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 Table of Contents  
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 408-417

Pre-emptive nebulized ketamine versus nebulized lidocaine for endoscopic nasal surgeries

Anaesthesia Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission20-Feb-2019
Date of Acceptance14-Apr-2019
Date of Web Publication06-Jan-2020

Correspondence Address:
MD Shereen E Abd Ellatif
Anaesthesia Department, Faculty of Medicine, Zagazig University, Zagazig, 44511
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/roaic.roaic_18_19

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Background Endoscopic nasal surgeries are commonly associated with mild to moderate postoperative pain owing to both nasal packing and surgical trauma itself.
Aim To compare the analgesic efficacy of pre-emptive nebulized ketamine versus nebulized lidocaine in patients undergoing these surgeries. This was a randomized controlled clinical trial.
Materials and methods A total of 60 adult patients scheduled for elective endoscopic nasal surgeries were randomly allocated in three groups (20 patients each). Patients in each group were nebulized 15 min before the surgery with the respective study drug, that is, ketamine group (group K) patients received ketamine 50 mg; lidocaine group (group L) received lidocaine 2% (40 mg), and control group (group C) received normal saline 0.9%. The outcome measures included hemodynamics, intraoperative opioids, sedation, time of first request for analgesia, the total dose of postoperative rescue analgesia given, and adverse effects. The collected data were coded and analyzed using SPSS version 20.
Results Lidocaine group showed the least hemodynamic changes to laryngoscope and intubation at 1, 3, 5, and 10 min after intubation, with no significant differences among the three groups from 15 min after intubation till extubation time. Intraoperative propofol and fentanyl doses were statistically significantly higher in group C compared with groups K and L, with no statistical significant difference between groups L and K themselves. The time to first analgesic request prolonged significantly in groups K and L (255.25±18.45 and 242.50±12.82 min, respectively) when compared with group C (119.75±18.88 min). Diclofenac consumption was significant lower in groups K and L (87.75±9.66 and 91.25±7.23 mg, respectively) compared with C group (150 mg), with no statistically significant difference between both treated groups.
Conclusion Nebulization with ketamine or lidocaine before induction of general anesthesia is efficacious, enhances postoperative analgesia, and reduces total doses of rescue analgesics used following endoscopic nasal surgeries.

Keywords: analgesia, endoscopic, ketamine, lidocaine, nasal, nebulization

How to cite this article:
Abd Ellatif SE, Mowafy SM. Pre-emptive nebulized ketamine versus nebulized lidocaine for endoscopic nasal surgeries. Res Opin Anesth Intensive Care 2019;6:408-17

How to cite this URL:
Abd Ellatif SE, Mowafy SM. Pre-emptive nebulized ketamine versus nebulized lidocaine for endoscopic nasal surgeries. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2020 Apr 6];6:408-17. Available from: http://www.roaic.eg.net/text.asp?2019/6/4/408/275136

  Introduction Top

Recently, several endoscopic ear, nose, and throat procedures such as endoscopic turbinectomy and functional endoscopic sinus surgery have been developed to minimize surgical invasiveness. Mild to moderate postoperative pain is commonly associated with these types of surgeries owing to both nasal packing and surgical trauma itself [1],[2]. Numerous studies investigating the treatment of this pain via delivery of opiate across the nasal mucosa conclude that this route is equivalent or even superior in pain control to intramuscular, intravenous, and subcutaneous delivery methods [3],[4],[5],[6].

Nebulization is primarily preferred for safety and ease of administration to the patient and also has the benefit of delivery of the drug to the lower airways. During nebulization, the liquid is broken up into droplets by the compressed air, and it produces large particles (10–25 µm), which mostly deposit in mouth and throat, and smaller particles (5–10 µm), which deposit in a transition from mouth to airway [7].

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist, with the primary site of action being at the central nervous system and parts of the limbic system, and it can be administered through different routes such as intravenously and intramuscularly; however, its use via nasal, gargle, and rectal routes proved that it also has peripheral effects [8],[9],[10],[11]. The pharmacokinetic properties of inhaled ketamine have not been studied officially, but the mechanism of its topical effect is through attenuating the local inflammation, and having peripheral analgesic effect. Ketamine in nebulized form at different concentrations was found to reduce inflammatory markers as confirmed by lung histological examination, total and differential cell counts, and the cytokine in the bronchoalveolar lavage fluid [9]. Moreover, several clinical studies reported that using topical ketamine produced analgesia in cases with cancer and neuropathic pain [12]. Nebulized ketamine was effective for attenuating postoperative sore throat [8]. Intranasal ketamine was successfully used as a nonopioid medication for postoperative acute pain [13], in burn dressing changes [14], and as a pre-emptive for endoscopic nasal surgeries [15].

Lidocaine hydrochloride is a widely available local anesthetic with a good safety profile when given by nebulization [16]. It is frequently nebulized before bronchoscopy procedures, allowing the bronchoscope to reach greater depths in the airway. It was found that it results in suppression of the excitatory sensory C fibers in airways and thus reduces the release of neuropeptide [17]. Lidocaine levels in the blood after nebulization for adults at normal doses were found to be safe and were well tolerated [18].

We hypothesized that achieving pre-emptive analgesia using either nebulized ketamine or nebulized lidocaine for patients undergoing endoscopic nasal surgeries can result in good postoperative pain management and less need for rescue analgesia in the recovery room.

  Patients and methods Top

Study population

This prospective randomized controlled clinical study was conducted in Zagazig University Hospitals from February to September 2018. Approval of Zagazig Institutional Review Board was obtained before the study, and patients’ informed written consent was also obtained.

The sample size was calculated to be 60 cases divided into three groups, with 20 in each group, which was calculated using open Epi program. At 95% confidence interval and power of test 80%, the visual analogue score (VAS) difference between groups from previous paper showed 50% reduction in VAS score in 7/12 patients in the ketamine, 4/12 in the lidocaine, and 2/12 in the placebo group [19]. We took 20% nonresponder rate with no intension to treat, so we began with 72 and then we excluded 12 for exclusion criteria.

Adult patients aged 18–60 years old, of either sex, classified as ASA I and ASA II, scheduled for elective endoscopic nasal surgeries, were included in this study. Patients with BMI more than 30 kg/m2; those with advanced respiratory, renal, hepatic, neurologic, or psychiatric disease; pregnant female; patients with history of allergy to any of the study drugs, patients using central nervous system depressants or analgesics over the previous 24 h, and patients with expected difficulties in laryngoscopy and intubation were excluded from this study.

Study design

The patients enrolled in this study were randomly divided into three groups by a computer-generated randomization table depending on the pre-emptive nebulized drug used: ketamine group (group K) patients received ketamine 50 mg (1 ml)+normal saline 0.9% (3 ml), lidocaine group (group L) patients received lidocaine 2% (40 mg) (2 ml)+normal saline 0.9% (2 ml), and control group (group C) patients received normal saline 0.9% (4 ml). Patients were instructed preoperatively in how to describe their own pain using VAS ranging from 0 to 10 (with 0=no pain and 10=the worst pain imaginable).

In the premedication room, intravenous access was secured. The baseline values of heart rate (HR), oxygen saturation, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded.

Fifteen minute before induction of general anesthesia, all the patients were nebulized with either of the study drugs (ketamine or lidocaine) or with normal saline. Nebulization was done using compressed O2 at 5 l/min. HR, oxygen saturation, SBP, and DBP were recorded immediately after nebulization. Then induction of general anesthesia was started with intravenous fentanyl 1 µg/kg, propofol 1–2 mg/kg (was given in 20 mg increments assessed by verbal contact), and cisatracurium 0.15 mg/kg to facilitate endotracheal intubation. Anesthesia was maintained with isoflurane (one minimum alveolar concentration) in oxygen/air mixture and propofol infusion (4–6 mg/kg/h). SBP was adjusted to be maintained 20–25% lower than the baseline values or mean arterial blood pressure (MAP) maintained at 50–65 mmHg. Adequate muscle relaxation was maintained by 0.05 mg/kg cisatracurium every 30 min. An additional bolus dose of fentanyl 1 µg/kg was given intraoperatively with an increase in SBP or MAP values more than the predetermined level or an increase in HR more than 20% from baseline values. Parameters of mechanical ventilation were adjusted to maintain an end-tidal CO2 around ∼32–35 mmHg. Intraoperative data were recorded at 1, 3, 5, 10, and 15 min after intubation, and then continuously monitored every 10 min during the surgery, as well as the total propofol induction and maintenance doses and total doses of intraoperative opioids used were recorded. At the end of the surgery, bilateral nasal packing was performed, and then anesthesia was discontinued and slowly intravenous neostigmine 40 µg/kg and atropine 20 µg/kg were administered to reverse neuromuscular relaxation. Then patients were turned aside in the recovery position. Awake extubation was performed after return of protective airway reflexes and fulfil criteria of extubation. Ramsay sedation score was noted at the extubation time and 1 h postoperatively aiming to assess the level of sedation [20]. The patients were assessed for pain using the VAS at rest in the following time points: at 30 min, and 1, 2, 4, 6, 12, and 24 h postoperatively. Diclofenac sodium 75 mg intramuscular was given if VAS scores were at least 3. The time of first rescue analgesic requirement and the total amount of diclofenac sodium given to each patient during first 24 h of the postoperative period were detected and recorded.

Any adverse effects in the first 24 h postoperatively were recorded and treated, including nausea and vomiting, hyperalgesia, salivation, sedation, hallucinations, delirium, dysphoria, disorientation, agitation, restlessness, nightmares, nystagmus, photophobia, skin rash, oropharyngeal numbness, bitter taste, throat tightness, bronchoconstriction, and others. Patients’ satisfaction regarding analgesia was graded as very satisfied, mildly satisfied, or not satisfied [15] at the end of the 24 h study period.

Statistical analysis

Data were collected throughout history, basic clinical examination, and laboratory investigations, and outcome measures were coded, entered, and analyzed using Microsoft Excel software. Data were then imported into statistical package for the social sciences (SPSS version 20.0, IBM, Armonk, NY, USA) software for analysis. According to the type of data, qualitative data were represented as number and percentage, quantitative continuous group was represent by mean±SD. The following tests were used to test differences for significance difference and association of qualitative variable by χ2. Differences between quantitative paired groups were analyzed by paired t, and multiple group comparisons by analysis of variance followed by post-hoc test or Kruskal–Wallis test. P value was set at less than 0.05 for significant results and less than 0.001 for highly significant result.

  Results Top

A total of 72 patients scheduled for elective endoscopic nasal surgeries were assessed for eligibility to participate in this study. Of them, 11 patients did not meet the study selection criteria, so 61 patients gave consent and were enrolled into three groups. Then, one patient dropped out in lidocaine group owing to bronchoconstriction, so the net result of patients followed up was 20 patients per group ([Figure 1]).
Figure 1 Consolidated trials’ flow diagram.

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As shown in [Table 1], there were no statistically significant differences in the three groups regarding age, sex, weight, and ASA class. However, the mean values of induction and maintenance doses of intravenous propofol and intraoperative fentanyl were statistically significant higher in group C compared with groups K and L, with no statistical significant difference between groups L and K themselves ([Table 2]).
Table 1 Patients’ characteristics of the studied groups

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Table 2 Intraoperative propofol and fentanyl doses in the studied groups

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For hemodynamic changes (HR, SBP, and DBP) measured at the prenebulization and postnebulization times, there were no statistical significant differences among the studied groups with either intra-group or inter-group comparisons ([Figure 2],[Figure 3],[Figure 4]). However, group L showed the least hemodynamic changes to laryngoscopy and intubation at 1, 3, 5, and 10 min after intubation, with no statistically significant difference among the three groups from 15 min after intubation till extubation time ([Figure 2],[Figure 3],[Figure 4]), and group K showed a statistically significant increase in HR when the baseline and prenebulization values were compared with those at 1, 3, 5, and 10 min after intubation times ([Figure 2]).
Figure 2 Heart rate (HR) assessment over time among the three groups.

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Figure 3 Systolic blood pressure (SBP) changes over time among the three groups.

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Figure 4 Diastolic blood pressure (DBP) changes over time among the three groups.

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In the first 6 h postoperatively, the VAS score mean values were statistically significant lower in groups K and L in comparison with those in group C, and then from 6 h to 24 h postoperatively, a nonstatistically significant difference in the score mean values was observed, though the values were still lower in both treated groups compared with the control group. Moreover, no statistically significant difference was observed between groups K and L through the first postoperative 24 h ([Figure 5]).
Figure 5 Visual analogue pain scale (VAS) over time among the three groups.

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Regarding the mean time of first analgesic requirement, there was a statistically significant prolongation in groups K and L (255.25±18.45 and 242.50±12.82 min, respectively) when compared with group C (119.75±18.88 min). Yet, there was no statistically significant difference in the mean time to the first analgesic request between groups K and L. For diclofenac consumption, patients in groups K and L consumed smaller doses than those in group C, as there were statistically significant lower mean values of diclofenac doses in groups K and L (87.75±9.66 and 91.25±7.23 mg, respectively) compared with C group (150 mg), with no statistically significant difference between both treated groups ([Table 3]).
Table 3 The first time and total dose of postoperative analgesic among the studied groups

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In the postoperative evaluation, there was no statistically significant difference in Ramsay sedation score in all patients ([Table 4]). However, patients in groups K and L were more satisfied with the perioperative care than group C patients. The indices of patients’ satisfaction were statistically significantly higher in groups K and L than in group C, with no statistically significant difference between both groups K and L ([Table 5]).
Table 4 Ramsay sedation scale among groups

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Table 5 Patient satisfaction among groups

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When comparing perioperative adverse effects among the three groups, the incidence of hallucination was statistically significantly higher in group K compared with groups L and C; however, oropharyngeal numbness was statistically significantly higher in group L compared with groups K and C, with no statistically significant difference among the three groups regarding the other adverse effects ([Table 6]).
Table 6 Perioperative complications among studied groups

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  Discussion Top

Nebulized lidocaine is known to suppress the excitatory sensory C fibers in the airways, and it also has local anesthetic effects. Thus, it has been used widely for many purposes such as awake intubation; to suppress acute cough associated with bronchoscopy, lung biopsy, and laryngoscopy [21]; to suppress the hemodynamic response to tracheal intubation; and to reduce the incidence of postoperative sore throat, cough, and hoarseness of voice [17].

Being a competitive NMDA-receptor antagonist, a subanesthetic dose of ketamine is hypothesized to prevent or reverse already established central sensitization and thus to reduce postoperative pain. Results of many studies evaluating the efficacy of pre-emptive ketamine are promising and consistent with the pharmacological and physiological importance of NMDA receptors in nociceptive pain pathogenesis [22],[23].

In this study, we tried to evaluate the role of pre-emptive nebulized ketamine and nebulized lidocaine to enhance and prolong postoperative analgesia after endoscopic nasal surgeries. Moreover, pre-emptive administration of the drugs was done trying to study the effects on the hemodynamics during the intubation and intraoperatively. Moreover, the presence of nasal packs postoperatively makes the administration of drugs very difficult.

Using nebulization of the drugs instead of other routes (e.g. gargle and intranasal) was primarily to ensure equal and effective distribution of the drug in the respiratory tract; to avoid the disadvantages of other routes like bitter taste, user variability, large volume required for gargle, and the drug rapid runoff into pharynx associated with intranasal route, and also owing to the ease of administration of the nebulized drugs to the patient in the immediate preoperative period.

Our results showed that the induction and intraoperative maintenance doses of propofol as well as the intraoperative fentanyl dose were markedly decreased in ketamine and lidocaine groups compared with the control group, with no difference between ketamine and lidocaine groups themselves. This is in accordance with Erden et al. [24] who found that addition of low dose of intravenous ketamine to propofol–fentanyl combination decreased the need for supplemental propofol dosage in pediatric patients. However, Abdel-Ghaffar et al. [15] found that pre-emptive intranasal ketamine did not significantly decrease the induction and maintenance doses of propofol in patients undergoing endoscopic nasal surgeries. This could be explained by the different route of ketamine administration, and also, Abdel-Gaffar et al. [15], in their study, depended on propofol infusion for adjusting intraoperative blood pressure rather than fentanyl–propofol, which were used in our study.

Topical and intravenous lidocaine has been used to abolish the pressor response to laryngoscopy and intubation. Numerous studies have shown that lidocaine spray is effective in preventing the pressor response to tracheal intubation [25],[26]. In addition, Mostafa et al. [25], in their study, confirmed that topical lidocaine sprayed before induction of anesthesia was more effective than after induction in attenuating the pressor response. Moreover, Abd El-Hamid et al. [27] found that preoperative lidocaine nebulizer decreased the pressor response to laryngoscopy and intubation. This is in agreement with our results that confirmed the least hemodynamic changes in response to tracheal intubation occurred in lidocaine nebulized group when compared with ketamine and control groups.

In this study, nebulized ketamine was found to increase the HR when baseline and prenebulization values were compared with those at 1, 3, 5, and 10 min postintubation times. However, there was no significant difference in hemodynamics (HR, SBP, and DBP) from 15 min after intubation till extubation time among the three studied groups.

This is in line with earlier studies such as by Charan et al. [28], who assessed the effectiveness and adverse effects of different doses of nebulized ketamine and found that MAP and HR were more stable in patients nebulized with 50 mg ketamine than with 25 mg ketamine and then control group nebulized with normal saline, as the last two groups were associated with more fluctuations in hemodynamics through the whole surgical procedure; Mostafa et al. [29], in their study to evaluate the effects of intranasal midazolam, ketamine, and dexmedetomidine when administered as preanesthetic medication for children undergoing bone marrow biopsy, found no significant difference in HR, SBP and respiratory rate among three groups; and Rajan et al. [30], who compared the effects of pre-emptive ketamine and magnesium sulfate nebulizations on the incidence and severity of postoperative sore throat (POST) and found no significant difference regarding MAP mean values when baseline and prenebulization readings were compared with those at postintubation time in all groups. Ironically, HR was increased significantly in 500-mg nebulized magnesium group when baseline and prenebulization values were compared with postintubation values in the same group, and no significance difference was observed in HR values before and after intubation in the other groups including ketamine group. They explained that it may be owing to stress response to laryngoscopy and intubation rather than systemic absorption in that group.

Our results were found to be inconsistent with Abdel-Ghaffar et al. [15], who found that intranasal ketamine significantly increased HR, SBP, and DBP monitored after induction of anesthesia and at 1, 3, and 5 min after intubation than intranasal fentanyl, with no difference at 10 and 15 min after intubation. This could be attributed to the larger ketamine dose (1.5 mg/kg) used in their study and the different route of ketamine administration (intranasal).

In this study, observed pain profile of our patients showed that VAS score values were significantly lower with nebulized ketamine and lidocaine than in control group for the first 6 h postoperatively, and then with the passage of time, the overall VAS score values decreased in all groups and tended to be lower in groups K and L than in control group. However, comparing the group K with group L, there was no difference through the first 24 h.

Our results were founded to be matched with Abdel-Ghaffar et al. [15], who reported significant lower VAS scores in intranasal ketamine and fentanyl groups in the first 4 h compared with placebo group, with trend toward lower values at all-time points, whereas there were no significant differences between both treated groups. Moreover, Mehrotra et al. [31] reported in their study to compare preoperative nebulization of either ketamine, lidocaine, budesonide, or distilled water on the incidence and severity of POST that the overall VAS score values decreased significantly in the three treated groups throughout the first postoperative 48 h, and Kang et al. [32], who studied the effectiveness of ketamine gargling for decreasing POST incidence in patients undergoing laparoscopic cholecystectomy using VAS score to measure the severity of POST and concluded that preoperative ketamine gargling decreased the VAS score during the early phase of POST as VAS scores were significantly lower with ketamine gargle compared with normal saline at 1 and 6 h postoperatively and no significant differences at 24 h.

The reduction in VAS score in our patients could be explained by the deposition of ketamine droplets in the upper airways producing topical analgesia and reducing the inflammatory reactions together with the NMDA-receptor antagonism of ketamine nebulization, but the possibility of systemic absorption cannot be excluded.

Moreover, our results had confirmed the postoperative analgesic effects of nebulized ketamine and lidocaine, as the time to the first analgesic requirement was significantly longer in groups K and L, with significant lower doses of diclofenac consumption in these groups compared with control group; however, comparing group K with group L, no difference was found.

In support of this, the findings of Kuo et al. [33] reported decreased postoperative pain in septoplasty patients packed with vaseline gauze prepared with lidocaine ointment, and Abd El-Hamid et al. [27] found that the time to the first analgesic request and total morphine dose were reduced significantly in nebulized lidocaine group compared with saline group, and they concluded that lidocaine nebulization enhanced postoperative analgesia and improved pack tolerance after nasal surgeries. Moreover, Abdel-Ghaffar et al. [15] concluded that pre-emptive intranasal ketamine at a dose of 1.5 mg/kg can effectively reduce postoperative pain after endoscopic nasal surgery.

Our results were not compatible with Rajan et al. [30], who reported no significant difference between nebulized ketamine and nebulized magnesium in different doses regarding patients’ requirements of fentanyl infusion for postoperative pain relief in elective abdominal surgeries, but these nebulizations effectively reduced the incidence and severity of POST. This may be justified by the different nature of the surgery, which is usually more painful and is associated with visceral pain, and therefore, it requires higher doses of analgesic drugs than our surgical procedures done for our patients.

The results of the present study showed that patients in groups K and L were more satisfied with the nebulization and postoperative pain relief than those in the control group. This is in accordance Reddy and Fiaz [34], who reported that nebulized ketamine was well accepted by all patients, and it was effective in reducing the POST severity, and Rao et al. [35], who found that therapeutic lidocaine nebulization was well tolerated by the patients and provided effective treatment of POST.

In this study, hallucinations occurred in four patients of ketamine group only, whereas oropharyngeal numbness was significantly higher in lidocaine group (18 patients). Hallucinations were reported by Abdel-Ghaffar et al. [15] to be higher with intranasal ketamine rather than fentanyl. However, Ahuja et al. [36] reported no adverse events with nebulized ketamine which could be attributed to the more diluted concentration used (50 mg ketamine+4 ml saline) in their study.

Oropharyngeal numbness following lidocaine nebulizations was also, proved by Chong et al. [37], who compared nebulized lidocaine with nebulized terbutaline to suppress cough in patients with chronic obstructive pulmonary disease, and they noticed that the incidence of oropharyngeal numbness and bitter taste was significant higher in nebulized lidocaine than in the bronchodilator group, and Rao et al. [35] reported nebulized lidocaine to be well tolerated except for transient oropharyngeal numbness and bitter taste in the mouth.

McAlpine and Thomson [38], as well as Slaton et al. [39], mentioned in their studies that nebulized lidocaine has been documented to cause initial bronchoconstriction in those patients with baseline bronchial hyperactivity such as chronic obstructive pulmonary disease and asthma, unlike ketamine, which is known to be a good bronchodilator [40],[41]. In this study, an asthmatic patient with a history of an intermittent attack who was clinically free from audible wheezes on auscultation at time of the study, exhibited symptoms and signs of bronchoconstriction when he nebulized lidocaine, so he has been managed and excluded from the study. Moreover, Elkoundi et al. [42] used successfully nebulized ketamine for awake fiberoptic intubation in their patient who documented to have lidocaine allergy.

So, it is worth mentioning that in the presence of such obstacles, nebulized ketamine can play a good role as an alternative drug to nebulized lidocaine.

A drawback of this study was the absence of the measurements of plasma levels of ketamine, so we cannot rule out the influence of the systemic effect of ketamine. Moreover, timing and safe doses of nebulizations before intubation need further evaluation as doses in this study were used quite less than that causing adverse effects.

  Conclusion Top

Nebulization with lidocaine as well as ketamine before induction of general anesthesia is efficacious and enhances postoperative analgesia following endoscopic nasal surgeries. This is an easy, simple, cost-effective method to reduce postoperative pain and total doses of rescue analgesics used. Ketamine also proved to be an effective alternative solution in certain conditions where lidocaine is contraindicated or hazardous (i.e. lidocaine allergy or in patients with bronchial hyperactivity).

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Conflicts interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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