Comparison of Nebulized Ketamine and Ketamine with Clonidine in Postoperative Sore Throat.

BACKGROUND: Various nonpharmacological and pharmacological trials have been used for attenuating postoperative sore throat (POST) with no proven single modality. Ketamine has been used as a gargle or nebulization in the attenuation of POST by its action on peripheral N-methyl-D-aspartate receptors. Topical administration of clonidine elicits antinociception through α2-adrenoceptors without producing undesirable side effect. AIM: This study aims to compare between nebulized ketamine and ketamine with clonidine in POST.
MATERIALS AND METHODS: The effects of nebulized ketamine and ketamine with clonidine in POST have been compared in 100 patients. Patients were divided into two groups: Group K patients were nebulized with ketamine 1 mL (50 mg) plus normal saline 3 mL and Group KC patients were nebulized with ketamine 1 mL (50 mg) plus clonidine 1 mL (50 mg) plus normal saline 2 mL. Online statistical software was used for analysis of the data.
RESULTS: At 4 h, seven patients experienced sore throat in Group K while no incidence was reported in group KC (0%). At 8 h, 12 (85.7%) patients experienced sore throat in Group K and 2 (14.28%) patients in Group KC. At 12 h, 13 (81.25%) patients experienced sore throat in Group K and 3 (18.75%) patients of Group KC. At 24 h, 6 (85.71%) patients experienced sore throat in Group K and 1 (14.28%) patient in Group KC. Patients in both groups remained hemodynamically stable with no complaint of nausea, vomiting, sedation, laryngospasm, or any other side effect.
CONCLUSION: Nebulization with ketamine plus clonidine preoperatively is more effective in reducing POST with no adverse effects as compared to preoperative nebulization with ketamine.

INTRODUCTION

A postoperative pharyngeal discomfort or postoperative sore throat (POST) is like an unavoidable outcome of general anesthesia (GA) following an endotracheal intubation. The incidence is estimated to be 18%–65% in different studies.[12] Localized trauma to the mucosa during laryngoscopy and intubation leads to aseptic inflammation of the pharyngeal mucosa leading to POST. Various nonpharmacological and pharmacological trials have been used for attenuating POST with no proven single modality. The pharmacological methods used to reduce POST include the use of beclomethasone gel, gargling with azulene sulfonate, ketamine, clonidine, and licorice.[345] Many prophylactic measures are used to decrease the incidence of POST like the use of smaller sized endotracheal tubes with low intracuff pressure. Ketamine, a phencyclidine derivative, has been used as a gargle or nebulization in the attenuation of POST by its action on peripheral N-methyl-D-aspartate (NMDA) receptors.[678] In gargle form, a large volume of the drug is used. Hence, patients are at a risk of aspiration, and it is difficult to perform. These complications can be avoided by using nebulized ketamine in a fixed dose of 50 mg plus 3 ml normal saline.[3910] Various studies have reported that clonidine produces antinociception regardless of the route of administration (central or peripheral).[11121314] The topical administration of clonidine elicits antinociception by blocking the emerging pain signals at peripheral terminals through α2-adrenoceptors without producing undesirable side effect observed after systemic administration.[15] Inhaled clonidine 75 μg was used to treat broncho-obstructive diseases and was found to improve basal respiratory functions without significantly influencing blood pressure.[16]

Aim

This study aims to compare between nebulized ketamine and ketamine with clonidine in POST.

Objectives

Comparison of POST at 4 h, 8 h, 12 h, and 24 h

Comparison of side effects between the two groups.

MATERIALS AND METHODS

After obtaining approval from the Institutional Ethics Committee, written informed consent was obtained from all the patients enrolled in the study. In the present study, we have compared the effects of nebulized ketamine and ketamine with clonidine in POST in 100 patients.

Inclusion criteria

Age groups 20–60 years

Either sex

American Society of Anesthesiologists (ASA) physical Status I–II

Surgery in supine position under GA lasting for up to 2 h.

Exclusion criteria

History of prior sore throat

Patients using steroids or nonsteroidal anti-inflammatory drugs

Patients with chronic obstructive pulmonary disease, asthma, hypertension

Mallampati grade >2

Patients with >2 attempts of intubation

Pregnant women

Patient and/or his/her legally acceptable representative not willing to provide their voluntary written informed consent for participation in the study.

Patients were divided into two groups:

Group K patients were nebulized with ketamine 1 mL (50 mg) plus normal saline 3 mL, so the total volume was 4 mL

Group KC patients were nebulized with ketamine 1 mL (50 mg) plus clonidine 1 mL (50 mg) plus normal saline 2 mL, so the total volume was 4 mL.

Randomization was done by an anesthesiologist who was not a part of the further study. In the preparation room, an intravenous cannula was inserted in the patients. Nebulizing solution was prepared by one of the anesthesiologists who not the part of the study. Patients were nebulized via compressor nebulizer for 15 min. Patients were blinded to the nebulizing solution. Patients were then transferred to the operation theatre; the standard monitor was applied (noninvasive blood pressure, pulse oximetry, electrocardiogram, and capnography) after induction of anesthesia.

After all postoperative preparations, the patient was preoxygenated with 5 L/min O2, 100% for 3–5 min, premedication with glycopyrrolate 0.01 mg/kg, midazolam 0.02 mg/kg. Induction was done with fentanyl 2 μg/kg, propofol 2 mg/kg, endotracheal intubation was facilitated with succinylcholine 2 mg/kg. Laryngoscopy was attempted after 60–90 s when fasciculation disappeared from the patient's body. Intubation was done. The maintenance of anesthesia was done using Isoflurane 1 minimum alveolar concentration and atracurium in both groups, O2 50% and H2O 50%. Muscle relaxant reversed with neostigmine 0.05 mg/kg, glycopyrrolate 0.01 mg/kg. The patient was extubated when fully conscious. In the recovery room, the patient received O2 2.5 L/min through the face mask. The intensity of sore throat was recovered at 4 h, 8 h, 12 h, and 24 h postoperatively. First observation was recorded at 4 h as patients became alert enough to take part in the study. Sore throat was measured on 4 points scale 0–3.

0- No sore throat

1- Mild sore throat (complains of sore throat on asking)

2- Moderate sore throat (complains of sore throat on his/her own)

3- Severe sore throat (change in voice or hoarseness associated with throat pain).

Protocol for pain management-IV diclofenac 1.5 mg/kg every 8 hourly.

Statistical analysis

Data were recorded on a customized pro forma initially and then was transferred to Microsoft Excel sheet. Online statistical software was used for analysis of the data. Proportional comparison between the two groups was done using Fisher's exact test/Z-test for two sample proportion. Mean comparisons between the two groups were done using unpaired t-test. P < 0.05 was taken statistically significant. The final data were presented in the form of tables and groups.

RESULTS

Demographic profile in terms of age, weight, sex, and ASA grading has been depicted in Table 1 with statistically no significant difference. Patients in both groups remained hemodynamically stable with no complaint of nausea, vomiting, sedation, laryngospasm, or any other side effect. The mean age between the two groups was comparable (35.17 ± 13.41 years in Group K and 38.94 ± 14.58 in group KC, P = 0.190). The mean weight between the two groups was also comparable (66.29 ± 7.93 kg in Group K and 63.67 ± 8.45 kg in group KC, P = 0.110) [Table 1]. There were 56% of females in Group K and 54% in Group KC. Similarly, there were 44% of males in Group K and 46% in Group KC.

Table 1

Comparison of mean age and weight between ketamine and ketamine-clonidine groups (n=100)

Parameter	Mean±SD		P
	Group K	Group KC
Age (years)	35.17±13.41	38.94±14.58	0.190 (NS)
Weight (kg)	66.29±7.93	63.67±8.45	0.110 (NS)
Male:female	22/28	23/27	1.01 (NS)
ASA (Grade I/II)	31/19	29/21	0.672 (NS)

K=Ketamine, KC=Ketamine-clonidine, ASA=American Society of Anesthesiologist, SD=Standard deviation

As shown in Table 2, all patients in Group K and Group KC were acceptable to ketamine and ketamine-clonidine nebulization (Acceptability score 0). None of the patients in both groups had an acceptability score of 1 and 2. However, acceptability score distribution in both the patient groups studied is not significant by Fisher's exact test (P = 1.000).

Table 2

Acceptability score distribution

Acceptability score	Group K (%)	Group KC (%)	Total (%)
Acceptable	50 (100)	50 (100)	100 (100)
Discomfort due to nebulization or taste of drug	0	0	0
Discomfort due to both nebulization and taste of drug	0	0	0
Total	50 (100)	50 (100)	100 (100)

K=Ketamine, KC=Ketamine-clonidine

At 4 h, seven patients experienced sore throat in Group K while there was no incidence of sore throat in Group KC (0%) [Table 3]. While at 8 h, 14 patients experienced sore throat, 12 (85.7%) patients experienced sore throat in Group K and 2 (14.28%) patients in Group KC. At 12 h, 16 patients experienced sore throat, 13 (81.25%) patients experienced sore throat in Group K while it was experienced by 3 (18.75%) patients of Group KC. At 24 h, seven patients experienced sore throat, 6 (85.71%) patients experienced sore throat in Group K and 1 (14.28%) patient in Group KC. Overall 44 patients experienced sore throat out of 100 patients in the study. Of these, higher number of patients of Group K 38 (86.36%) experienced sore throat as compared to Group KC where 6 (13.64%) patients experienced the same. The difference was found to be statistically significant (P < 0.05).

Table 3

Comparison of sore throat at different time intervals between group ketamine and group ketamine-clonidine (n=100)

Time interval (h)	n	Group K	Group KC	Z/Fisher’s exact test	P
4 h	7	7 (100)	0	Fisher	0.002*
8 h	14	12 (85.7)	2 (14.28)	5.93	0.000*
12 h	16	13 (81.25)	3 (18.75)	4.84	0.000*
24 h	7	6 (85.71)	1 (14.28)	4.23	0.000*
Overall	44	38 (86.36)	6 (13.64)	10.22	0.000*

K=Ketamine, KC=Ketamine-clonidine. *Statistically significant

As shown in Table 4, there was an overall incidence of sore throat in 44 patients. Of these 44, 6 patients (13.64%) of Group KC reported sore throat and all these patients had a severity score of 1 while 31 (67.39%) patients reported sore throat in Group K. However, only 7 patients (15.21%) reported the severity of score 2.

Table 4

Distribution of sore throat at different time intervals between group ketamine and group ketamine-clonidine according to severity (n=100)

Time interval	Severity	n	Group KC, n (%)	Group K, n (%)
4 h	1	7	0 (0.0)	7 (100)
	2		0 (0.0)	0 (0.0)
8 h	1	14	2 (14.28)	10 (71.42)
	2		0 (0.0)	2 (14.28)
12 h	1	16	3 (18.75)	10 (62.50)
	2		0 (0.0)	3 (18.75)
24 h	1	7	1 (14.28)	4 (57.14)
	2		0 (0.0)	2 (28.57)
Overall	1	44	6 (13.64)	31 (67.39)
	2		0 (0.0)	7 (15.21)

K=Ketamine, KC=Ketamine-clonidine

DISCUSSION

POST is a simple yet distressing complain in several patients following endotracheal intubation. Several trials had been done recently in reducing POST with conflicting results. The present study was designed to evaluate the difference in the effect of nebulized ketamine and ketamine with clonidine in POST; the effect was observed on the incidence and severity of POST at 4, 8, 12, and 24 h following GA, with tracheal intubation lasting up to 2 h. In the present study, the total incidence of POST was 44% as compared to 18%–65% in previous studies.[1] Out of which it was 6% in Group KC and 38% in Group K, significantly less in Group KC (P = 0.000).

Several factors have been identified in earlier studies contributing to sore throat after surgery, including patient's age, sex, cuff design, intracuff pressure, and tracheal tube size.[101718] In our study, both groups were comparable in distribution of age, weight, gender, and ASA physical status and hence no correlation with sore throat was noted.

The incidence and severity of POST was significantly less in Group KC than in Group K at the following time intervals, 4 h after extubation (P = 0.002), 8 h after extubation (P = 0.000), 12 h after extubation (P = 0.000) and 24 h after extubation (P = 0.05). In a study, nebulized ketamine was found to be better than saline to attenuate POST at 2 h.[19] Six patients in saline and 0 patient in ketamine group (P = 0.02) and at 4 h, 13 patients in saline and seven patients in ketamine group (P = 0.03) had POST. In the present study, 38 patients in ketamine group had POST, comparable outcome, but six patients in Group KC had POST. The decreased incidence and severity of POST is suggestive that combined administration of ketamine and clonidine for nebulization was effective at early hours and also for a prolonged period. The analgesia due to ketamine was achieved through topical action of ketamine through NMDA antagonistic action and anti-inflammatory action.[202122] Experimental animal studies have shown that ketamine has protective effect on airway inflammatory injury and also relaxes airway smooth muscles probably through interference with Ca++. The addition of clonidine to ketamine in nebulizing solution gave better results not only due to synergistic topical action of ketamine and clonidine, but long terminal half-life of clonidine also contributed to such result.[21]

The combination of oral clonidine and low dose intravenous ketamine reduces the consumption of morphine through patient-controlled analgesia after spine surgery suggesting that interaction of ketamine and clonidine does exist because these drugs act through different mechanism. Dogruel et al. demonstrated that topical clonidine elicits antinociception by blocking the emerging pain signals at peripheral terminals through α2-adrenoceptors without producing undesirable central side effect. Inhaled clonidine was found to be broncho-protective in a study done in anesthetic patients.[1516] As both the drugs were used through nebulization, the concentration achieved around airway was high and produced the effective outcome, possibly due to the synergistic action of ketamine clonidine. Group KC had better analgesia than Group K.

Limitations

There was no record of coughing or bucking on extubation. Another drawback in our study was lack of measurement of plasma ketamine levels during the study. Furthermore, no formal sedation scale was used. We cannot rule out the contribution of the systemic effect of the drugs on our result. Moreover, further studies are needed on comparing the efficacy between ketamine nebulization and ketamine with clonidine nebulization and also on the time of administration of nebulization-before or after the surgery. Bigger sample size in a similar study could add strength to the findings.

CONCLUSION

Nebulization with ketamine plus clonidine preoperatively is more effective in reducing POST with no adverse effects as compared to preoperative nebulization with ketamine. However, larger population studies and estimation of serum ketamine levels are needed to compare ketamine nebulization and ketamine with clonidine nebulization to prevent POST after GA in an ambulatory care setting.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.