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Abstract
Introduction Coughing during extubation can lead to several postoperative complications, including surgical site bleeding, intracranial hypertension and high intraocular pressure. Currently, various pharmacological and non-pharmacological interventions are employed in clinical practice to reduce coughing during extubation. However, it is unclear which of these interventions has the best preventive effect and the fewest adverse events. Therefore, we plan to conduct a systematic review and network meta-analysis to compare the effects of all interventions.
Methods and analysis We will search MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, CNKI and Wanfang databases, as well as reference lists from previously published papers, from the date of their inception to April 2024. We will only include randomised controlled trials, regardless of publication in any language. The primary outcome is the incidence of cough during extubation, using the modified Minogue scales. The secondary outcomes are as follows: (1) the incidence of severe coughing (grade 4); (2) the incidence of other types of postoperative airway complications, such as laryngospasm, apnoea, hypoxaemia and sore throat, which will be evaluated within 24 hours after surgery; (3) the side effects related to the interventions, such as bradycardia (heart rate less than 60 beats per minute), hypotension or allergic reactions, which will be evaluated within 24 hours from the start of the drug to the postoperative period and (4) the time from the end of the surgery to the extubation of the endotracheal tube. The articles meeting the criteria will be independently evaluated by two researchers based on the established screening criteria. The data will then be extracted. Bias will be assessed for all included studies using the Cochrane Risk of Bias Risk Assessment Tool Version 2. We will use the Netmeta package of the R software with a random-effects model to make direct and indirect comparisons through the frequency framework. We will assess the quality of evidence using Confidence in Network Meta-Analysis.
Ethics and dissemination Ethical approval is not required for this protocol, as we will only pool published data. We plan to submit our manuscript for publication in a peer-reviewed academic journal.
PROSPERO registration number CRD42023401609.
- Adult anaesthesia
- Protocols & guidelines
- Meta-Analysis
- Systematic Review
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STRENGTHS AND LIMITATIONS OF THIS STUDY
We will comprehensively compare pharmacological and non-pharmacological interventions that may reduce or alleviate coughing during extubation after general anaesthesia.
Only randomised controlled trials will be included in this study, and the primary outcome is the risk of cough during tracheal extubation.
We will evaluate the quality and assess the risk of bias in all included studies.
Although a subgroup analysis is planned, the potential heterogeneity cannot be completely eliminated.
Introduction
A large proportion of patients require endotracheal intubation for general anaesthesia.1 During recovery from general anaesthesia, approximately 15–94% of patients experienced coughing during extubation.2 3 The observed wide variation in the incidence of coughing was associated with the different preventive interventions both pharmacological and non-pharmacological employed. Although it is a protective reflex, coughing can lead to adverse effects such as hypertension and tachycardia,4 5 which can cause haemodynamic changes. The changes can alter the intracranial or intraocular pressure, potentially resulting in adverse postoperative outcomes such as cerebral haemorrhage or herniation.6 7
Various techniques have been studied to manage this issue, including pharmacologic (eg, the use of topical or intravenous lidocaine, dexmedetomidine, remifentanil and fentanyl) and non-pharmacological (eg, extubation in the prone position) methods.8–12 These techniques work by reducing the local or systemic stress response, thereby minimising the occurrence of cough during extubation. However, they are also associated with certain side effects. For instance, intravenous injection of lidocaine, dexmedetomidine or remifentanil may prolong recovery time.13 14 Increasing doses of dexmedetomidine can also pose risks of hypotension and bradycardia.15 A meta-analysis comparing local endotracheal anaesthesia with controls (placebo or no medication) found that local endotracheal anaesthesia significantly reduced immediate cough during extubation compared with placebo.16 However, the comparison was limited to local anaesthetics for tracheal intubation, and the control group received either a placebo or no treatment at all. This study did not compare differences in the effects of local endotracheal anaesthetic drugs when compared with other pharmaceutical agents. Additionally, a network meta-analysis comparing various interventions (including lidocaine, dexmedetomidine, fentanyl and remifentanil) concluded that dexmedetomidine had the highest cumulative reduction in the incidence of severe cough at extubation.17 However, dexmedetomidine can cause side effects such as prolonged sedation or bradycardia.
Although these meta-analyses have compared several pharmacological interventions to reduce emergence cough after general anaesthesia, a considerable number of other clinical pharmacological interventions were excluded from the analysis. These exclusive interventions included such drugs (ie, alfentanil,18 tramadol,19 sulgamonol sodium,20 and oxycodone21 and non-pharmacological interventions (ie, body position adjustment during extubation11 and nerve block.12 We do not have sufficient evidence to show whether these measures have similar or better effects on the reduction of coughing during extubation.
To find an optimal method for reducing cough during extubation and determine the comparative efficacies of pharmacological and non-pharmacological interventions, we will conduct this systematic review and network meta-analysis to compare all interventions found by our analysis that may reduce the incidence or severity of cough during extubation under general anaesthesia.
Methods
The study protocol (registration number: CRD42023401609) was registered with the International Prospective Register of Systematic Reviews. The study protocol will be published in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.22
Patient and public involvement
The patients and the public had no role in the design, conduct, reporting or dissemination of the study.
Data sources and searches
We will search the following databases: MEDLINE, Embase, Web of Science, the Cochrane Central Register of Controlled Trials via OVID, the Chinese databases CNKI and Wanfang, as well as reference lists from previously published papers. The language of retrieval is not limited. The search period for all databases will be limited to the period from the date of database establishment to April 2024. The original keywords are ‘cough’ and ‘extubation’, and the details of the original search strategy are presented in online supplemental file 1. In addition, we will search for conference papers via SCOPUS by restricting the ‘source type’ to ‘conference proceedings’. At the same time, we will search ClinicalTrials.gov and the Chinese Clinical Trial Registry for ongoing studies. A reassessment of the subject headings and free-text terms related to coughing or extubation, which have not been used, will be conducted. Newly identified subject headings and free-text words will be added to the modified search strategy. The final version of the search strategy will be reported in our review.
Supplemental material
Eligibility criteria
Types of study
We will include only randomised controlled trials, regardless of language or publication status. Conference abstracts will also be included if they have sufficient data.
Types of participants
We will include all adult patients (≥18 years old) who received general anaesthesia with endotracheal intubation and were extubated in the operating room, regardless of the type of surgery performed.
Types of interventions
We will include all interventions to prevent postoperative cough including pharmacological treatments such as intravenous medications and local medications and non-pharmacological treatments such as adjustment of body position during extubation.
Types of comparisons
We will compare the different interventions or placebo.
Types of outcomes
The primary outcome is the incidence of coughing during tracheal extubation. We will define the incidence of cough using the modified Minogue scale (grade 1 (none cough) means no coughing or muscular stiffness; grade 2 (mild cough) means coughing once or twice; grade 3 (moderate cough) means ≤3 coughs lasting 1–2 s, or total duration of coughing last ≤5 s; grade 4 (severe cough) means ≥4 coughs with each lasting ≥2 s, total duration of coughing last >5 s).23 If no direct data related to the modified Minogue scale can be extracted from the study, we will attempt to interpret the data from the original source using the descriptions provided or other related measures of cough severity. The secondary outcomes are as follows: (1) the incidence of severe coughing (grade 4); (2) the incidence of other types of postoperative airway complications, such as laryngospasm, apnoea, hypoxaemia and sore throat, which will be evaluated within 24 hours after surgery; (3) the side effects related to the interventions, such as bradycardia (heart rate less than 60 beats per minute), hypotension or allergic reactions,24 which will be evaluated within 24 hours from the start of the drug to the postoperative period and (4) the time from the end of the surgery to the extubation of the endotracheal tube.
Study selection
All abstracts will be independently reviewed by two researchers (ZG and YW) to determine their eligibility. The full text will be reviewed if the abstract does not provide sufficient information to determine eligibility. In the event that two researchers diverge in their opinions regarding the suitability of including literature in the review, the full text will be re-reviewed by a third researcher, who will then make the decision on the inclusion of literature. Two researchers (ZG and YW) independently completed selection forms (online supplemental file 2). Disagreements after discussion will be decided by a third person (DY). Finally, we will show all eligible studies that were included in the review.
Supplemental material
Data extraction and quality assessment
We will obtain and extract data from the full texts of all eligible studies. Two researchers (ZG and YW) will independently extract the data from the studies and enter them into a data extraction form (online supplemental file 3). A third researcher (LoY) will verify the results.
Supplemental material
Two researchers (ZG and YW) will independently assess the quality of all included studies using the Cochrane Risk of Bias Risk Assessment Tool Version 2 from the Cochrane Handbook for Systematic Reviews of Interventions,25 which includes the following five domains: bias arising from the randomisation process, bias due to deviations from the intended interventions, bias due to missing outcome data, bias in the measurement of the outcome and bias in the selection of reported results. Each domain will be assigned a risk of bias level, which is one of the following: low risk of bias, some concerns or high risk of bias. Disagreements will be resolved through discussion. In this review, we will report the risk of bias table and the risk of bias summary figure.
Data synthesis
We plan to use the relative risk between the intervention and control groups to estimate the incidence of coughing or severe coughing and calculate the 95% CI. For continuous variables, such as the time from the end of surgery to extubation, we plan to use the mean difference and calculate the 95% CI.
We will use the Netmeta package of R software with a random-effects model to make direct and indirect comparisons through the frequency framework. A network diagram and rank probabilities will be generated and presented. We will use different imputation methods (low risk of bias and large sample size studies) and statistical methods (including fixed-effect models) for the sensitivity analyses. We will also generate a funnel plot to assess publication bias.26
We will use statistical methods (Q statistics and I2 statistics) to test the heterogeneity between studies. When the p value is <0.05, the variation between studies exceeds what can be explained by sampling error, and the existence of heterogeneity should be considered. We will quantify the heterogeneity by calculating I2 statistics. When I2>50%, it is considered that there is a high degree of heterogeneity between the studies. When significant statistical heterogeneity exists, we will investigate the clinical heterogeneity using a subgroup analysis, which will be performed based on the patient’s age, sex, surgical procedure and anaesthetics used during surgery. When patient characteristics, interventions and outcomes are similar, the transitivity between the study results will be considered. Based on previous studies and preliminary screenings, the number of studies is sufficient. We will draw a network diagram using nodes to represent different research interventions and edges to represent head-to-head comparisons between network nodes. If there is an inconsistency among three or more nodes in the loop, we will use the node-splitting method for evaluation. If the p value is >0.05, the difference between the direct and indirect comparisons will not be statistically significant. When the results are inconsistent, the results of direct comparison will be used as the estimated effect quantity.
Assessing the quality of evidence
We will grade the quality of evidence for network meta-analysis based on Confidence in Network Meta-Analysis, which includes six domains, namely (1) within-study bias, (2) between-study bias, (3) indirectness, (4) imprecision, (5) heterogeneity and (6) inconsistency.27
Ethics and dissemination
Ethical approval was not required for this study, as we only pooled published data. We plan to present our review at academic conferences and in peer-reviewed journals.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to thank Adham (www.editage.com) for English language editing.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
ZG and YW contributed equally.
Contributors DY and LoY conceived and designed the study. LeY developed the search strategy. ZG, YW, DY, QL and LeY drafted the manuscript. All the authors have agreed to submit this article for publication. LeY is the guarantor.
Funding This research was supported by the Key Research and Development Project of the Ministry of Science and Technology of Sichuan Province (No. 2023YFS0139) and Sichuan Science and Technology Program (No. 2023ZYD0168).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.