British Journal of Anaesthesia, xxx (xxx): xxx (xxxx)

doi: 10.1016/j.bja.2019.11.033
Advance Access Publication Date: xxx
Review Article

REVIEW ARTICLE

Intravenous lidocaine to prevent postoperative airway

complications in adults: a systematic review and meta-analysis
Stephen S. Yang1,*, Ning-Nan Wang1, Tatyana Postonogova1, Grace J. Yang2, Michael McGillion3,
Francois Beique1 and Thomas Schricker1
1
Department of Anesthesia, McGill University, Montreal, QC, Canada, 2University of Toronto, Toronto, ON, Canada and
3
Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada

*Corresponding author. E-mail: stephen.yang@mail.mcgill.ca

Abstract
Background: In surgical patients undergoing general anaesthesia, coughing at the time of extubation is common and can
result in potentially dangerous complications. We performed a systematic review and meta-analysis to assess the effi-
cacy and safety of i.v. lidocaine administration during the perioperative period to prevent cough and other airway
complications.
Methods: We searched Medical Literature Analysis and Retrieval System, Excerpta Medica database, and Cochrane
Central Register of Controlled Trials for RCTs comparing the perioperative use of i.v. lidocaine with a control group in
adult patients undergoing surgery under general anaesthesia. The RCTs were assessed using risk-of-bias assessment,
and the quality of evidence was assessed using Grading of Recommendations, Assessment, Development and Evalua-
tions (GRADE).
Results: In 16 trials (n¼1516), the administration of i.v. lidocaine compared with placebo or no treatment led to large
reductions in post-extubation cough (risk ratio [RR]: 0.64; 95% confidence interval [CI]: 0.48e0.86) and in postoperative
sore throat at 1 h (RR: 0.46; 95% CI: 0.32e0.67). There was no difference in incidence of laryngospasm (risk difference [RD]:
0.02; 95% CI: e0.07 to 0.03) or incidence of adverse events related to the use of lidocaine.
Conclusions: The use of i.v. lidocaine perioperatively decreased airway complications, including coughing and sore
throat. There was no associated increased risk of harm.

Keywords: anaesthesia; cough; lidocaine; pharyngitis; tracheal tube

patients will undergo general anaesthesia performed with a

Editor’s key points
 The authors performed a systematic review and meta-
analysis of 16 RCTs to examine the use of i.v. lidocaine
on postoperative airway outcomes.
 The pooled data show a decrease in post-extubation
cough and in postoperative sore throat with a moder-
ate level of evidence.
Globally, more than 230 million major surgical procedures are
performed annually, and a large proportion of surgical
tracheal tube (TT).1 Normally, coughing is a protective mech-
anism; it removes foreign material from the airway and pro-
tects against aspiration.2 However, in the surgical population,
coughing at the time of extubation often occurs, with an
incidence of 15e94%, and can trigger potentially dangerous
complications.3,4 During carotid endarterectomies, such
coughing may cause a neck haematomada catastrophic event
if complicated by airway obstruction.5 In craniotomies,
coughing augments intracranial pressure, increasing the risk
of intracranial haematoma formation or brain herniation.6
During ophthalmology procedures, coughing-induced

Accepted: 10 November 2019

© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

1
 2 - Yang et al.
intraocular hypertension can cause vitreous extrusion,
potentially leading to loss of vision.7 In rare cases, coughing
has been shown to be associated with arrhythmias, such as
ventricular tachycardia8 and atrioventricular block,9,10 and
cardiovascular collapse.11 In addition to coughing, post-
operative sore throat is another common adverse event after
general anaesthesia with an incidence ranging from 21% to
72%.3,4,12,13 The mechanism of postoperative sore throat is
likely mediated by mucosal trauma, erosion, and inflamma-
tion attributable to irritation by the TT.12,13 Postoperative sore
throat is an important factor for patient dissatisfaction and
delay in returning to normal activities.14
Many interventions have been proposed to decrease the
incidence of airway complications after surgery, such as
extubation under deep general anaesthesia,15 i.v. opioids,16,17
and topical18 or intra-cuff administration of lidocaine.19,20
The use of i.v. lidocaine is another prophylactic measure
that is commonly used by anaesthetists. The mechanism
underlying the inhibitory effect of lidocaine on coughing is
not completely understood. Many mechanisms have been
proposed, including the following: the suppression of airway
sensory C fibres,21 the reduction of neural discharge of pe-
ripheral nerve fibres,22 and the selective depression of pain
transmission in the spinal cord.23 Several small RCTs were
published on its use in patients undergoing specific surgical
procedures.14,24e26 However, it is unclear whether these re-
sults are applicable to all surgical patients undergoing gen-
eral anaesthesia with TT. Moreover, because of its known
side-effects, such as seizures or arrhythmia,27,28 lidocaine
also has a potential for harm. A systematic review and meta-
analysis on this topic is needed to summarise the available
evidence on the effect of i.v. lidocaine on the incidence of
coughing and related postoperative airway complications.
Methods
This review followed the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA) guidelines,29
and the protocol was registered in the International Prospec-
tive Register of Systematic Reviews (trial registration number:
CRD42018106682).
Eligibility criteria
Type of studies
RCTs that evaluated the use of i.v. lidocaine compared with
placebo or no treatment were included.
Type of participants
Trials that included patients 18 yr old who underwent gen-
eral anaesthesia with a TT were included.
Type of interventions
Trials that evaluated the use of i.v. lidocaine in surgical pa-
tients were included. There was no restriction on the timing or
the dosing of lidocaine.
Type of comparisons
We included trials that compared i.v. lidocaine with placebo or
no treatment. Trials that compared lidocaine with an active
control (i.e. another medication to suppress cough) were
excluded.
Primary outcome
The primary outcome was the incidence of post-extubation
cough. We defined the post-extubation period as the time of
extubation to 30 min after removal of the TT.
Secondary outcomes
Secondary outcomes included the following: number of
coughing episodes, incidence of laryngospasm, time to extu-
bation, incidence of postoperative sore throat, and adverse
events. These outcomes were assessed during the first 24 h
after operation.
Electronic search
We performed a comprehensive search to identify published,
in press, and unpublished studies. The search included the
following databases: Medical Literature Analysis and Retrieval
System (MEDLINE), Excerpta Medica database (EMBASE),
Cochrane Central Register of Controlled Trials (CENTRAL), and
Web of Science. The search was conducted from database
inception to February 20, 2018. We used a combination of
keywords and database-specific subjects (i.e. MESH or EMTREE
headings) to describe ‘lidocaine’ and ‘tracheal tube’. In MED-
LINE, we used a sensitivity-maximising version of Cochrane’s
highly sensitive search strategy to identify RCTs.30 A modified
version of this strategy was used in other databases. No re-
striction was applied to language or publication status
(Supplementary Appendix B).
Searching other resources
We reviewed previously published systematic reviews on this
topic to identify additional RCTs. The citations from the
included RCTs were also reviewed to look for additional
studies not found in the electronic search. Grey literature
(including reports, conferences, and workshop proceedings)
and ongoing trials were identified using Google Scholar and
https://clinicaltrials.gov/.
Identification and selection of studies
The results from the search strategy were uploaded to Dis-
tillerSR (Evidence Partners, Ottawa, ON, Canada).31 Screening
forms were developed with inclusion and exclusion criteria,
and a calibration exercise was performed before initial
screening. Titles and abstracts were screened by two inde-
pendent reviewers (TP and GJY), who determined whether the
citation would undergo review. If one or both reviewers
believed the citation has met the eligibility criteria, then it
underwent a full-text review. Full-text reviews were per-
formed by two independent reviewers (TP and GJY) based on
the eligibility criteria. A disagreement between the reviewers
was resolved through a consensus process. When the two
reviewers did not agree, the final decision went to the third
reviewer (SSY).
Data extraction and management
Two reviewers (SSY and N-NW) performed data extraction
independently using standardised forms in Microsoft Excel.

Any discrepancies were resolved through the consensus pro-
cess discussed previously.
Risk-of-bias assessment
Two reviewers (SSY and N-NW) independently performed
risk-of-bias assessment. We used the Cochrane Collaboration
risk-of-bias tool32 to assess the following aspects of a trial:
random sequence generation (selection bias), allocation
concealment (selection bias), blinding of participants and
personnel (performance bias), blinding of outcome assess-
ment (detection bias), incomplete outcome data (attrition
bias), selective reporting (reporting bias), and other potential
sources of bias. Risk of bias was categorised as high risk, low
risk, or unclear. Any discrepancies were resolved through the
consensus process discussed previously.
Measure of treatment effect
The effect size of primary and secondary outcomes was ana-
lysed with a random-effects model (DerSimonian and Laird
method) using Review Manager 5.3.33 Dichotomous outcomes
were reported using risk ratio (RR) or risk difference (RD).
Continuous outcomes were reported using mean difference
(MD). Point estimates and 95% confidence intervals (CIs) were
reported. If the data reported median and inter-quartile
ranges, the data were converted to estimate mean and stan-
dard deviation using the method described by Wan and col-
leagues.34 For any missing or unclear data, we contacted the
authors of those trials to obtain this information.
Assessment of heterogeneity
Trials were evaluated for statistical heterogeneity using I2
statistics. When substantial heterogeneity was identified,
defined as I2 50%,30 we explored potential subgroup analyses
to determine if the source of heterogeneity could be explained.
The following subgroups, defined a priori, were examined: low
vs high risk of bias, low dose (<1.5 mg kg1) vs high dose (1.5
mg kg1) of lidocaine, and intraoperative vs preoperative dose
of lidocaine.
Trial sequential analysis
To determine if the results of our meta-analysis were reliable
and conclusive, we performed a trial sequential analysis. This
analysis is a cumulative random-effects meta-analysis
method that estimates the ‘required information size’ needed
for a single, optimally powered RCT.35,36 This method also
accounts for study-level heterogeneity and multiple compar-
isons when new RCTs are added. We used the TSA software,
version 0.9 (Copenhagen Trial Unit, Copenhagen, Denmark) to
conduct a trial sequential analysis. For the primary outcome,
our calculation, defined a priori, was based on an anticipated
25% relative risk reduction in the intervention group, using a
two-sided a of 0.05 and a power of 80%. We assumed, a priori, a
heterogeneity level of 30% in the surgical population and used
the control-group event rate from the meta-analysis.
Quality of the evidence
We assessed the overall quality of the evidence for each
outcome using the Grading of Recommendations, Assess-
ment, Development and Evaluations (GRADE) system.37 Two
reviewers (SSY and N-NW) examined the following five
Lidocaine to prevent airway complications - 3
categories: risk of bias, consistency, directness, imprecision,
and reporting bias. RCTs began as high quality of evidence and
were rated down based on the described criteria. The quality of
evidence was categorised as high (we are very confident that
the true effect lies close to that of the estimated effect),
moderate (we are moderately confident in the effect estimates:
the true effect is likely to be close to the estimate of the effect),
low (our confidence in the effect estimate is limited: the true
effect may be substantially different from the estimate of the
effect), or very low (we have very little confidence in the effect
estimate: the true effect is likely to be substantially different
from the estimate of effect).37
Results
Description of studies
A total of 4293 articles were identified from the primary elec-
tronic databases (MEDLINE: 658, EMBASE: 1164, CENTRAL: 966,
and Web of Science: 1505). A search of grey literature,
including https://clinicaltrials.gov/, Google Scholar, and a
bibliographic review of relevant systematic reviews, identified
two additional articles. Forty-one articles were retrieved for
full-text review. After full-text screening, 16 articles were
identified for inclusion in the meta-analysis (15 English and
one Spanish). No ongoing trial was found. The agreement be-
tween two independent reviewers during the full-text review
was considered very good (k¼0.91; 95% CI: 0.78e1.00)
(Supplementary Appendix A).
Included trials
The 16 included studies involved a total of 1516 partic-
ipants.14,24e26,38e49 All studies were RCTs with placebo or no
treatment control arms. Three trials were conducted in
Japan,43,44,47 three in India,24,25,42 three in Iran,40,45,46 and one
in each of the following countries: Saudi Arabia,38 Denmark,26
USA,39 Korea,41 China,14 Turkey,48 and Spain.49 The mean age
of participants ranged from 22.5 to 63.0 yr, and the proportion
of males ranged from 24% to 68%. Two trials included patients
with an ASA physical status of 1 only.43,44 Nine trials included
patients with an ASA status of 1 and 2.14,24,25,38,40,45,47e49 Two
trials included patients with an ASA status of 1, 2, and 3.39,46
The median sample size was 78 (range: 19e240). The type of
surgeries included eight mixed elective surgeries,39e44,47,49 one
general surgery,38 one orthopaedic surgery,48 two ophthal-
mological surgeries,45,46 two otorhinolaryngological sur-
geries,14,26 and two neurosurgeries.24,25 In terms of
intraoperative opioids, 12 trials used
fentanyl,24,25,38e41,43e45,47e49 two trials used no opioid,26,41 one
trial used alfentanil,46 and one trial used sufentanil.14 None of
the trials used remifentanil. All trials received neuromuscular
blockers at the time of intubation.14,24e26,38e49 Seven trials
used a dose of i.v. lidocaine at 1 mg kg1,24,38,41e45 seven trials
used a dose of 1.5 mg kg1 or higher,14,25,26,39,46,48,49 and two
trials had two intervention arms with a dose of 1 and 1.5 mg
kg1 or higher40,47 (Table 1).
Risk-of-bias and GRADE assessment
Seven trials were judged to be low risk of bias in all
domains.14,24,25,38,40,43,45 Five trials had unclear risk of bias,
mostly related to random sequence generation and allocation
concealment.26,42,44,47,49 Four trials had high risk of
bias.39,41,46,48 The domain judged to have the highest risk of
Table 1 Characteristics of included trials. N2O, nitrous oxide; NR, not reported; PGE, prostaglandin E

4
-
Trial Country Age (yr) Male Sample ASA Surgery Anaesthesia Intervention/ Timing of lidocaine Outcomes

Yang et al.
(%) size physical comparator injection
status

Aljonaieh38 Saudi NR NR 72 1, 2 Laparoscopic Desflurane 1: Lidocaine 1 mg kg1 After discontinuation Laryngospasm

(2018) Arabia cholecystectomy 2: Placebo of desflurane
Gefke and Denmark 22.5 (15e37) NR 19 NR Tonsillectomy Halothane/N2O 1: Lidocaine 2 mg kg1 End of Incidence of cough,
colleagues26 2: Placebo anaesthesia, laryngospasm,
(1983) when swallow and time to
or cough extubation
reflexes are
seen
George and India 37.5 (18e65) 59 76 1, 2 Craniotomy Isoflurane/ 1: Lidocaine 1 mg kg1 Time of wound Incidence of cough,
colleagues24 sevoflurane 2: Placebo dressing number of cough,
(2013) and time to
extubation
Gonzalez and USA 57.3 (NR) NR 50 1, 2, 3 Orthopaedic, Fentanyl 1: Lidocaine 1.67 mg kg1 After discontinuation Incidence of cough
colleagues39 urological, plastic, infusion/ 2: No treatment of isoflurane and and time to
(1994) and vascular isoflurane/N2O after application of extubation
surgical cast
1
Honarmand and Iran 32.6 (16e85) 62 90 1, 2 Gynaecological, Isoflurane 1: Lidocaine 1 mg kg Before tracheal Incidence of cough,
Safavi40 (2008) orthopaedic, and 2: Lidocaine 1.5 mg kg1 intubation sore throat, and
abdominal 3- Placebo hoarseness
Jee and Park41 Korea 31.2 (18e50) 68 50 NR Orthopaedic, Enflurane/N2O 1: Lidocaine 1 mg kg1 3 min before Incidence of cough
(2003) plastic, and lower 2: No treatment extubation and number of
abdominal cough
Khan and India 52.0 (NR) NR 30 NR Gynaecological and Halothane/N2O 1: Lidocaine 1 mg kg1 After reversal was Incidence of cough
colleagues42 orthopaedic 2: Placebo given
(1990)
Mikawa and Japan 39.5 (NR) 34 100 1 Gynaecological and Sevoflurane/N2O 1: Lidocaine 1 mg kg1 2 min before Incidence of cough
coleagues43 urological 2: Placebo extubation and
(1997) 3: Lidocaine 1 mg laryngospasm
1
kg þverapamil 0.1 mg
kg1
4: Verapamil 0.1 mg kg1
Nishina and Japan 39.0 (NR) 24 100 1 Gynaecological and Sevoflurane/N2O 1: Lidocaine 1 mg kg1 2 min before Incidence of cough
colleagues44 urological 2: Placebo extubation
(1997) 3: Lidocaine 1 mg
kg1þPGE1 0.1 mg kg1
min1
4: PGE1 0.1 mg kg1 min1
Saghaei and Iran 61.1 (NR) 60 200 1, 2 Cataract Halothane/N2O 1: Lidocaine 1 mg kg1 Before extubation, Incidence of cough,
colleagues45 2: Placebo and after number of cough,
(2005) administration of and time to
atropine and extubation
prostigmine
Shabnum and India 41.4 (18e70) 60 60 1, 2 Craniotomy Sevoflurane/N2O 1: Lidocaine 1.5 mg kg1 Administered at time Incidence of cough
colleagues25 2: Placebo of wound dressing
(2017)
Soltani and Iran 63.0 (NR) 58 204 1, 2, 3 Cataract Halothane/N2O 1: Lidocaine 1.5 mg kg1 End of surgery Number of cough
Aghadavoudi46 2: Placebo and sore throat
(2002)

Continued
 Lidocaine to prevent airway complications - 5

bias was blinding of participants and personnel (performance

bias) (Supplementary Appendices C and D). The GRADE

Incidence of cough,

Incidence of cough

Incidence of cough
sore throat, and
assessment demonstrated an overall moderate level of evi-

and number of
Sore throat and
dence for each of the following outcomes: incidence of post-

hoarseness
extubation cough, incidence of laryngospasm, and post-
Outcomes

sputum operative sore throat at 1 and 24 h. The levels of evidence for

cough
the following outcomes were considered low: number of
coughing episodes and time to extubation (Supplementary
Appendix E).
Timing of lidocaine

Before intubation

Incidence of post-extubation cough

induction of
anaesthesia

10 min before
extubation
5 min before

Preoperative
Based on the pooling of data from 13 trials
(n¼931),24e26,39e45,47e49 the use of i.v. lidocaine demonstrated a
injection

large reduction in post-extubation cough (RR: 0.64; 95% CI:

0.48e0.86) (Fig. 1). There was no subgroup difference related to
the dose of lidocaine (P¼0.92) and the risk of bias (P¼0.50). As
1: Lidocaine 1.5 mg kg1

1: Lidocaine 1.5 mg kg1

1: Lidocaine 1.5 mg kg1

2: Lidocaine 1.5 mg kg1

2: Lidocaine 1.5 mg kg1

for the timing of lidocaine administration, there was a trend

1: Lidocaine 1 mg kg1

that was not statistically significant (P¼0.06) towards

decreased cough in the preoperative lidocaine administration
group (RR: 0.36; 95% CI: 0.19e0.70) compared with intra-
Intervention/

3: Saline (6.0)
4: Saline (7.0)

operative lidocaine administration group (RR: 0.73; 95% CI:

comparator

3: Placebo

2: Placebo

2: Placebo

0.55e0.96). There was no subgroup difference related to the

(6.0)

(7.0)

type of volatile anaesthetic agent (Supplementary Appendix

L). Almost all trials included in this review performed an
‘awake’ extubation, in which the patients met one of the
following criteria: eye openings to command, purposeful
Inhalational or

Isoflurane/N2O
Anaesthesia

movements, and end-tidal volatile agent

Sevoflurane

Sevoflurane

<0.1%.14,24e26,38,39,41,43,44,46,48,49 However, there were four trials

i.v./N2O

that either did not specify the extubation criteria or was un-
clear whether a deep extubation was performed.40,42,45,47 A
post hoc sensitivity analysis demonstrated a consistent
decrease in incidence of post-extubation cough (RR: 0.69; 95%
gynaecological,
urological, and

CI: 0.50e0.97) (Supplementary Appendix J). Another post hoc

Elective surgery
orthopaedic

sensitivity analysis was performed to examine the effect of

Abdominal,

opioid infusion. One trial used fentanyl infusion during the

Thyroid
Surgery

case, whilst all other trials administered boluses of opioids.39

Lumbar

After excluding the opioid infusion trial, the sensitivity anal-

ysis demonstrated a consistent reduction in post-extubation
physical

cough (RR: 0.62; 95% CI: 0.53e0.74). In this analysis, the het-
status

erogeneity decreased significantly with an I2¼22%

Male Sample ASA

1, 2

1, 2

1, 2

1, 2

(Supplementary Appendix K).

Number of coughing episodes

size

240

105
80

40

Five trials with 450 participants24,41,45,46,48 demonstrated that

NR
(%)

i.v. lidocaine led to an overall trend towards decreased post-

37

59

48

extubation coughing episodes, however, not statistically sig-

nificant (MD: e0.77 coughs; 95% CI: e2.18 to 0.64 coughs)
46 (20e70)
53.3 (NR)
Age (yr)

(Fig. 2). With regard to subgroup analysis, high-dose lidocaine

43 (NR)

40 (NR)

seemed to have a significant effect to reduce the number of

coughs (MD: e2.32 coughs; 95% CI: e3.75 to e0.89 coughs)
compared with the low-dose lidocaine (MD: 0.15 coughs; 95%
Country

Turkey

CI: e0.56 to 0.85 coughs). There was no subgroup effect in

China

Spain
Japan

terms of risk of bias (P¼0.31).

and colleagues49
Table 1 Continued

Incidence of laryngospasm
Zamora Lozano
 lu and
Takekawa and
colleagues47

colleagues14

colleagues48

Six trials that included 349 participants25,26,38,41,43,46 demon-

strated that the incidence of postoperative laryngospasm was
€ rükog
(2006)

(2012)

(2006)

(2007)
Xu and

no different in the i.v. lidocaine group compared with placebo

Trial

(RD: 0.02; 95% CI: e0.07 to 0.03) (Fig. 3). There was no subgroup
Yo

effect in terms of the dosing of lidocaine (P¼0.49) or the risk of

bias (P¼0.46).
 6 - Yang et al.

Fig 1. Incidence of post-extubation cough. CI, confidence interval; M-H, ManteleHaenszel.

Fig 2. Number of coughs. CI, confidence interval; M-H, ManteleHaenszel; SD, standard deviation.

Fig 3. Incidence of laryngospasm. CI, confidence interval; M-H, ManteleHaenszel.

Time to extubation bias (P¼0.43). There was a significant subgroup effect related to
the type of volatile anaesthetic agent. Halothane led an in-
Based on a pooling of data from seven trials
crease in time to extubation (MD: 2.70 min; 95% CI: 2.60e2.79),
(n¼509),24e26,39,45,46,48 the time to extubation was significantly
whilst sevoflurane (MD: e1.34 min; 95% CI: e3.91 to 1.23 min)
longer in the lidocaine group compared with placebo (MD: 1.94
and isoflurane (MD: 1.99 min; 95% CI: e1.37 to 5.35 min) did not
min; 95% CI: 0.84e3.04 min) (Fig. 4). There was no subgroup
result in a statistically significant difference.
effect related to the dosing of lidocaine (P¼0.40) or the risk of

Fig 4. Time to extubation. CI, confidence interval; M-H, ManteleHaenszel;
Incidence of sore throat at 1 h
Three trials that included 398 participants14,40,46 demonstrated
a large reduction in postoperative sore throat at 1 h with the
use of i.v. lidocaine (RR: 0.46; 95% CI: 0.32e0.67) (Fig. 5). There
was no subgroup effect seen with different dosing (P¼0.43),
timing of lidocaine (P¼0.91), or risk-of-bias assessment
(P¼0.13).
Incidence of sore throat at 24 h
The data from four trials (n¼478)14,40,46,47 indicate that i.v.
lidocaine reduced the incidence of postoperative sore throat at
24 h (RR: 0.40; 95% CI: 0.24e0.68) (Supplementary Appendix G).
In the subgroup analysis, there was a greater reduction with
the use of preoperative i.v. lidocaine (RR: 0.27; 95% CI:
0.15e0.50) compared with intraoperative use (RR: 0.59; 95% CI:
0.43e0.82). There was no subgroup effect related to the dosing
of lidocaine (P¼0.46) or risk of bias (P¼0.43).
Adverse events
One study reported the occurrence of phlebitis in one patient
in the lidocaine group and one patient in the placebo group.44
Another study reported transient bigeminy that lasted for
approximately 10 s in the placebo group.43 A third study was
terminated early because of safety concerns related to lar-
yngospasm. The authors stated that this was likely attribut-
able to a rapid increase in the concentration of inspired
desflurane, resulting in airway irritation.38 None of the trials
reported any adverse events directly related to the use of i.v.
lidocaine.
Fig 5. Incidence of sore throat at 1 h. CI, confidence interval; M-H, ManteleHaenszel.
Lidocaine to prevent airway complications - 7
SD, standard deviation.
Discussion
Our systematic review and meta-analysis demonstrated that
the use of i.v. lidocaine, compared with placebo, led to a large
reduction in the incidence of post-extubation cough with
moderate quality of evidence. This large effect had a number
needed to treat (NNT) of five, suggesting that its use can
potentially benefit numerous surgical patients if it were to be
implemented in our clinical practice. The trial sequential
analysis suggested that the accrued information size exceeded
the optimal information size (Supplementary Appendix H).
Therefore, the evidence from this meta-analysis was sufficient
to conclude the effectiveness of i.v. lidocaine to prevent
coughing at the time of extubation, and further trials are un-
likely to alter this conclusion.
The use of i.v. lidocaine also showed a large reduction in
the incidence of sore throat at 1 and 24 h after operation with
moderate quality of evidence and an NNT of four. The exact
mechanism of reduction in sore throat appears to be un-
known. One postulated mechanism could be because of the
fact that i.v. lidocaine suppresses the airway’s excitatory
sensory C fibres and the release of sensory neuropeptides.50
This, in turn, may decrease throat irritation and inflamma-
tion, which would lead to better patient satisfaction and
quicker return to normal function in the post-anaesthetic re-
covery room.
It is also important to examine the toxicity of i.v. lidocaine.
A possible downside of administering lidocaine is that it may
prolong the time to extubation. Based on low quality evidence,
surgical patients who received lidocaine took approximately 2
min longer to be extubated compared with the control group.
However, when we performed a subgroup analysis based on
 8 - Yang et al.
the type of volatile agents, halothane was the main volatile
agent that caused an increase in time to extubation. Other
volatiles agents, such as isoflurane and sevoflurane, did not
appear to be affected by the use of i.v. lidocaine. Based on our
systematic review and meta-analysis, i.v. lidocaine appeared
to be safe and did not result in any difference in adverse
events. With regard to lidocaine’s toxicity, an important
consideration is the fact that all the surgical procedures were
done under general anaesthesia without the use of any addi-
tional local anaesthetic (e.g. regional anaesthesia). Two trials
inserted an epidural catheter before operation without injec-
tion of a local anaesthetic intraoperatively.43,44 In one trial, the
surgeon injected subcutaneous bupivacaine, but the dose was
not specified.38 None of the other trials used any additional
local or regional anaesthesia techniques.14,24e26,39e42,45e49 In
patients who require regional anaesthesia, the additional use
of i.v. lidocaine may place the patients at risk of local anaes-
thetic toxicity. We would like to emphasise the importance of
ensuring that the total local anaesthetic dose is below the toxic
dose, as recommended by clinical practice.
It is difficult to determine the best timing of i.v. lidocaine
administration. Our subgroup analysis suggested that lido-
caine given before operation may be more beneficial with
respect to post-extubation cough. This seems feasible for
short surgeries, given that the half-life of i.v. lidocaine is
approximately 1.5 h.51 In this systematic review, most sur-
geries were short in duration, suggesting that early lidocaine
administration may indeed have been advantageous by vir-
tue of lidocaine reaching clinically significant plasma con-
centrations at the time of extubation. This supposition could
not be extrapolated to surgeries of longer duration. As a part
of an Enhanced Recovery After major Surgery protocol, lido-
caine infusion is used for many laparoscopic abdominal
surgeries.52 Although it is biologically plausible that lidocaine
infusion may decrease the incidence of coughing at the time
of extubation, none of the trials included in this review used
an infusion as part of their protocol. Therefore, at this time, it
is unclear whether the use of a lidocaine infusion would be
beneficial in suppressing cough or decreasing sore throat.
There are insufficient data to determine a conclusion on
the ideal dose of i.v. lidocaine for the prevention of post-
extubation cough. Both low dose (<1.5 mg kg1) and high
dose (1.5 mg kg1) represent effective measures for cough
prevention with a non-significant statistical difference.
The results of our systematic review appear similar to a
previous review by Clivio and colleagues,53 who examined the
use of i.v. lidocaine to prevent intubation, extubation, and
opioid-induced cough. They reported a large reduction in
cough with the use of i.v. lidocaine at 1.5 mg kg1 (RR: 0.44; 95%
CI: 0.33e0.58).53 Some dissimilarities were also noted. First,
unlike our systematic review, the previous review combined
both paediatric and adult patients. Second, the incidence of
cough at the time of intubation, extubation, and opioid-
induced cough was examined. There are some key differ-
ences in the mechanism of cough at the time of intubation
compared with cough at the time of extubation. During intu-
bation, it is the introduction of the instrumentation of the
airway (laryngoscopy and TT) in an incompletely paralysed
patient and the too rapid administration of opioids that act as
a cough stimulus,54 whereas at the time of extubation, the
presence of a TT activated the coughing reflex.55 A meta-
analysis combining all three time points, seen in the previ-
ous review, would fail to examine the true effect of i.v. lido-
caine during the extubation period, which is the critical period
when a patient is at risk for surgical complications attributable
to coughing.5 Third, our systematic review included 16 arti-
cles, whereas the previous review only incorporated nine RCTs
with adult surgical patients at the time of extubation. The
additional trials allowed the primary outcome to meet the
optimal information size and allowed us to make conclusive
inferences on the effect of i.v. lidocaine. Finally, our system-
atic review is comprehensive and examined many important
outcomes related to airway complications.
The strengths of this review include an exhaustive literature
search, which included an examination of major databases and
grey literature. This review contained the largest number of
RCTs published on this topic. The methodology of this review
followed rigorous guidelines set forth by the Cochrane Collab-
oration.30 Our protocol also featured pre-specified subgroup
analyses, thereby mitigating the risk of creating a spurious
finding.56 The review of eligibility criteria, data extraction, and
outcome assessment were all performed in duplicate with a
high degree of inter-rater agreement. A risk-of-bias assessment
was performed for each trial. Moreover, the quality of the
available evidence was evaluated using the GRADE criteria. The
robustness of our results was also examined using a trial
sequential analysis, supporting definitive conclusions about
the effectiveness of i.v. lidocaine on the incidence of cough.
The main limitation of this systematic review is the pres-
ence of significant heterogeneity, despite our predefined sub-
group analyses. Clinically, some of the important variables
that may alter post-extubation cough and postoperative sore
throat include the following: deep vs ‘awake’ extubation, use
of intraoperative opioid infusion, and type of volatile anaes-
thetic agent used. To address these possible confounders, we
performed post hoc sensitivity and subgroup analyses. These
analyses demonstrated that i.v. lidocaine consistently
decreased post-extubation cough despite the important ef-
fects of these confounders. Of note, when we performed a post
hoc sensitivity analysis of trials without the use of intra-
operative opioid infusion, the degree of heterogeneity
observed was virtually eliminated. Nonetheless, there are
other variables that we could not analyse that may contribute
to heterogeneity in our results, for instance, smoking history,
duration of the surgery, amount of air inflated in the TT cuff,
size of TT, expertise of the anaesthetist, and laryngeal view.
Many of these variables were not reported systematically
across trials, and therefore, could not be analysed. Post-
extubation cough and postoperative sore throat are complex
issues, in which many factors are involved. In addition to i.v.
lidocaine, it is important for an anaesthetist to address all
variables listed previously to minimise these complications.
In conclusion, the preoperative and intraoperative admin-
istration of i.v. lidocaine decreases the incidence of cough at the
time of extubation and postoperative sore throat in adult sur-
gical patients. It is an easy, affordable, and relatively safe option
that anaesthetists can use in high-risk surgical patients.
Authors’ contributions
Conception/design: SSY, N-NW, MM, FB, TS.
Data acquisition/analysis: SSY, N-NW, TP, GJY.
Data interpretation: SSY, N-NW
Article drafting: all authors.
Revising the draft critically for important intellectual content:
SSY, N-NW, TP, GJY.
Final approval of the version to be published: all authors.

Agreement to be accountable for all aspects of the work,
thereby ensuring that questions related to the accuracy or
integrity of any part of the work are appropriately investigated
and resolved: all authors.
Declaration of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
The authors would like to thank Tara Landry for helping them
develop the search strategy. The authors would also like to
thank Ann Wright, Ken Kardash, and Matt Cameron for
proofreading the manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bja.2019.11.033.
References
1. Weiser TG, Regenbogen SE, Thompson KD, et al. An esti-
mation of the global volume of surgery: a modelling
strategy based on available data. Lancet 2008; 372: 139e44
2. Pitts T. Airway protective mechanisms. Lung 2014; 192:
27e31
3. Park SY, Kim SH, Lee SJ, et al. Application of triamcinolone
acetonide paste to the endotracheal tube reduces post-
operative sore throat: a randomized controlled trial. Can J
Anaesth 2011; 58: 436e42
4. Thomas S, Beevi S. Dexamethasone reduces the severity
of postoperative sore throat. Can J Anaesth 2007; 54:
897e901
5. Saghir R, Humm G, Rix T. Haematomas after carotid
endarterectomy can be reduced by direct pressure to the
neck postoperatively. Ann R Coll Surg Engl 2018; 100: 580e3
6. Carney N, Totten AM, O’Reilly C, et al. Guidelines for the
management of severe traumatic brain injury. Neurosur-
gery 2017; 80: 6e15. fourth edition
7. Miller R, Cohen N, Erikksson L, Fleisher L, Wiener-
Kronish J, Young W. In: Miller’s Anesthesia. 8th Edn. Phil-
adelphia, PA: Elsevier; 2015
8. Reisin L, Blaer Y, Jafari J, Manoach M. Cough-induced
nonsustained ventricular tachycardia. Chest 1994; 105:
1583e4
9. Irani F, Sanchis J. Inspiration- and cough-induced atrio-
ventricular block. Can Med Assoc J 1971; 105: 735e6
10. Francis CK, Singh JB, Polansky BJ. Interruption of aberrant
conduction of atrioventricular junctional tachycardia by
cough. N Engl J Med 1972; 286: 357e8
11. Kim HJ, Kim JS. A cardiovascular collapse following
vigorous cough during spinal anesthesia. Korean J Anes-
thesiol 2013; 65: S49e50
12. Scuderi PE. Postoperative sore throat: more answers than
questions. Anesth Analg 2010; 111: 831e2
13. McHardy FE, Chung F. Postoperative sore throat: cause,
prevention and treatment. Anaesthesia 1999; 54: 444e53
14. Xu YJ, Wang SL, Ren Y, Zhu Y, Tan ZM. A smaller
endotracheal tube combined with intravenous lido-
caine decreases post-operative sore throatda ran-
domized controlled trial. Acta Anaesthesiol Scand 2012;
56: 1314e20
Lidocaine to prevent airway complications - 9
15. Neelakanta G, Miller J. Minimum alveolar concentration of
isoflurane for tracheal extubation in deeply anesthetized
children. Anesthesiology 1994; 80: 811e3
16. Lee B, Lee JR, Na S. Targeting smooth emergence: the effect
site concentration of remifentanil for preventing cough
during emergence during propofoleremifentanil anaes-
thesia for thyroid surgery. Br J Anaesth 2009; 102: 775e8
17. Kim HY, Kim JY, Ahn SH, Lee SY, Park HY, Kwak HJ. Pre-
dicting effective remifentanil concentration in 95% of
patients to prevent emergence cough after lar-
yngomicroscopic surgery. Medicine 2018; 97, e11258
18. Crerar C, Weldon E, Salazar J, Gann K, Kelly JA,
Pellegrini JE. Comparison of 2 laryngeal tracheal anes-
thesia techniques in reducing emergence phenomena.
AANA J 2008; 76: 425e31
19. Lam F, Lin YC, Tsai HC, Chen TL, Tam KW, Chen CY. Effect
of intracuff lidocaine on postoperative sore throat and the
emergence phenomenon: a systematic review and meta-
analysis of randomized controlled trials. PLoS One 2015;
10, e0136184
20. Soares SM, Arantes VM, Modolo MP, et al. The effects of
tracheal tube cuffs filled with air, saline or alkalinised
lidocaine on haemodynamic changes and laryngotracheal
morbidity in children: a randomised, controlled trial.
Anaesthesia 2017; 72: 496e503
21. Burki NK, Lee LY. Blockade of airway sensory nerves and
dyspnea in humans. Pulm Pharmacol Ther 2010; 23: 279e82
22. Tanelian DL, MacIver MB. Analgesic concentrations of
lidocaine suppress tonic A-delta and C fiber discharges
produced by acute injury. Anesthesiology 1991; 74: 934e6
23. Woolf CJ, Wiesenfeld-Hallin Z. The systemic administra-
tion of local anaesthetics produces a selective depression
of C-afferent fibre evoked activity in the spinal cord. Pain
1985; 23: 361e74
24. George SE, Singh G, Mathew BS, Fleming D, Korula G.
Comparison of the effect of lignocaine instilled through
the endotracheal tube and intravenous lignocaine on the
extubation response in patients undergoing craniotomy
with skull pins: a randomized double blind clinical trial.
J Anaesthesiol Clin Pharmacol 2013; 29: 168e72
25. Shabnum T, Ali Z, Naqash IA, et al. Effects of lignocaine
administered intravenously or intratracheally on airway
and hemodynamic responses during emergence and
extubation in patients undergoing elective craniotomies
in supine position. Anesth Essays Res 2017; 11: 216e22
26. Gefke K, Andersen LW, Friesel E. Lidocaine given intra-
venously as a suppressant of cough and laryngospasm in
connection with extubation after tonsillectomy. Acta
Anaesthesiol Scand 1983; 27: 111e2
27. Jayanthi R, Nasser K, Monica K. Local anesthetics systemic
toxicity. J Assoc Physicians India 2016; 64: 92e3
28. El-Boghdadly K, Chin KJ. Local anesthetic systemic
toxicity: continuing professional development. Can J
Anaesth 2016; 63: 330e49
29. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred
reporting items for systematic reviews and meta-
analyses: the PRISMA statement. PLoS Med 2009; 6,
e1000097
30. version 6.0 (updated July 2019). Cochrane. In: Higgins JPT,
Thomas J, Chandler J, et al., editors. Cochrane Handbook for
Systematic Reviews of Interventions; 2019. Available from:
www.training.cochrane.org/handbook
31. Partners Evidence. DistillerSR systematic review 2018.
https://www.evidencepartners.com
 10 - Yang et al.
32. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane
Collaboration’s tool for assessing risk of bias in rando-
mised trials. BMJ 2011; 343: d5928
33. Review Manager (RevMan). Copenhagen: the Nordic Cochrane
centre. The Cochrane Collaboration, https://handbook-5-
1.cochrane.org/chapter_8/table_8_5_a_the_cochrane_col-
laborations_tool_for_assessing.htm; 2014. https://
handbook-5-1.cochrane.org/chapter_8/table_8_5_a_the_
cochrane_collaborations_tool_for_assessing.htm
34. Wan X, Wang W, Liu J, Tong T. Estimating the sample
mean and standard deviation from the sample size, me-
dian, range and/or interquartile range. BMC Med Res
Methodol 2014; 14: 135
35. Wetterslev J, Jakobsen JC, Gluud C. Trial sequential anal-
ysis in systematic reviews with meta-analysis. BMC Med
Res Methodol 2017; 17: 39
36. Pogue JM, Yusuf S. Cumulating evidence from randomized
trials: utilizing sequential monitoring boundaries for cu-
mulative meta-analysis. Control Clin Trial. 1997; 18:
580e93. discussion 661e6
37. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y,
Schunemann HJ. What is “quality of evidence” and why is
it important to clinicians? BMJ 2008; 336: 995e8
38. Aljonaieh KI. Effect of intravenous lidocaine on the inci-
dence of postextubation laryngospasm: a double-blind,
placebo-controlled randomized trial. Saudi J Anaesth
2018; 12: 3e9
39. Gonzalez RM, Bjerke RJ, Drobycki T, et al. Prevention of
endotracheal tube-induced coughing during emergence
from general anesthesia. Anesth Analg 1994; 79: 792e5
40. Honarmand A, Safavi M. Beclomethasone inhaler versus
intravenous lidocaine in the prevention of postoperative
airway and throat complaints: a randomized, controlled
trial. Ann Saudi Med 2008; 28: 11e6
41. Jee D, Park SY. Lidocaine sprayed down the endotracheal
tube attenuates the airway-circulatory reflexes by local
anesthesia during emergence and extubation. Anesth
Analg 2003; 96: 293e7
42. Khan RM, Khan TZ, Haq G, Zafruddin M. Tracheal extu-
bation under intravenous xylocaine. Indian J Med Res 1990;
92: 189e91
43. Mikawa K, Nishina K, Takao Y, Shiga M, Maekawa N,
Obara H. Attenuation of cardiovascular responses to
tracheal extubation: comparison of verapamil, lidocaine,
and verapamil-lidocaine combination. Anesth Analg 1997;
85: 1005e10
44. Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N,
Obara H. Prostaglandin E1, lidocaine, and prostaglandin
E1-lidocaine combination for attenuating
cardiovascular responses to extubation. Can J Anaesth
1997; 44: 1211e4
45. Saghaei M, Reisinejad A, Soltani H. Prophylactic versus
therapeutic administration of intravenous lidocaine for
suppression of post-extubation cough following cataract
surgery: a randomized double blind placebo controlled
clinical trial. Acta Anaesthesiol Taiwan 2005; 43: 205e9
46. Soltani HA, Aghadavoudi O. The effect of different lido-
caine application methods on postoperative cough and
sore throat. J Clin Anesth 2002; 14: 15e8
47. Takekawa K, Yoshimi S, Kinoshita Y. Effects of intrave-
nous lidocaine prior to intubation on postoperative airway
symptoms. J Anesth 2006; 20: 44e7
48. Yo€ rükog
 lu D, Alanog lu Z, Dilek UB, Can OS, Keçik Y.
Comparison of different extubation techniques in lumbar
surgery: prone extubation versus supine extubation with
or without prior injection of intravenous lidocaine.
J Neurosurg Anesthesiol 2006; 18: 165e9
49. Zamora Lozano J, Cruz Villasenor JA, Rodriguez Reyes J,
Sanchez Rodriguez JP, Briones Corona G, Gallardo
Alonso LA. [Comparison of topical, intravenous, and
intracuff lidocaine for reducing coughing after extubation
during emergence from general anesthesia]. Rev Esp
Anestesiol Reanim 2007; 54: 596e601
50. Solway J, Leff AR. Sensory neuropeptides and airway
function. J Appl Physiol 1991; 71: 2077e87. 1985
51. Nation RL, Triggs EJ, Selig M. Lignocaine kinetics in cardiac
patients and aged subjects. Br J Clin Pharmacol 1977; 4:
439e48
52. Weibel S, Jokinen J, Pace NL, et al. Efficacy and safety of
intravenous lidocaine for postoperative analgesia and re-
covery after surgery: a systematic review with trial
sequential analysis. Br J Anaesth 2016; 116: 770e83
53. Clivio S, Putzu A, Tramer MR. Intravenous lidocaine for
the prevention of cough: systematic review and meta-
analysis of randomized controlled trials. Anesth Analg
2019; 129: 1249e55
54. Artru AA, Strumwasser TA. Intratracheal aerosolized eti-
docaine to attenuate cardiovascular and cough responses
to laryngoscopy and intubation. Ann Emerg Med 1985; 14:
1069e73
55. Gaur P, Ubale P, Khadanga P. Efficacy and safety of using
air versus alkalinized 2% lignocaine for inflating endo-
tracheal tube cuff and its pressure effects on incidence of
postoperative coughing and sore throat. Anesth Essays Res
2017; 11: 1057e63
56. Sun X, Ioannidis JP, Agoritsas T, Alba AC, Guyatt G. How to
use a subgroup analysis: users’ guide to the medical
literature. JAMA 2014; 311: 405e11
Handling editor: Jonathan Hardman