European Journal of Cardiovascular Medicine

Postoperative sore throat (POST) is a prevalent complication following endotracheal intubation, affecting 20–70% of patients undergoing general anaesthesia ¹ . Nebulized medications, delivered directly to the airway, offer a targeted approach with minimal systemic side effects¹. Characterized by pharyngeal discomfort, hoarseness, or dysphagia, POST significantly reduces patient satisfaction, delays recovery, and increases healthcare costs due to prolonged hospital stays or additional interventions ² . The aetiology of POST is multifactorial, involving mechanical trauma from intubation, mucosal inflammation, and irritation from prolonged airway manipulation ³ . Despite advances in anaesthetic techniques, such as smaller endotracheal tubes and cuff pressure monitoring, POST remains a clinical challenge, particularly in procedures requiring prolonged intubation or in vulnerable populations like paediatric or thyroid surgery patients ⁴ .

Pharmacological strategies to prevent POST have gained attention, with topical and systemic agents targeting inflammation and pain pathways⁵. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, reduces peripheral inflammation and hyperalgesia when applied topically, making it a promising candidate for POST prevention⁶. Dexmedetomidine, a highly selective α2-adrenergic agonist, provides anti-inflammatory, sedative, and analgesic effects, potentially mitigating airway irritation during intubation⁷. Clonidine, another α2-agonist, has been explored in combination with ketamine, demonstrating synergistic antinociceptive effects that may enhance POST prevention⁸. These agents, administered via nebulization, bypass systemic metabolism, achieving high local concentrations in the pharynx and trachea⁹.

Recent randomized controlled trials (RCTs) and meta-analyses have evaluated nebulized ketamine, dexmedetomidine, and their combinations, reporting significant reductions in POST incidence and severity compared to placebo or non-analgesic controls^10-14. However, comparative efficacy among these agents remains unclear due to heterogeneity in study designs, dosing regimens, and outcome measures¹⁵. For instance, dexmedetomidine appears superior in early postoperative periods, while ketamine-based combinations may offer sustained benefits^8,16. Safety profiles also vary, with dexmedetomidine associated with mild hemodynamic changes and ketamine notable for its lack of psychomimetic effects at nebulized doses^6,17. This systematic review and meta-analysis aims to synthesize evidence from RCTs to determine the efficacy and safety of nebulized ketamine, clonidine, dexmedetomidine, and their combinations in preventing POST. By employing network meta-analysis, we seek to rank these interventions and provide evidence-based recommendations for clinical practice^18-20.

Current study is PRISMA-compliant revie. Eligibility included RCTs evaluating nebulized ketamine, clonidine, dexmedetomidine, or combinations in adults (≥18 years) under general anaesthesia with intubation and comparators were placebo, non-analgesic methods, or active agents. Primary outcome was POST incidence and severity at 1, 2, 6, 12, and 24 hours. Secondary outcome was incidence of adverse effects. PubMed, EMBASE, and Cochrane Library (inception to March 2025) were searched using terms  “nebulized ketamine” and “postoperative sore throat.”

Data Extraction was done by two reviewers who extracted data on design, sample size, interventions, POST outcomes, and adverse effects.

Statistical Analysis RR for incidence and MD for severity were calculated with 95% CIs using random-effects models (RevMan 5.4). Heterogeneity used I^2. Bayesian network meta-analysis (R netmeta) ranked interventions. Publication bias was assessed via funnel plots and Egger’s test. GRADE evaluated evidence quality.

Study Selection From 1,234 records, 20 RCTs (n=2,346) were included, evaluating ketamine (n=9), dexmedetomidine (n=6), ketamine + clonidine (n=3), and others (n=2).

Study Characteristics Table 1 summarizes the 20 RCTs. Sample sizes ranged from 40 to 1,500. Ketamine doses were 50 mg or 1 mg/kg, dexmedetomidine 1 μg/kg, clonidine 50 mg (with ketamine). Surgeries included general, orthopaedic, thyroid, and paediatric procedures. POST was assessed via incidence and severity (VAS or 4-point scales)^8,9.

Table 1: Characteristics and Outcomes of Included RCTs

"Ket" = Ketamine, "Dex" = Dexmedetomidine, "Clon" = Clonidine, "Mid" = Midazolam, "MgSO4" = Magnesium Sulfate. "meta" indicates meta-analysis sample size; others are individual RCTs.

POST Incidence Ketamine: Eight RCTs showed reduced POST at 24 hours (RR 0.45, 95% CI 0.37–0.54, I^2=30%, P<0.001) and 6 hours (RR 0.60, 95% CI 0.50–0.72, I^2=25%).

Dexmedetomidine: Five RCTs confirmed efficacy at 2 hours (RR 0.52, 95% CI 0.41–0.66, I^2=20%, P<0.001) and 6 hours (RR 0.44, 95% CI 0.32–0.60, I^2=15%).

Ketamine + Clonidine: Three RCTs showed superiority over ketamine alone at 24 hours (RR 0.16, 95% CI 0.07–0.36, I^2=10%, P<0.001).

POST Severity Ketamine reduced VAS at 6 hours (MD -1.2, 95% CI -1.8 to -0.6, I^2=40%)^9^. Dexmedetomidine lowered severity at 2 hours (MD -1.5, 95% CI -2.1 to -0.9, I^2=30%)^13^. Ketamine + clonidine showed the largest reduction at 24 hours (MD -2.0, 95% CI -2.8 to -1.2, I^2=20%).

Network Meta-Analysis Bayesian analysis ranked dexmedetomidine highest for early POST prevention (SUCRA 0.92), followed by ketamine + clonidine (0.85) and ketamine (0.65).

Adverse Effects Ketamine had no significant adverse effects. Dexmedetomidine caused mild hypotension (e.g., 84.09 mmHg at 15 min, P=0.018). Clonidine combinations showed no additional risks. Publication Bias Funnel plots suggested mild asymmetry for ketamine (Egger’s test, P=0.06). Trim-and-fill analysis confirmed robustness. Evidence Quality GRADE rated evidence as moderate for ketamine and dexmedetomidine, low for ketamine + clonidine due to limited studies.

This meta-analysis confirms nebulized dexmedetomidine, ketamine, and ketamine + clonidine as effective for POST prevention. Dexmedetomidine’s early efficacy (2–6 hours) stems from α2-adrenergic-mediated anti-inflammatory and sedative effects¹³. Ketamine’s 24-hour effect aligns with NMDA receptor antagonism¹¹. Ketamine + clonidine’s superior efficacy (RR 0.16) suggests synergistic antinociception, possibly via central and peripheral pain modulation¹⁰.

Clinically, dexmedetomidine suits short procedures, while ketamine + clonidine is ideal for sustained relief. Ketamine’s affordability enhances its utility in resource-limited settings¹. Safety is favorable with nebulized ketamine avoids psychomimetic effects, dexmedetomidine’s hypotension is manageable, and clonidine adds no risks^9,15.

Limitations include heterogeneity in dosing, comparators, and scales, and small clonidine study sizes. Regional bias and publication bias in ketamine studies may overestimate effects¹¹. Future RCTs should standardize assessments, compare dexmedetomidine vs. ketamine + clonidine, and explore long-term outcomes and cost-effectiveness ^14,20.

Nebulized dexmedetomidine effectively prevents early postoperative sore throat, while ketamine with clonidine provides sustained relief. Both are safe and clinically viable. Larger, standardized RCTs are needed to optimize protocols and confirm long-term benefits.

Conflicts of Interest: None declared.

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