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ORIGINAL ARTICLE
Year : 2023  |  Volume : 17  |  Issue : 1  |  Page : 39-44

Can low dose of intratracheal dexmedetomidine be used to attenuate peri-extubation cough? - A prospective, double-blinded, randomized clinical trial


Department of Anaesthesiology, Chettinad Hospital and Research Institute, Chennai, Tamil Nadu, India

Correspondence Address:
Merlin Shalini Ruth
Department of Anaesthesiology, Chettinad Hospital and Research Institute, Chennai - 603 103, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sja.sja_619_22

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Date of Submission31-Aug-2022
Date of Decision06-Sep-2022
Date of Acceptance19-Sep-2022
Date of Web Publication02-Jan-2023
 

  Abstract 


Background: Peri-extubation cough is an undesirable event during extubation, prevention of which has been studied with multiple drugs, amongst which intravenous dexmedetomidine has emerged as one of the favourable drugs. Intratracheal route is attractive because of its ease of administration, provided it avoids the hypotension and bradycardia that occurs during intravenous bolus administration. There is a paucity of data exploring the utility, doses, and adverse effect of intratracheal dexmedetomidine.
Methods: After obtaining ethical committee approval, 60 eligible, consenting adult patients undergoing surgery under general anesthesia in a tertiary teaching hospital were recruited and randomised into three groups—DEX0.3, DEX0.5, and NS. The plan of general anesthesia was standardized. Half an hour prior to extubation, study drug was instilled intratracheally—dexmedetomidine 0.3 mic/kg, 0.5 mic/kg, and NS in groups DEX0.3, DEX0.5, and NS, respectively. 4-point cough score was used to assess extubation response. Hemodynamic response and time to Ramsay sedation score 3 was also recorded.
Results: Majority of patients in DEX0.3 (60%) and DEX0.5 (85%) group had no cough (cough score 0), while majority of the patients in the NS group (70%) had either mild or moderate cough (cough score 1, 2). Kruskal Wallis test followed by post-hoc pairwise comparison showed statistically significant difference in 4-point cough score between GroupDEX0.3 and GroupNS (P < 0.001) and between GroupDEX0.5 and GroupNS (P = 0.038). DEX0.5 group, compared to DEX0.3 group, had significantly higher time from reversal to extubation (P < 0.001) and time to achieve Ramsay sedation score of 3 (P < 0.001).
Conclusion: We conclude that both 0.3 mic/kg and 0.5 mic/kg of dexmedetomidine when given intratracheally are effective in preventing peri-extubation cough. Further, 0.3 mic/kg dexmedetomidine showed a better recovery profile compared to 0.5 mic/kg dexmedetomidine when administered intratracheally.

Keywords: Dexmedetomidine, general anesthesia, intratracheal, peri-extubation cough


How to cite this article:
Nahar AR, Gopinath V, Ruth MS. Can low dose of intratracheal dexmedetomidine be used to attenuate peri-extubation cough? - A prospective, double-blinded, randomized clinical trial. Saudi J Anaesth 2023;17:39-44

How to cite this URL:
Nahar AR, Gopinath V, Ruth MS. Can low dose of intratracheal dexmedetomidine be used to attenuate peri-extubation cough? - A prospective, double-blinded, randomized clinical trial. Saudi J Anaesth [serial online] 2023 [cited 2023 Feb 3];17:39-44. Available from: https://www.saudija.org/text.asp?2023/17/1/39/364878




  Introduction Top


The process of extubation is ubiquitous to that of general anesthesia with controlled ventilation. A smooth extubation experience allays distress to both patients and anesthesiologists alike.

Cough, although primarily a protective reflex, during extubation and emergence can be adversely associated with cardiovascular changes such as extreme tachycardia and hypertension that might be poorly tolerated by patients with limited cardiovascular reserve. There are also reports of cough being followed by hematoma, wound dehiscence, and raised intracranial pressure.[1]

A recent meta-analysis concluded that though drugs such as lidocaine—intravenous (IV), intracuff, topical, or intratracheal (IT), dexmedetomidine IV, and opioids IV such as remifentanil and fentanyl showed better odds of reducing moderate to severe cough at extubation and among these options, IV dexmedetomidine has emerged as the most favourable drug in terms of highest cumulative rank for decreasing the frequency of moderate to severe emergence.[2] More recently, the use of IT route of dose 0.5 mcg/kg for the administration of dexmedetomidine has been introduced[3],[4] but there is a paucity of studies which have used IT dexmedetomidine. Further, there are no dose comparing studies comparing different doses of IT dexmedetomidine for alleviating cough at extubation. We hypothesized that a lower dose of 0.3 mcg/kg would also attenuate cough response.

So, we conducted a prospective, randomised, double-blinded trial to study the effect of 0.5 and 0.3 mcg/kg doses of intratracheal dexmedetomidine on the occurrence of cough and recovery characteristics in patients undergoing general anesthesia.


  Methodology Top


Sample size calculation

Based on the study by Wang et al.,[3] the cough score (mean (standard deviation)) in the saline group was 1.2 (0.8) and was reduced to 0.5 (0.6) in response to the intratracheal administration of Dex. With statistical significance set to 5% (two sided) and assuming a power of 80% and setting the cough score as the primary variable, we determined that a sample size of 20 was necessary for each group.

Patient selection

This trial was in concordance with the Declaration of Helsinki. After obtaining approval from Institutional Human Ethics Committee, and registering the study in Clinical trials registry of India (CTRI) Reg. No-CTRI/2020/11/028886, and obtaining written informed consent, 60 ASA I and II adult patients aged 18–65 years scheduled for surgeries under general anesthesia in a tertiary care teaching hospital were included in the study. Patients with recent upper respiratory tract infection, uncontrolled/untreated hypothyroidism, heart disorders—bradycardia, heart block, sick sinus syndrome, coronary heart disease, uncontrolled hypertension, hepatic and renal insufficiency, long term use of sedative drugs (benzodiazepines, barbiturates), anticipated difficult airway, and those who received alpha2 agonists preoperatively were excluded. The 60 adult patients were randomly divided into three groups (20 patients in each group) using a computer-generated randomization code and allotted through sequentially numbered opaque envelopes.

Plan of anesthesia

All anesthesia drugs and procedures were standardized. On arrival inside the operating room, heart rate (HR), oxygen saturation (SpO2), and non-invasive blood pressure (NIBP) were recorded prior to induction and every 5 min thereafter. After preoxygenating with 100% oxygen for 3 min, they were administered fentanyl 2 mcg/kg IV and injection propofol 2 mg/kg IV, followed by injection atracurium 0.5 mg/kg IV. After 3 min, endotracheal intubation was carried out with endotracheal tube (ETT)—7 mm internal diameter (ID) for all female and 8 mm ID ETT for all male patients. Cuff pressure in ETT was maintained between 20 and 30 cm H2O. Isoflurane was used for maintaining minimum alveolar concentration (MAC) between 0.8 and 1, along with air and oxygen mixture with FiO2 0.5. Paracetamol 15 mg/kg IV was used for analgesia. Atracurium was used intermittently for muscle relaxation as required. Roughly 30 min before the end of surgery as confirmed with the surgeon, study drug was instilled into ETT.

An anaesthesiologist not engaged in the study or the surgery, opened a sealed envelope outside the operating room, and the medications were loaded correctly and tagged with the study number and administered the same intratracheally. As a result, the treating anaesthesiologist was rendered blind to the group allocation. Isoflurane was stopped when the closure of skin was initiated. When regular spontaneous breathing attempts were seen, patient was reversed with inj. glycopyrrolate 0.01 mg/kg + neostigmine 0.05 mg/kg IV and extubated when extubation criteria were met.

The calculated dose of dexmedetomidine was diluted to 2 ml in a 5 ml syringe according to the allocated group—GroupDEX0.3 (0.3 mcg/kg), GroupDEX0.5 (0.5 mcg/kg), and GroupNS (normal saline) and instilled into the intratracheal tube followed by a positive pressure breath.

We recorded cough during extubation. A four-point scale used previously was used for grading cough.[3],[5] Scores were designated as 0—No cough, 1—Mild cough (single cough), 2—Moderate cough (more than one episode of unsustained cough for ≤5 s), 3—Severe cough (sustained bouts of coughing for >5 s).

The dependent hemodynamic variables were measured at 10-time points: at the time of drug administration, 5 min after drug administration; 15 min, 10 min, 5 min before extubation; at extubation; and 2 min, 5 min, 15 min, and 30 min post extubation.

In case of severe cough, lignocaine 1.5 mg/kg was administered IV to supress the cough response. Duration of anesthesia, duration of surgery, and time to extubation after reversing patient were recorded. Time taken for the patient to achieve a Ramsay sedation score of three was also noted.

The primary outcome was peri-extubation cough score. The secondary outcome parameters were hemodynamic variables, time from reversal to extubation, and time taken to achieve Ramsay sedation score of three.

Statistical analysis

Demographic data was analysed with descriptive statistics such as mean and SD for continuous variables and frequencies and percentages for the categorical variables. The categorical variables associated with the outcome between three groups was analysed using the Chi-square test. Hemodynamic parameters at different time points were compared across the groups using repeated measures ANOVA with Greenhouse Geisser corrections followed by post-hoc analysis. Time between reversal and extubation and time for patient to achieve Ramsay sedation score of three was analysed using one-way ANOVA. The 4-point cough scale scores between the groups were compared using Kruskal Wallis test followed by post-hoc analysis to find the differences between groups. P value of less than 0.05 was considered statistically significant. Data was entered in Excel and analysed using IBM SPSS Statistics for Windows, Version 25.0. Chicago, IL.


  Results Top


Seventy-six adult patients who were to undergo general anesthesia were assessed for eligibility for inclusion in the study. Sixteen of these patients were excluded as they did not fit the inclusion criteria. The remaining 60 patients were randomised into three groups [Figure 1].
Figure 1: CONSORT flow diagram

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The demographic characteristics and American Society of Anesthesiologists (ASA) physical status of patients were comparable between all three groups (P > 0.05) [Table 1].
Table 1: Patients' demographic data

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Repeated measures ANOVA with post-hoc Bonferroni correction showed statistically significant difference between DEX0.5 and NS group in HR over time (P 0.012), but there was no significant difference in mean arterial pressure (MAP) measured over time (P 0.290). Line graphs showing trends in HR and MAP over the ten time points chosen are shown in [Figure 2] and [Figure 3], respectively.
Figure 2: Line graph showing trends in mean heart rate after intratracheal drug administration. SDA Study drug administration; EXT Extubation. *P 0.012 for DEX0.5 vs NS group

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Figure 3: Line graph showing trends in mean arterial pressure after intratracheal drug administration. MAP Mean arterial pressure; SDA Study drug administration; EXT Extubation *P 0.001 for DEX0.5 vs NS group

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Analysis of distribution of 4-point cough scale showed that majority of patients in the DEX0.3 (60%) and DEX0.5 (85%) had no cough, while majority of the patients in the NS group (70%) had either mild or moderate cough [Figure 4].
Figure 4: Bar graph showing distribution of cough score between the groups. Cough score 0—No cough, 1—Mild cough (single cough), 2—Moderate cough (more than one episode of unsustained cough for ≤5 s), 3—Severe cough (sustained bouts of coughing for >5 s)

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Kruskal Wallis test showed that there is statistically significant difference between the three groups (test statistic = 20.26, degree of freedom is two, two-sided asymptotic significance P < 0.001). On pairwise inter-group analysis for distribution of 4-point cough scale, there was statistically significant difference between DEX0.3 and NS group (P < 0.001) and between DEX0.5 and NS groups as well (P = 0.038). There was no significant difference in the distribution of cough between the DEX0.3 and DEX0.5 groups [Table 2].
Table 2: Kruskal Wallis test with post hoc Bonferroni correction for pairwise comparison of cough scores

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Time from reversal to extubation was 9.85 ± 1.42 min in DEX 0.5, 5.15 ± 0.93 min in DEX 0.3 and 4.80 ± 1.61 min in the NS group. Analysis showed statistically significant increase in time to extubation in DEX0.5 group compared to DEX0.3 (P < 0.001) and DEX0.5 vs NS groups (P < 0.001). The time taken to achieve Ramsay Sedation Score 3 between groups revealed that there is statistically significant difference in DEX 0.5 vs DEX 0.3 (13.25 ± 2.770 vs 7.15 ± 1.725 min) (P < 0.001), and NS vs DEX 0.5 (5.60 ± 1.569 vs 13.25 ± 2.770 min), (P < 0.001). There was no statistically significant difference between the DEX 0.3 and NS (P = 0.068) [Table 3].
Table 3: Comparison of recovery characteristics

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  Discussion Top


In this study, we found that dexmedetomidine 0.3 mic/kg and 0.5 mic/kg given intratracheally approximately 30 min prior to end of surgery effectively reduces the occurrence of cough at extubation compared to saline. Further, between the two doses, dexmedetomidine 0.3 mic/kg was found to produce faster recovery in terms of time to extubation and time to Ramsay sedation score of three when compared to dexmedetomidine 0.5 mic/kg. In addition, the HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP was lower in the dexmedetomidine groups in comparison to saline, but none of the patients had hypotension or bradycardia that needed intervention.

Dexmedetomidine is a highly selective alpha-2 agonist which has demonstrated multiple advantages as a useful sedative agent with analgesic properties and ability to preserve respiration.[6] Although many studies have shown IV dexmedetomidine to be effective in attenuating cough response,[2],[7],[8],[9],[10] our study has added to the current evidence that IT dexmedetomidine 0.5 mic/kg and 0.3 mic/kg is also effective. This effectiveness can be explained by its systemic absorption across the airway epithelium. As the thickness of pulmonary epithelium decreases distally along the airways, small molecules have shown to have excellent absorption through this route.[11] Dexmedetomidine, being a small hydrophilic compound, has a propensity to be absorbed effectively through the pulmonary route. Further, drugs when delivered as aerosols with 1–3 micron particles are shown to be best absorbed through the pulmonary epithelium. In our study, we simulated an aerosol mechanism by spraying the drug through the needle of a 5 ml syringe down the ETT and following it up with a positive pressure breath. Due to possible slower onset of action of dexmedetomidine and prior evidence that intranasal dexmedetomidine achieved a maximum concentration at a median time of 37 min,[12] we timed intratracheal administration 30 min before extubation.

IT route for dexmedetomidine assumes importance because it has the advantage of ease of administration as a single shot without the hassle of infusion pumps. IV dexmedetomidine, even as bolus infusion over 10 min used for attenuating extubation response is consistently seen to be associated with dose-dependent side effects such as hypotension, bradycardia, and delayed emergence.[8],[9],[13] In contrast, none of the patients in our study had bradycardia or hypotension. Although we found that the mean HR in the peri-extubation period was significantly low in the DEX0.5 group (93.5 ± 6.6 bpm) compared to DEX0.3 group (108.3 ± 11.1) and NS group (108.3 ± 11.2) [P < 0.001], this statistically significant difference in HR was not clinically significant. This lack of bradycardia and hypotension can be explained by pharmacokinetic data that shows that intratracheal absorption of drugs is only about 15–20% of the intravenous route.[14] Hence, when given IT, the possibly lesser absorption of dexmedetomidine could cause lesser hemodynamic perturbations. Therefore, this route can be utilised to exploit the beneficial effects of dexmedetomidine on producing smooth extubating conditions without manifestation of its adverse effects profile.

In the present study, we also found that a lower dose of intratracheal dexmedetomidine (0.3 mic/kg) was significantly better than placebo in reducing incidence of cough (P < 0.001), proving our initial hypothesis. Aouad et al.[9] demonstrated that 0.25 mic/kg intravenous bolus of dexmedetomidine prior to extubation reduced the incidence of cough and significantly reduced the occurrence of emergence reaction at extubation. Extrapolating this intravenous dose, we chose a dose of 0.3 mic/kg intratracheal dexmedetomidine to study if it is effective in reducing peri-extubation cough. Whether this effect is a cause of local action of dexmedetomidine at the tracheal receptors in addition to the systemic absorption is a direction for future research.

In terms of recovery characteristics, subjects in the DEX0.5 group had longer time from reversal to extubation (9.85 ± 1.42 min) compared to those in the DEX0.3 group (5.15 ± 0.93 min) (P < 0.001). Similarly, time to achieve Ramsay sedation score of three was also longer in the DEX0.5 group (13.25 ± 2.770 min) compared to DEX0.3 group (7.15 ± 1.725 min) (P < 0.001). These are important parameters to consider, especially when the turnover rate of the operating theatres is high.

Our study is not without limitations. We included all surgeries performed under general anesthesia without limiting to one type of surgery. As the surgical stimulus differs between surgeries, there could have been some discrepancies in the magnitude of emergence response too.

Further scope of the study includes studying the absorption characteristics of dexmedetomidine when given intratracheally and whether it exerts any local effects on the tracheal receptors in addition to its effects after systemic absorption. Another parameter to study further will be to compare intranasal and IT dexmedetomidine to determine if it is the systemic absorption that is the main mechanism for attenuating cough.


  Conclusion Top


Both 0.3 mic/kg and 0.5 mic/kg of dexmedetomidine when given intratracheally are effective in preventing peri-extubation cough. Further, 0.3 mic/kg dexmedetomidine showed a better recovery profile compared to 0.5 mic/kg dexmedetomidine when administered intratracheally.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Tung A, Fergusson NA, Ng N, Hu V, Dormuth C, Griesdale DGE. Pharmacological methods for reducing coughing on emergence from elective surgery after general anesthesia with endotracheal intubation: Protocol for a systematic review of common medications and network meta-analysis. Syst Rev 2019;8:32.  Back to cited text no. 1
    
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Tung A, Fergusson NA, Ng N, Hu V, Dormuth C, Griesdale DEG. Medications to reduce emergence coughing after general anaesthesia with tracheal intubation: A systematic review and network meta-analysis. Br J Anaesth 2020:S0007-0912 (20) 30012-X. doi: 10.1016/j.bja. 2019.12.041.  Back to cited text no. 2
    
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Wang F, Zhong H, Xie X, Sha W, Li C, Li Z, et al. Effect of intratracheal dexmedetomidine administration on recovery from general anaesthesia after gynaecological laparoscopic surgery: A randomised double-blinded study. BMJ Open 2018;8:e020614.  Back to cited text no. 3
    
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Niu J, Hu R, Yang N, He Y, Sun H, Ning R, et al. Effect of intratracheal dexmedetomidine combined with ropivacaine on postoperative sore throat: A prospective randomised double-blinded controlled trial. BMC Anesthesiol 2022;22:144.  Back to cited text no. 4
    
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Aksu R, Akin A, Biçer C, Esmaoǧlu A, Tosun Z, Boyaci A. Comparison of the effects of dexmedetomidine versus fentanyl on airway reflexes and hemodynamic responses to tracheal extubation during rhinoplasty: A double-blind, randomized, controlled study. Curr Ther Res Clin Exp 2009;70:209–20.  Back to cited text no. 8
    
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Rani P, Hemanth Kumar V, Ravishankar M, Sivashanmugam T, Sripriya R, Trilogasundary M. Rapid and reliable smooth extubation—Comparison of fentanyl with dexmedetomidine: A randomized, double-blind clinical trial. Anesth Essays Res 2016;10:597.  Back to cited text no. 10
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Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc 2004;1:338–44.  Back to cited text no. 11
    
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Anjum N, Tabish H, Debdas S, Bani HP, Rajat C, Anjana Basu GD. Effects of dexmedetomidine and clonidine as propofol adjuvants on intra-operative hemodynamics and recovery profiles in patients undergoing laparoscopic cholecystectomy: A prospective randomized comparative study. Avicenna J Med 2015;05:67–73.  Back to cited text no. 13
    
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