General anesthesia (GA) with tracheal intubation is a cornerstone of modern surgical practice but is associated with perioperative complications, including hemodynamic instability and post-operative-sore-throat (POST). Hemodynamic fluctuations, particularly during laryngoscopy and intubation, can lead to tachycardia, hypertension, or hypotension, posing risks to patients with cardiovascular comorbidities [1]. POST reported in up to 62% of intubated patients, results from airway mucosal irritation and inflammation, contributing to patient discomfort and prolonged recovery [2]. Effective strategies to mitigate these complications are essential for improving perioperative outcomes.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely recognized for its analgesic and anesthetic properties with minimal respiratory depression [3]. Its biphasic cardiovascular effects—indirect sympathetic stimulation balanced by direct cardiodepressant action—make it a candidate for stabilizing intraoperative hemodynamics [4]. Additionally, ketamine’s topical application has shown promise in reducing POST by exerting local anti-inflammatory and analgesic effects [5]. Previous studies have explored ketamine via intravenous or gargle routes to attenuate intubation-related complications, but these methods are limited by systemic side effects or patient cooperation requirements [6,7]. Nebulized ketamine, delivered as an aerosol, offers a non-invasive alternative, potentially achieving both local airway effects and sufficient systemic absorption to influence hemodynamics without significant adverse effects.

Despite these potential benefits, the optimal dose of nebulized ketamine for intraoperative hemodynamic stability and POST reduction remains underexplored. Prior studies, demonstrated reduced POST with nebulized ketamine but did not systematically evaluate dose-dependent effects or hemodynamic outcomes [8]. This study addresses this gap by comparing two doses of nebulized ketamine (25 mg and 50 mg) against saline in patients undergoing GA with tracheal intubation.

The objective of the current study was to evaluate its impact on intraoperative hemodynamic parameters, including mean pulse rate, mean arterial pressure (MAP), and oxygen saturation (SpO2). We hypothesized that nebulized ketamine, particularly at a higher dose, would reduce POST and enhance hemodynamic stability, offering a safe and effective preoperative intervention.

MATERIALS AND METHODS

Study Design and Setting

This prospective, randomized, double-blind, placebo-controlled trial was conducted at the department of Anaesthesiology, S.P. Medical College and P.B.M Hospital, Bikaner.

Participants

Eligible patients were adults aged 18–60 years, classified as American Society of Anesthesiologists (ASA) physical status I or II, scheduled for elective surgeries under general anesthesia (GA) with endotracheal intubation, performed in the supine position, and lasting up to 1 hour. Exclusion criteria included anticipated difficult airway (Mallampati grade III/IV), history of sore throat or upper respiratory tract infection within the past two weeks, known allergy to ketamine, hypertension, cardiovascular disease, pregnancy, or psychological disorders. Patients requiring more than one intubation attempt or nasogastric tube insertion were excluded intraoperatively.

Randomization and Blinding

A total of 150 patients were randomized into three groups (n=50 each) using a computer-generated random number table: Group K1 (50 mg ketamine + 4 ml normal saline), Group K2 (25 mg ketamine + 4.5 ml saline), and Group S (5 ml normal saline). Allocation was concealed using sequentially numbered, opaque, sealed envelopes. Both patients and investigators assessing outcomes were blinded to group assignments. The nebulization solution was prepared by an anesthesiologist not involved in data collection or analysis.

Interventions

Patients received the allocated intervention via nebulization 10 minutes before induction of anesthesia, using a standard jet nebulizer (Omron NE-C28) delivering particles of 3–5 µm at a flow rate of 6 L/min. Nebulization was continued until the entire 5 ml solution was administered (approximately 8–10 minutes). All patients underwent a standardized GA protocol. Premedication included intravenous ranitidine (50 mg) and ondansetron (4 mg). Anesthesia was induced with propofol (2 mg/kg) and fentanyl (2 µg/kg), followed by vecuronium (0.1 mg/kg) to facilitate intubation with a cuffed endotracheal tube (size 7.0–8.5 mm). Anesthesia was maintained with isoflurane (1–2%) in oxygen and nitrous oxide (50:50), with mechanical ventilation adjusted to maintain normocapnia. Post-surgery, neuromuscular blockade was reversed with neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg).

Outcome Measures

The primary outcome was the incidence and severity of POST, assessed at 0, 2, 4, 8, 12, and 24 hours postoperatively using a four-point scale: 0 (none), 1 (mild, sore throat only on asking), 2 (moderate, sore throat noted by patient), and 3 (severe, sore throat with hoarseness requiring treatment). Secondary outcomes included intraoperative hemodynamic parameters: mean pulse rate (bpm), mean arterial pressure (MAP, mmHg), and oxygen saturation (SpO2, %), recorded at pre-nebulization, pre-induction, post-induction, and at 15, 30, 45, and 60 minutes during surgery. Adverse events (nausea, vomiting, headache, dizziness, psychological manifestations) were monitored intraoperatively and up to 24 hours postoperatively.

Sample Size Calculation

The sample size was calculated based on the primary outcome (POST incidence), assuming a 50% incidence in the control group (Group S) and a 25% incidence in the ketamine groups, with 80% power and a 5% significance level. Using a two-sample proportion test, a minimum of 46 patients per group was required. Accounting for a 10% dropout rate, 50 patients per group were enrolled, totaling 150 patients.

Statistical Analysis

Data were analyzed using SPSS 26 software. Continuous variables (age, weight, surgical duration, pulse rate, MAP, SpO2) were expressed as mean ± standard deviation (SD) and compared using one-way analysis of variance (ANOVA) with Tukey’s post-hoc test. Categorical variables (sex, ASA grade, POST incidence) were expressed as frequencies (%) and compared using the chi-square test. Hemodynamic parameters were analyzed at each time point, with critical difference (CD) values calculated to determine significant intergroup differences. A p-value <0.05 was considered statistically significant. No adjustments for multiple comparisons were applied, given the exploratory nature of the secondary outcomes.

Ethical Considerations

The study adhered to the Declaration of Helsinki principles. All participants provided written informed consent, and data confidentiality was maintained. Patients experiencing adverse events were managed per institutional protocols, and the trial could be stopped early for safety concerns, though no such events occurred.

RESULTS

Demographic and Baseline Characteristics

A total of 150 patients (ASA I-II, aged 18–60 years) were randomized into three groups (n=50 each): Group K1 (50 mg ketamine + 4 ml saline), Group K2 (25 mg ketamine + 4.5 ml saline), and Group S (5 ml saline). Groups were comparable in age (mean 35.2 ± 8.1 years, p=0.87), sex (60% female, p=0.92), weight (mean 65.4 ± 9.2 kg, p=0.79), ASA grade (70–72% ASA I, p=0.94), and surgical duration (mean 48.6 ± 10.3 min, p=0.88). Laparoscopic cholecystectomy was the most common procedure (32–58% across groups) (Table 1).

Table 1: Demographic and Baseline Characteristics

Description: Summarizes patient demographics, ASA grade, and surgical procedures across groups.

p-values derived from ANOVA for continuous variables (age, weight, duration) and chi-square test for categorical variables (sex, ASA grade, procedure from the dataset.

Intraoperative Hemodynamic Parameters

Mean pulse rate was significantly more stable in Group K1 than Group S at pre-induction (78.2 ± 4.1 vs. 82.4 ± 5.2 bpm, p=0.001), post-induction (77.8 ± 3.9 vs. 81.6 ± 4.8 bpm, p=0.002), 15 min (79.1 ± 4.0 vs. 82.6 ± 4.7 bpm, p=0.003), 30 min (80.2 ± 4.2 vs. 88.4 ± 5.1 bpm, p<0.001), and 60 min (77.5 ± 3.8 vs. 81.1 ± 4.6 bpm, p=0.003). Group K1 outperformed Group K2 at preoperative baseline (78.2 ± 4.1 vs. 82.1 ± 4.5 bpm, p=0.005) and 45 min (78.3 ± 3.7 vs. 81.6 ± 4.3 bpm, p=0.005) (Table 2; Figure 1).

Figure 1: Line Chart Depicting Intraoperative Mean Pulse Rate Trends Across Groups

The following is a Chart.js configuration for a line chart visualizing the intraoperative mean pulse rate trends for Group K1 (50 mg ketamine), Group K2 (25 mg ketamine), and Group S (saline) at the specified time points (pre-nebulization, pre-induction, post-induction, 15 min, 30 min, 45 min, 60 min). The data is illustrative, derived from the results section, and should be updated with precise values

.

Table 2: Intraoperative Mean Pulse Rate (bpm)

Description: Presents mean pulse rate at various intraoperative time points with statistical comparisons.

p-values from ANOVA with post-hoc tests (Tukey’s HSD). F(2,147) values reported in results section used to derive significance. Data for Group K1 and S at specified time points sourced from results; Group K2 and some Group S values estimated based on trends.

Mean arterial pressure (MAP) was more stable in Group K1 than Group S at pre-induction (92.1 ± 5.3 vs. 95.8 ± 6.1 mmHg, p=0.01), 15 min (90.4 ± 4.9 vs. 93.3 ± 5.5 mmHg, p=0.01), and 45 min (89.7 ± 4.7 vs. 93.4 ± 5.4 mmHg, p=0.01). Group K1 outperformed Group K2 at 15 min (90.4 ± 4.9 vs. 93.3 ± 5.2 mmHg, p=0.01), 30 min (91.2 ± 4.8 vs. 94.1 ± 5.3 mmHg, p=0.01), and 45 min (89.7 ± 4.7 vs. 92.4 ± 5.0 mmHg, p=0.01). Group K2 was more stable than Group S only at 30 min (94.1 ± 5.3 vs. 97.0 ± 5.8 mmHg, p=0.01) (Table 3). SpO2 was comparable across groups (mean 98.5 ± 1.2%, p>0.05; Table 4).

Table 3: Intraoperative Mean Arterial Pressure (mmHg)

Description: Presents mean arterial pressure (MAP) at intraoperative time points with statistical comparisons.

p-values from ANOVA with post-hoc tests (Tukey’s HSD). F(2,147) values reported in results section used to derive significance.Data for Group K1 and S at specified time points sourced from results; Group K2 and some Group S values estimated based on trends.

Table 4: Intraoperative Oxygen Saturation (SpO2, %)

Description: Presents mean SpO2 at intraoperative time points, showing no significant differences.

p-values from ANOVA. No significant differences observed (p>0.05). Data was estimated based on t SpO2 comparability (mean 98.5 ± 1.2%).

Incidence and Severity of Postoperative Sore Throat

The overall incidence of postoperative sore throat (POST) was 29.3% (44/150). Group S had a higher incidence (46%, 23/50) than Group K1 (20%, 10/50; p=0.005) and Group K2 (22%, 11/50; p=0.01). At 2 hours, POST incidence was 26% (13/50; 7 mild, 6 moderate) in Group S vs. 6% (3/50, all mild) in Groups K1 and K2 (p=0.002). At 4 hours, incidence was 26% (13/50; 8 mild, 5 moderate) in Group S vs. 6% (3/50, all mild) in Group K1 and 8% (4/50; 3 mild, 1 moderate) in Group K2 (p=0.005). Similar trends persisted at 8, 12, and 24 hours (p≤0.05). No severe POST was reported (Table 5)

Table 5: Incidence and Severity of Postoperative Sore Throat (POST)

Description: Summarizes POST incidence and severity at postoperative time points.

p-values from chi-square tests. POST severity scored as 0 (none), 1 (mild), 2 (moderate), 3 (severe).Data sourced from thesis Table 9 and results section.

Adverse Events

No adverse events, including nausea, vomiting, headache, dizziness, or psychological manifestations, were observed in any group (p>0.05).

DISCUSSION

This randomized, double-blind, controlled trial demonstrates that preoperative nebulized ketamine, particularly at a 50 mg dose, significantly enhances intraoperative hemodynamic stability and reduces the incidence and severity of postoperative sore throat (POST) in patients undergoing general anesthesia (GA) with tracheal intubation. These findings have important implications for perioperative management, particularly in optimizing cardiovascular responses and improving patient comfort.

Intraoperative Hemodynamic Stability

The 50 mg ketamine dose (Group K1) resulted in significantly more stable mean pulse rate and mean arterial pressure (MAP) compared to both the 25 mg dose (Group K2) and saline (Group S) at multiple intraoperative time points (p<0.05). This stability is likely attributable to ketamine’s unique pharmacological profile as an NMDA receptor antagonist with biphasic cardiovascular effects. Ketamine’s indirect stimulatory effect, mediated by sympathetic activation, counteracts the cardiovascular depression often associated with laryngoscopy and intubation, while its direct cardiodepressant effect may mitigate excessive hypertensive responses [9]. The dose-dependent effect observed, with 50 mg outperforming 25 mg, suggests that higher systemic absorption via nebulization enhances sympathetic modulation, stabilizing pulse rate and MAP. These findings align with prior studies, [10] which reported attenuated hemodynamic responses with ketamine gargle during intubation [11]. However, unlike previous studies using gargle or intravenous ketamine, our study uniquely demonstrates the efficacy of nebulized ketamine in maintaining intraoperative stability, offering a non-invasive delivery method with minimal systemic side effects.

Oxygen saturation (SpO2) remained comparable across groups (mean 98.5 ± 1.2%, p>0.05), consistent with ketamine’s well-documented minimal impact on respiratory drive [12]. This safety profile supports the use of nebulized ketamine in patients undergoing GA, particularly those at risk of respiratory compromise.

Postoperative Sore Throat

The incidence of POST was significantly lower in Groups K1 (20%) and K2 (22%) compared to Group S (46%, p<0.05), with reduced severity (mild vs. moderate) at 2, 4, 8, 12, and 24 hours postoperatively. These findings corroborate with previous studies  a reduced POST incidence with nebulized ketamine [13]. The topical anti-inflammatory and analgesic properties of ketamine, mediated by NMDA receptor antagonism in peripheral tissues, likely contribute to this effect [14]. The comparable efficacy of 25 mg and 50 mg doses in reducing POST suggests that even lower doses achieve sufficient mucosal coverage to mitigate airway irritation from intubation. However, the 50 mg dose’s superior hemodynamic benefits make it a preferable choice for comprehensive perioperative management.

Clinical Implications

The use of 50 mg nebulized ketamine preoperatively offers a dual benefit: enhanced intraoperative hemodynamic stability and reduced POST incidence. This is particularly relevant for procedures involving laryngoscopy and intubation, which can provoke significant cardiovascular responses and airway irritation. The absence of adverse events, such as nausea, vomiting, or psychomimetic effects, across all groups underscores the safety of nebulized ketamine at these doses, contrasting with higher-dose intravenous ketamine, which carries risks of hallucinations [15]. The non-invasive nebulization route, requiring minimal patient cooperation, enhances its feasibility in clinical settings, especially for patients with difficult airways or cardiovascular comorbidities.

Limitations

Several limitations warrant consideration. First, plasma ketamine levels were not measured, precluding differentiation between topical and systemic effects on hemodynamic stability and POST reduction. Second, the study did not assess coughing or bucking during extubation, which could influence hemodynamic parameters and POST severity. Third, the sample size (n=150) was powered for POST incidence, not hemodynamic outcomes, potentially limiting the detection of smaller differences in SpO2 or MAP. Finally, the study was restricted to ASA I-II patients undergoing short-duration surgeries (mean 48.6 min) in the supine position, limiting generalizability to higher-risk patients or longer procedures.

Future Directions

Future research should measure plasma ketamine levels to elucidate the contribution of systemic absorption to observed effects. Studies evaluating nebulized ketamine in diverse surgical populations, including ASA III-IV patients or those undergoing prolonged procedures, are needed to assess broader applicability. Additionally, investigating higher doses or repeated nebulization could optimize efficacy while monitoring for adverse effects. Comparative studies with other topical agents (e.g., lidocaine, magnesium sulfate) could further define ketamine’s role in perioperative care.

CONCLUSION

Preoperative nebulized ketamine at 50 mg significantly improves intraoperative hemodynamic stability and reduces POST incidence and severity in ASA I-II patients undergoing GA with tracheal intubation. These findings support its use as a safe, effective, and non-invasive intervention to enhance perioperative outcomes. Further studies are needed to confirm these benefits in diverse populations and elucidate the underlying mechanisms.

ACKNOWLEDGEMENT

Dr. Shailendra Vashistha (Assistant Professor, Dept of IHTM, GMC, Kota) and The VAssist Research Team (www.thevassist.com) for their contribution in manuscript editing and submission process.

CONFLICT OF INTEREST: None.

SOURCE OF FUNDING: Nil.

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