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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 3  |  Page : 126-134

Clinical techniques to prevent cough at emergence from general anaesthesia: A meta-analysis


1 Department of Anesthesiology, Changi General Hospital, Singapore
2 Department of Anaesthesia and Intensive Care, Wycombe Hospital, High Wycombe, Buckinghamshire, UK

Date of Submission25-Oct-2019
Date of Acceptance30-Nov-2019
Date of Web Publication30-Jan-2020

Correspondence Address:
Dr. Alex Joseph
Department of Anesthesiology, Changi General Hospital
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ARWY.ARWY_31_19

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  Abstract 


Brief summary: Various techniques can reduce the incidence of cough at tracheal extubation. Whilst effect size differs between treatments, homogeneity was identified within each subgroup of treatments. This meta-analysis allows anaesthesiologists to make informed choices on the use of techniques to prevent emergence cough. Background: Cough at extubation increases the risk of morbidity following surgical procedures. So, prevention of cough may aid perioperative risk management. Several techniques have been described for prevention of cough at or immediately after tracheal extubation. This meta-analysis compares various pharmacological methods for prevention of cough at emergence from general anaesthesia and aims to establish an evidence base for the rational use of these techniques. Methods: Several electronic databases (1966-2018) were searched systematically for randomised controlled trials that reported the incidence of cough at extubation. The quality of the studies identified was assessed using the Jadad methodology. Six techniques to prevent cough were analysed using the Mantel-Haenszel fixed-effects model. The odds ratio (OR) and number needed to treat (NNT) were used as the summary efficacy measures. Results: Of 1114 articles screened, 22 comparisons in 17 studies (1007 patients) were included in the final analysis. Significant heterogeneity of effect was observed when all studies were analysed together. However, there was homogeneity within each treatment subgroup. This reflected significant effect-size differences between techniques. The largest effect-sizes were seen with endotracheal tube cuff inflation with alkalinised lignocaine (pooled OR 0.052; 95% CI 0.027-0.102; NNT 1.67) and topical lignocaine (pooled OR 0.065; 95% CI 0.015-0.274; NNT 2.35). Conclusion: The incidence of cough at extubation of the trachea can be reduced. The overall effect size of the studied strategies was useful (pooled OR 0.149; 95% CI 0.13-0.18; NNT 2.62). No single technique prevented cough in all patients but cuff inflation with alkalinised lignocaine and topical 4% lignocaine were most effective.

Keywords: Cough, endotracheal tube, extubation, lignocaine, LITA tracheal tube


How to cite this article:
Joseph A, Rajendram R. Clinical techniques to prevent cough at emergence from general anaesthesia: A meta-analysis. Airway 2019;2:126-34

How to cite this URL:
Joseph A, Rajendram R. Clinical techniques to prevent cough at emergence from general anaesthesia: A meta-analysis. Airway [serial online] 2019 [cited 2020 Apr 5];2:126-34. Available from: http://www.arwy.org/text.asp?2019/2/3/126/277328




  Introduction Top


Cough during emergence from general anaesthesia (GA) occurs in up to 96.5% of cases.[1],[2] Coughing occurs at three different stages in the context of tracheal extubation:

  1. Coughing with an endotracheal tube (ETT) in situ (bucking)
  2. Coughing whilst the ETT is being removed
  3. Coughing post-extubation in the subsequent recovery period


Coughing may be harmful because it causes acute increases in blood pressure, heart rate, intrathoracic pressure, intraabdominal pressure, intracranial pressure and intraocular pressure. As a result, coughing exacerbates pain, oedema, venous bleeding, haematoma and bronchospasm.[3],[4],[5],[6] Rarely, if severe, coughing may disrupt an abdominal wound closure.

The development of severe oedema or a haematoma after surgery to the head, neck or airway is associated with significant morbidity and mortality. Premature extubation of the trachea, particularly after upper airway surgery, may result in laryngospasm and subsequent desaturation. Thus, smooth emergence from GA with minimal coughing is highly desirable.

Several techniques have been described to minimise emergence cough. However, their comparative reliability is not known.

Aim

The primary aim of this study was to perform a quantitative and qualitative assessment of pharmacological techniques to reduce cough during extubation of the trachea of patients emerging from GA. Coughing on removal of the ETT and coughing in the immediate post-extubation period were included.

Protocol

Search strategy

Two reviewers (AJ and RR) independently searched for articles published in English from 1966 to 10 Feb 2018 using the phrases cough, buck, sore throat, emergence phenomena, trachea, extubation, prevent, reduce, stop and combinations of the various derivatives of these phrases.

Data sources

Two reviewers (AJ and RR) independently searched electronic databases (i.e., PubMed, Medline, CINAHL, Ovid, Cochrane Controlled Trials Register) for relevant articles. The following journals were also hand-searched: Anesthesiology, Anesthesia and Analgesia, British Journal of Anaesthesia, Anaesthesia, Canadian Journal of Anaesthesia, Acta Anaesthesiologica Scandinavica, and European Journal of Anaesthesia. The bibliography of each article identified for inclusion in the meta-analysis and any associated articles were then hand-searched for other relevant studies.

Inclusion criteria and assessment of study quality

Studies that compared coughing during or immediately after tracheal extubation in adult patients (age >18 years) emerging from GA were included. Studies that did not provide the incidence of coughing and studies of post-extubation cough were excluded. Techniques with only one published study of that technique were excluded. Studies without controls were also excluded. Controls were defined as patients who received either saline injection or inflation of the ETT cuff with air.

Data collection process

[Figure 1] describes the study inclusion flow-process. The reviewers (RR and AJ) independently screened the titles and abstracts of all articles identified by the search strategy. Guided by established methodological standards [QUOROM], the reviewers independently determined which studies should be included in the meta-analysis. Full text copies of all selected articles were obtained and reviewed. Disagreements regarding inclusion and exclusion were resolved by discussion between reviewers. This process involved manually rechecking the data from each disputed article.
Figure 1: Study inclusion flow-process

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Assessment of risk of bias in included studies

Two reviewers independently used the Jadad methodology for completeness and accuracy of study report to assess the risk of bias of the identified studies.[7] Only studies with a Jadad score of 5 were included in the meta-analysis.

Data items

The studies that were identified for inclusion in the meta-analysis could be divided into six groups:

  1. Remifentanil infusion
  2. Dexmedetomidine infusion
  3. Intravenous lignocaine
  4. ETT cuff inflation with plain lignocaine
  5. ETT cuff inflation with alkalinised lignocaine
  6. Direct mucosal application of lignocaine through LITA (laryngotracheal instillation of topical anaesthetic) tracheal tube.


Method of synthesis

Contingency tables (2 × 2) were constructed to identify the responders (no cough) and nonresponders (who coughed) in the treatment and control groups. If the value of any of the four cells was zero, 0.5 was added to each cell in the contingency table.[8] The odds ratio (OR) with 95% confidence intervals (95% CI) was used as the primary summary measure of treatment efficacy. It was calculated as the ratio of the odds of cough occurring in the treatment group versus the control group. Interventions with the smallest OR were considered the most effective techniques to prevent emergence cough. The number needed to treat (NNT i.e., the number of patients who need to be treated in order to prevent one patient from having emergence cough) was determined for each individual technique and for data pooled from all techniques. This was calculated as the inverse of the absolute risk difference (i.e., treatment group cough rate - control group cough rate). All analyses were performed using MetaAnalyst software (Version 3.13, Tufts Medical Center, Boston, MA).[9]

The homogeneity of the effect size within all studies was assessed using the Cochran Q test based on inverse variance weights. This has a Chi-square distribution with k-1 degrees of freedom. A P value <0.05 was considered to indicate significant heterogeneity between the studies. If heterogeneity was observed, the I2 index was used to quantify this. Low, moderate, and high I2 values of 25-50%, 50-75%, and >75% were chosen to quantify heterogeneity.[10] Heterogeneity was low (P value 0.012 on Cochran Q test, with I2 valueof 44.3%). So, the studies were stratified into homogeneous subgroups for analysis with individual fixed effects modelling to provide the pooled odds ratio. The DeSimonian-Laird random effects model would have been used if the subgroups had significant heterogeneity.[11] However, homogeneity was demonstrated in all subgroups. Instead of a formal meta-regression, the fixed effect Mantel-Haenszel model was used.[12],[13]


  Results Top


Synthesis of Data

Data from 1007 subjects in 17 studies were analysed using 22 comparisons; 434 in the treatment group, and 573 controls. The median number of patients (sample size) of the included studies was 50 (range 30-100). The median rate of emergence cough in the control groups was 0.700 (range 0.158-0.960). Cough could be significantly reduced by pharmacological intervention. The overall effect size was moderate [OR of 0.149 (range 0.003-1; 95% CI 0.13-0.18)] but clinically significant with pooled NNT of 2.62 (95% CI; 2.4-3.0). [Table 1] describes the characteristics of the included studies. [Figure 2] displays the individual and pooled effect sizes for each study analysed.
Table 1: Characteristics of studies included in the meta-analysis grouped into six techniques which were investigated

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Figure 2: Forest plot of all studies

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Intravenous remifentanil infusion

Four trials with four distinct dose regimens were selected for final review: remifentanil bolus only prior to extubation, remifentanil infusion at one-tenth the average intraoperative dose, and remifentanil target controlled infusion (TCI) at two target levels: 1 ng.mL -1 and 1.5 ng.mL -1.[14],[15],[16],[17] These studies demonstrated significant heterogeneity in methodology and effect size. So, only two studies which used remifentanil TCI at 1.5 ng.mL -1 in 110 patients were included for final analysis (55 patients in the treatment group and 55 patients in the control group). The P value of the Cochran Q test was 0.007 before exclusion of these studies and 0.182 after the exclusion. Remifentanil TCI at 1.5 ng.mL -1 reduces the risk of emergence cough with pooled OR (0.108; 95% CI: 0.024-0.490; NNT 2.19) [Figure 3]. The one-tenth average intraoperative dose technique had comparable effect size for OR (0.167; 95% CI: 0.053-0.529). A single bolus dose of remifentanil has a significantly lower effect on emergence cough (OR 0.669; 95% CI: 0.193-2.327). [Figure 3]a displays the individual and pooled effect sizes for each study analysed.
Figure 3: Forest plot of studies which used an intravenous therapy to reduce cough at extubation. (a) Remifentanil (b) Dexmedetomidine (c) Lignocaine

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Intravenous dexmedetomidine

Two studies of dexmedetomidine infusions [18],[19] (100 patients) which used the same protocol (0.5 μg.kg -1 bolus 30 minutes prior to planned tracheal extubation) were included in the subgroup analysis. This technique significantly reduced emergence cough (pooled OR 0.133; 95% CI 0.053-0.337; NNT 2.21). These studies were homogenous (Cochran Q test P value 0.072). [Figure 3]b displays the individual and pooled effect sizes for each study analysed.

Intravenous lignocaine

Seven comparisons in five studies which included a total of 320 patients were included in this subgroup.[20],[21],[22],[23],[24] Two studies had one set of controls for two different treatment groups. Three doses of lignocaine were used in these studies: 100 mg bolus, 1 mg.kg -1 and 1.5 mg.kg -1. There was no evidence of a dose-response within the treatment group. The ranges of the observed ORs were 0.036-0.560 with 1 mg.kg -1, 0.271-0.327 with 1.5 mg.kg -1, and 1.000 with the 100 mg doses of intravenous lignocaine. There was homogeneity in this study subgroup (Cochran Q test P value 0.675). Intravenous lignocaine had the lowest pooled effect size of all the techniques assessed in this meta-analysis (pooled OR 0.309; 95% CI 0.189-0.505; NNT 4.48). [Figure 3]c displays the individual and pooled effect sizes for each study analysed.

Cuff inflation with aqueous lignocaine

Four studies which included 197 patients were included in this subgroup analysis.[25],[26],[27],[28] The doses of lignocaine used differed between each study and there was evidence of a modest dose-response. Individual dose effect sizes, presented as a range of OR (range of CI) were:

2% lignocaine 0.219 (0.023-2.114)

4% lignocaine 0.325-0.627 (0.071-4.259)

10% lignocaine 0.101 (0.095-0.424)

Two studies reported a low control event rate (38.1% and 15.8%). The P value was 0.355 on Cochran Q test, confirming homogeneity in effect size across studies included in this subgroup. Pooled OR was 0.2 (95% CI 0.095-0.424; NNT 3.77) for ETT cuff inflation with aqueous lignocaine. [Figure 4]a displays the individual and pooled effect sizes for each study analysed.
Figure 4: Forest plot of studies which used inflation of the endotracheal tube cuff with lignocaine to prevent cough at extubation (a) Plain lignocaine (b) Alkalinised lignocaine

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Cuff inflation with alkalinised lignocaine

Six studies were initially screened for analysis. However, only five comparisons in four studies that used similar dilution ratios and doses of lignocaine were pooled in the final subgroup analysis (250 patients, one study shared controls between two separate treatment comparisons).[25],[29],[30],[31] In the studies included in the subgroup analysis, 40 mg of lignocaine (2 mL of 2% lignocaine) was initially injected into the ETT cuff and the supplemental volume required to achieve a cuff seal was achieved with injection of sodium bicarbonate in 3 different concentrations (1.4%, 7.5% and 8.4%). Homogeneity was observed in the included studies (Cochran Q test, P value 0.056). Of the six techniques included in this meta-analysis; cuff inflation with alkalinised lignocaine was the most effective. The use of this technique resulted in a 19-fold reduction in risk (pooled OR 0.052; 95% CI 0.027-0.102; NNT 1.67). [Figure 4]b displays the individual and pooled effect sizes for each study analysed.

Direct mucosal application of lignocaine through LITA (laryngotracheal instillation of topical anaesthetic) tracheal tube

Two studies with a combined total of 80 patients were included in this subgroup.[20],[32] There was evidence of a dose response, with OR (95% CI) of 0.074 (0.009-0.643) for 100 mg of 2% lignocaine and 0.056 (0.009-0.366) for 2 mg.kg -1 of 4% lignocaine. Homogeneity was observed in this study subgroup (P value 0.661). Pooled OR was 0.065 (95% CI 0.015-0.274; NNT 2.35).

The number needed to treat for the 6 techniques to reduce cough at extubation that have been analysed in this meta-analysis are summarised in [Figure 5].
Figure 5: The number needed to treat of techniques used to reduce cough at extubation

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  Discussion Top


The literature was reviewed to identify randomised controlled trials of techniques used to prevent cough during tracheal extubation at emergence from GA. The techniques included in the present meta-analysis could be classified into six groups:

  1. Remifentanil infusion
  2. Dexmedetomidine infusion
  3. Intravenous lignocaine
  4. ETT cuff inflation with plain lignocaine
  5. ETT cuff inflation with alkalinised lignocaine
  6. Direct mucosal application of lignocaine through LITA (laryngotracheal instillation of topical anaesthetic) tracheal tube.


Studies of each evaluated subgroup were homogenous for effect size allowing direct comparisons between described techniques. The most effective methods of preventing cough included topical application of lignocaine to the airway, cuff inflation with alkalinised lignocaine and topical application of aqueous lignocaine through a LITA tube.

The doses of topical lignocaine used to prevent cough in the published literature are significantly lower than that required to allow tolerance of fibreoptic intubation of the trachea under sedation. The British Thoracic Society guidelines suggest that an upper limit of 8.4 mg.kg -1 is appropriate for bronchoscopy.[33] Arousal from anaesthesia is associated with acute increases in upper airway reflexes during the excitatory phase of recovery from anaesthesia. It is therefore, not surprising that the doses used in the studies included in this meta-analysis are insufficient to prevent cough in all patients.

The use of topical laryngotracheal lignocaine before tracheal intubation may reduce the haemodynamic response to intubation. However, this is unlikely to prevent emergence cough as the duration of action will rarely extend to the extubation period. However, when inflated with lignocaine, the cuff of the ETT acts as a reservoir. This allows lignocaine to diffuse across the cuff membrane and anaesthetise the underlying mucosa.[25],[26],[27],[28] Alkalinisation and warming are often used to facilitate diffusion by increasing the proportion of the nonionised form of local anaesthetic.[25],[30],[31]

Most of the data on alkalinised lignocaine has been reported by a single group of researchers. This may suggest the presence of some bias in the findings. However, the effect size of their data was homogenous with the findings of an independent study. This supports the assertion that cuff inflation with alkalinised lignocaine is currently the most effective strategy to prevent emergence cough. No other significant risk of selection, performance, detection, attrition or reporting bias was identified.

The potential complications associated with this technique include the risks of systemic absorption and damage to the ETT cuff with subsequent soiling of the lungs with lignocaine and sodium bicarbonate. In this context, it may be safer to use 1.4% sodium bicarbonate which has the same clinical effect as 8.4% sodium bicarbonate.[25],[30],[31]

Although the cost-benefit ratio of this approach is unclear, the currently available data suggests that this is the most effective single technique to prevent emergence cough. Interestingly, simply inflating the cuff of an ETT with saline has also shown to decrease the incidence of coughing.[29] The mechanism is unclear but may be because intraoperative increases in intracuff pressure are prevented by cuff inflation with saline.

Intravenous lignocaine has been used to obtund the response to intubation. In this meta-analysis, the range of OR for prevention of cough with intravenous lignocaine was 0.286-1.000 across the range of doses observed. The differences in effect size were not dose-dependent. Like most other membrane stabilising agents, intravenous lignocaine causes dose-dependent sedation. This effect could delay tracheal extubation and prolong the recovery period.[34] The use of intravenous lignocaine is the least reliable technique to prevent emergence cough. The lack of a dose-dependent effect suggests that other unmeasured factors may be, at least partially, responsible for the risk reduction.

Remifentanil depresses the cough reflex in a dose-dependent manner similar to its effect on respiratory depression.[17] In comparison to other opioids, the ease of titrating remifentanil allows a rapid shift from the state of respiratory depression and profound analgesia during GA to a state of calm arousal with minimal cough, nonpurposeful movements and sympathetic stimulation.

Lee et al.,[35] reported that a remifentanil target controlled infusion effect site concentration of 2.14 ng.mL -1 was required to abolish emergence cough in 95% of cases (i.e., EC95).[14] However, Lee et al.,[35] did not include a suitable control group. So their data was not included in the current meta-analysis. A bolus dose of remifentanil 1 μg.kg -1 attenuated increases in blood pressure and heart rate during emergence, but did not decrease the incidence of cough.[14] Achieving a specific plasma or effect-site concentration by administration of a single bolus of a drug is clinically difficult and unreliable. This is probably why a single bolus dose of remifentanil does not reliably suppress cough during emergence.[17]

Dexmedetomidine 0.5 μg.kg -1 administered intravenously before extubation attenuates both the incidence and severity of airway and circulatory reflexes on emergence from anaesthesia without prolonging recovery.[18] Dexmedetomidine was associated with significant reduction of risk of cough, but the cost of this agent could prohibit its use solely for this purpose.

There are several limitations in the literature included in this meta-analysis. Many factors which may have influenced the incidence of cough were not specifically studied or defined in any of the study protocols. These factors include the diameter of the ETT, ETT cuff design and pressure, process of laryngoscopy and tracheal intubation, movement of the ETT during surgery, excessive bucking on the ETT and excessive pharyngeal suctioning during extubation.

The two major confounders of the studies included in this meta-analysis were maintenance of GA with volatile anaesthetics and history of smoking. Hans et al., reported that the incidence of severe coughing was higher after sevoflurane than propofol-based anaesthesia (59% vs 6%), and also in smokers than in non-smokers (50% vs 17%).[36] Volatile anaesthetics increase the incidence of coughing and therefore should be avoided when prevention of cough is absolutely required. As no similar studies could be found in the published literature, we could not include the data from Hans et al., in this meta-analysis.

In summary, this meta-analysis provides a synthesis of the currently available data on the prevention of cough during tracheal extubation at emergence from GA. Although the incidence of emergence cough can be reduced, no single technique will prevent cough in all treated patients. The two most effective techniques were cuff inflation with alkalinised lignocaine (pooled OR 0.052; 95% CI 0.027-0.102; NNT 1.67) and topical lignocaine (pooled OR 0.065; 95% CI 0.015-0.274; NNT 2.35).

Financial support and sponsorship

Nil.

Conflicts of interest

Support for this work was provided solely from institutional and departmental sources. There are no financial disclosures to be made with regard to this study.



 
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    Figures

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

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