 mg and IV diclofenac 75 mg. At surgery conclusion, the oropharynx was gently suctioned, volatile anesthetics were discontinued, and inspired oxygen was increased to 100%. Neuromuscular blockade was reversed with IV neostigmine 0.5 mg/kg and IV glycopyrrolate 0.1 mg/kg following spontaneous ventilation return. During extubation, if excessive bucking occurred, IV lidocaine 1.5 mg/kg was administered and the patient was excluded from analysis. POST assessment was performed immediately after extubation and at 6, 12, and 24 hours postoperatively. Severity was graded on a 4-point scale: 0 (no symptoms), 1 (mild throat discomfort), 2 (moderate sore throat), and 3 (severe sore throat with difficulty swallowing). Outcome Measurements Primary outcome: Incidence of postoperative sore throat at 4 hours postoperatively. Secondary outcomes: (1) Incidence and severity of POST at 6, 12, and 24 hours postoperatively; (2) severity of pain assessed using a 4-point scale (0 = no sore throat, 1 = mild, 2 = moderate, 3 = severe); (3) hemodynamic parameters (systolic and diastolic blood pressure, mean arterial pressure, heart rate) at predetermined intervals; (4) incidence of voice hoarseness and cough. Statistical Analysis: Data were entered into Microsoft Excel spreadsheets and analyzed using SPSS version 22.0 for Windows (IBM Corporation, Armonk, NY). Descriptive statistics included means and standard deviations for continuous variables and frequencies with percentages for categorical variables. Comparative analysis between groups employed independent t-tests for continuous variables and chi-square tests for categorical variables. Hemodynamic parameters were compared at each time interval using appropriate statistical tests. Statistical significance was established at p < 0.05.

Eighty-eight patients completed the study protocol without protocol violations. Table 1 presents demographic data stratified by study group. There were approximately equal distributions of males and females between groups. Mean age was 37.79 ± 9.52 years in the ketamine group and 38.93 ± 9.85 years in the magnesium sulfate group (p = 0.81). Over 63% of subjects in both groups belonged to ASA physical status grade I. Mean surgical duration was 86.32 ± 11.49 minutes in the ketamine group and 81.65 ± 10.59 minutes in the magnesium sulfate group (p = 0.61). No significant differences were identified in baseline demographic variables between groups (p > 0.05 for all comparisons) as shown in table 1.

Table 1: Demographic profile of study participants stratified by treatment group

Systolic blood pressure (SBP) increased acutely in both groups immediately following intubation (baseline ketamine: 127.9 ± 8.1 mmHg; baseline magnesium: 129.2 ± 9.5 mmHg; immediately post-intubation ketamine: 130.5 ± 7.7 mmHg; magnesium: 132.8 ± 9.7 mmHg). After 10 minutes, SBP decreased in both groups through 60 minutes, then remained within physiologically appropriate ranges through surgery completion. SBP remained comparable between groups at all intervals (p > 0.05). Similarly, diastolic blood pressure (DBP) increased immediately following intubation in both groups and decreased gradually through 2 hours, then stabilized. DBP was comparable between groups at all intervals (p > 0.05).

Mean arterial pressure (MAP) demonstrated acute elevation immediately post-intubation in both groups, subsequently decreasing over the first hour and remaining within normal ranges through surgery completion. MAP was comparable between groups throughout all monitoring intervals (p > 0.05). Heart rate increased acutely following intubation, gradually decreased through 60 minutes, and remained stable thereafter in both groups, with no significant differences between groups at any interval (p > 0.05) as shown in table 2.

At immediate postoperative period (0 hours), no patients in either group complained of sore throat immediately upon arrival at the post-anesthesia care unit. At 4 hours postoperatively, in the ketamine group, 5 patients (11.4%) complained of sore throat compared to 12 patients (27.3%) in the magnesium sulfate group, representing a statistically significant difference (p = 0.002, 95% CI). At 6 hours postoperatively, sore throat was reported in 3 patients (6.8%) in the ketamine group versus 8 patients (18.2%) in the magnesium sulfate group (p = 0.039). At 24 hours postoperatively, no patients in either group reported sore throat at the 24-hour assessment. Pain severity at 4 and 6 hours postoperatively was significantly greater in the magnesium sulfate group compared to the ketamine group (p < 0.05). At 12 and 24 hours, pain scores were higher in the magnesium sulfate group compared to ketamine, although differences did not reach statistical significance (p > 0.05). No patient in the ketamine group complained of voice hoarseness, while hemodynamic parameters remained stable and comparable between groups throughout the perioperative period.

Table 3: Visual Analogue Scale (VAS) scores for postoperative sore throat severity at different time intervals. *Statistically significant difference (p < 0.05).

This comparative observational study evaluated the relative efficacy of nebulized ketamine and magnesium sulfate in preventing postoperative sore throat in 88 patients undergoing general anesthesia with endotracheal intubation. The principal finding was that preoperative nebulization with ketamine resulted in significantly lower incidence of POST at 4 and 6 hours postoperatively compared to magnesium sulfate nebulization.

The superiority of ketamine in POST prevention aligns with recent literature. Segaran et al. reported that nebulized ketamine 50 mg significantly decreased POST incidence at 4 and 6 hours compared to magnesium sulfate 250 mg[16]. Similarly, Teymourian et al. demonstrated that magnesium sulfate gargle was more effective than ketamine gargle when both were administered at lower concentrations[15], whereas at higher magnesium doses and with ketamine nebulization (rather than gargling), ketamine demonstrated superior efficacy[13]. These observations suggest that drug concentration and delivery method substantially influence therapeutic outcomes.

The mechanisms underlying ketamine's superior efficacy likely relate to its pharmacological profile. Ketamine, as an NMDA receptor antagonist, provides rapid analgesic effects through blockade of N-methyl-D-aspartate receptors distributed throughout peripheral and central nervous systems[10]. Additionally, ketamine possesses inherent local anesthetic properties attributable to inhibition of sodium channels, similar to lidocaine in terms of pKa and molecular weight[11,18]. This dual mechanism—NMDA antagonism combined with local anesthetic activity—may provide additive protective effects against mucosal injury. Magnesium sulfate, while also functioning as an NMDA antagonist, lacks local anesthetic properties[10].

The delivery method substantially influences therapeutic efficacy. Nebulization was selected over gargling because it ensures uniform distribution of medication to all mucosal surfaces subjected to instrumentation-induced injury, eliminates aspiration risk, requires smaller drug volumes, and demonstrates superior patient acceptability[12,13]. This study employed 15-minute nebulization administered 5 minutes prior to anesthesia induction, allowing adequate drug exposure to airway tissues before surgical manipulation and intubation trauma. Shorter nebulization periods or different timing regimens may yield suboptimal results.

Our findings demonstrate that ketamine nebulization was well-tolerated with no adverse effects reported, consistent with prior investigations[13,19]. Hemodynamic parameters remained stable and comparable between groups, demonstrating the safety of both agents. Neither study drug produced emergence delirium, psychotomimetic effects, or other serious complications. This favorable safety profile contrasts with some older literature describing psychodysleptic effects following ketamine administration[11]; such effects are substantially less common with low-dose nebulized administration compared to systemic bolus or infusion dosing[12].

The timing and intensity of POST differed notably between groups. Peak sore throat incidence occurred at 4–6 hours postoperatively, with symptom resolution by 24 hours in both groups. The ketamine group demonstrated earlier symptom improvement, with significantly lower pain severity at 4 and 6 hours. This temporal pattern aligns with the known pharmacokinetics of topical drug deposition and mucosal wound healing. The anti-inflammatory effects of both agents likely contribute to symptom resolution beyond the 6-hour time point, explaining the absence of sore throat by 24 hours in both groups.

The present investigation extends prior comparative research by demonstrating ketamine's consistent superiority over magnesium sulfate at higher therapeutic doses via nebulization. However, several limitations warrant acknowledgment. First, this was a single-center observational study with relatively modest sample size (n = 44 per group); multicenter randomized controlled trials with larger populations would strengthen evidence. Second, we did not measure serum or local tissue concentrations of study drugs, precluding investigation of concentration-response relationships. Third, cuff pressure was maintained uniformly at 20 cm H₂O in all patients; variation in cuff management might yield different results. Fourth, intubation trauma was not systematically quantified; objective measurement of airway injury severity would enhance understanding of mechanisms. Finally, additional variables including nasogastric tube placement, specific volatile anesthetic agents, and extended surgery duration were not systematically evaluated.

Despite these limitations, the study demonstrates that preoperative ketamine nebulization provides effective prophylaxis against postoperative sore throat in patients undergoing general anesthesia with endotracheal intubation. The clinical benefit is particularly notable in the early postoperative period (4–6 hours), when discomfort is most pronounced and impacts patient satisfaction. The simplicity, safety, and cost-effectiveness of nebulized ketamine administration render it practical for routine anesthetic practice. Furthermore, ketamine's analgesic properties may provide ancillary benefits beyond POST prevention, potentially reducing overall postoperative pain and opioid requirements.

Preoperative nebulization with 50 mg ketamine significantly reduced the incidence and severity of postoperative sore throat at 4 and 6 hours postoperatively compared to 250 mg magnesium sulfate nebulization. Both agents demonstrated favorable safety profiles with stable hemodynamics and no serious adverse events. Ketamine nebulization represents a simple, cost-effective, and safe prophylactic measure for POST prevention and should be considered for routine use in patients undergoing general anesthesia with endotracheal intubation, particularly those at elevated risk for significant postoperative morbidity.

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