Alkalinization of Intracuff Lidocaine: Efficacy and Safety

Jean-Pierre Estebe, MD, PhD*, Marc Gentili, MD, PhD*, Pascal Le Corre, PharmD, PhD,
Gilles Dollo, PharmD, PhD, Francois Chevanne, BSc, and Claude Ecoffey, MD*
*Service dAnesthesie Reanimation Chirurgicale 2; Laboratoire de Biopharmacie, UPRES EA 3892, Universite Rennes 1,
Polyclinique Saint Vincent, Rennes, France

When alkalinized lidocaine instead of air is used to fill

the endotracheal tube (ETT) cuff, coughing, and bucking are decreased during extubation when ventilation is
controlled with N2O. However, sodium bicarbonate
(NaHCO3) used to transform lidocaine hydrochloride
(L-HCl) to lidocaine base induces a pH increase that
could be irritating for mucosa in the case of cuff rupture.
Therefore, we determined, in a randomized controlled
study with controlled patient ventilation without N2O,
whether the smallest concentrations of NaHCO3 (1.4%
versus 8.4%) reduced diffusion (in vitro evaluation) and
other secondary clinical benefits. After pH determination of different solutions (2 mL of 2% L-HCl and 2 to
6 mL of 8.4%, or 1.4% NaHCO3), an in vitro lidocaine
diffusion through the ETT cuffs was evaluated (2 mL of
2% L-HCl and 3 mL of 8.4% or 1.4% NaHCO3). Then,
adult patients scheduled for total thyroidectomy surgery were consecutively enrolled (n 20 for each
group). The ETT cuff was filled with air (group air) or
with alkalinized lidocaine (2 mL of 2% L-HCl) using
8.4% (group large dose) or 1.4% (group small dose) of

n endotracheal tube (ETT) induces emergence

phenomena. Controlling the pressure of the cuff
and inflation of the cuff by filling it with nitrous
oxide (N2O) (1) with close monitoring of N2O concentration (2) were proposed to improve ETT cuff tolerance. Deflation of the cuff (3) and filling the cuff with
saline (4) or with lidocaine (L-HCl) have been also
recommended (59). However, a very small amount
(1%) of L-HCl diffuses through the ETT cuff (10).
Hence, large L-HCl doses (200 to 500 mg) have been
used (7), which may be dangerous if the cuff ruptures
as a result of L-HCl vascular absorption. The addition
of 8.4% of sodium bicarbonate (NaHCO3) (i.e., alkalinization) to small doses of L-HCl (40 mg) increased

Accepted for publication May 12, 2005.

Address correspondence and reprint requests to Jean-Pierre Estebe, MD, PhD, Service dAnesthesie Reanimation Chirurgicale 2,
Hopital Hotel Dieu: 2 rue de lHotel Dieu, 35000, Rennes, France.
Address e-mail to jean-pierre.estebe@chu-rennes.fr.
DOI: 10.1213/01.ANE.0000180995.24211.89

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Anesth Analg 2005;101:153641

NaHCO3. After tracheal extubation, sore throat was

evaluated by visual analog scale as the main end-point
of the study. Hoarseness, bucking, dysphonia, dysphagia, cough, restlessness, and postoperative nausea and
vomiting were also evaluated. There was a slight tendency toward a slower release when a small concentration of NaHCO3 was used (i.e., 1.4%). Compared with
group air, the alkalinized-lidocaine groups had a significant reduction in sore throat during the 24-h postoperative period (P 0.0001). The difference was not significant between the two alkalinized lidocaine groups.
This increase in ETT tolerance was confirmed by the
analysis of secondary end-points. No laryngospasm,
rupture of ETT cuff, or depression of the swallowing
reflex were recorded. A decrease in sore throat during
the postoperative period was recorded when the cuff
was inflated with a small dose of alkalinized lidocaine
(i.e., 40 mg of L-HCl and 1.4% of NaHCO3) rather than
with air when ventilation was controlled without N2O.
(Anesth Analg 2005;101:1536 41)

diffusion of L-HCl through the ETT cuff (11,12). However, the clinical relevance of alkalinized L-HCl was
never evaluated during anesthesia without N2O.
Although L-HCl is used clinically as spray or jelly, its
pH, reported around 5, could be irritating for tracheal
mucosa during clinical use or in case of rupture of a cuff
filled with L-HCl (13). NaHCO3 is necessary to transform L-HCl in lidocaine-base to increase diffusion
through the ETT cuff (i.e., 65% of diffusion for 6 h for
hydrophobic neutral form versus 1% of diffusion for
charged L-HCl) (10). On the other hand, the pH of some
NaHCO3 and L-HCl mixtures, in the high range of human physiology, could be irritative if a cuff ruptures
(14). The aim of this study was to determine a mixture
with the most efficient diffusion of L-HCl together with
the most physiological pH in case of cuff rupture.
To evaluate the consequences of using different concentrations and volumes of NaHCO3, we first performed an in vitro evaluation. To evaluate the local
anesthetic effect in vivo of using alkalinized L-HCl, we
conducted a double-blind randomized on three parallel trial groups (i.e., control group with air and two
2005 by the International Anesthesia Research Society
0003-2999/05

ANESTH ANALG
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groups with two concentrations of NaHCO3 added to

the same dose of lidocaine) in patients scheduled for
thyroidectomy, ventilated without N2O, to evaluate
ETT-induced emergence phenomena.

Methods
A 2% L-HCl solution was used (Xylocaine 2%, AstraZeneca, Rueil Malmaison, France). After injection of
2 mL of 2% L-HCl (40 mg) into the ETT cuff (Sheridan,
Hudson Respiratory Care, Temecula, CA; polyvinyl
chloride (PVC) cuff), a supplementary volume of 3 mL
was added at 2 concentrations: 8.4%, or 1.4% of
NaHCO3 (B. Braun Medical S.A., Boulogne, France).
Release of lidocaine from ETT cuffs was performed
using a Distek dissolution test system model 5100A
(Distek INC, North Brunswick, NJ). It consisted of 4
independent cylindrical flasks with spherical bottoms
each containing 900-mL release medium (i.e., simulated intestinal fluid: monobasic potassium phosphate
6.8 g/L) consisting of pH 7.4 phosphate buffer thermostated at 37C and a rotating paddle apparatus
operating at 100 rpm. To check if variable concentrations of NaHCO3 in the cuff could modify L-HCl
release, 4 sets of ETT were immersed in cylindrical
flasks, and one of the following 2 solutions was placed
inside the cuff (2 cuffs for each concentration). The
L-HCl concentration was measured continuously at
205 nm every 15 min during a 24-h period using an
Uvikon spectrophotometer model 922 (Kontron Instruments, St. Quentin en Yvelines, France). Each ETT
was tested only once. Intracuff pressure before or after
immersion was not recorded. pH determination of
different solutions was performed with the same dose
of L-HCl (2 mL of 2%) and various volumes of
NaHCO3 (2 to 6 mL of 8.4%, or 1.4% of NaHCO3).
Institutional Ethics Committee approval and written informed patient consent were obtained. Adult
patients scheduled for total thyroidectomy surgery
(ASA physical status III) were consecutively enrolled. Patients were excluded from the study if they
had an anticipated difficult tracheal intubation, had
risk factors for postoperative aspiration of gastric contents, or had respiratory disease or recent respiratory
tract infection. Patients were randomized into one of
three groups: ETT cuff was filled with air (group air)
or with alkalinized L-HCl using 8.4% (group large
dose) or 1.4% (group small dose) of NaHCO3. The ETT
was lubricated with sterile water.
Oral alprazolam (0.5 mg) was administered 23 h
before the surgery. The anesthetic care team performed the standard anesthesia. After establishing IV
access and routine monitors, propofol 2.5 mg/kg,
sufentanil 0.35 g kg1 h1, and atracurium
0.6 mg/kg were used for anesthesia. Tracheal intubation was performed using tracheal tube (Murphy,

ESTEBE ET AL.
ALKALINIZATION OF INTRACUFF LIDOCAINE

1537

Allegiance, Malaysia, low volume, high pressure; PVC

cuff) 6.57.0 mm inner diameter for women and 7.0
7.5 mm inner diameter for men) by the anesthesiology
team. Lubrication of the ETT was performed with
sterile water. ETT cuffs (low volume and high pressure) were inflated according to the randomized protocol by the experimenter. ETT cuffs were inflated at
the minimal occlusive volume (i.e., no leakage was
detected under controlled ventilation). In the control
group, the cuff was initially slowly inflated with air.
For alkalinized-L-HCl-filled cuff groups, 2 mL of
L-HCl 2% (Xylocaine, AstraZeneca, Paris, France)
was initially injected into a cuff, and then a supplementary volume of 8.4% or 1.4% NaHCO3 was added.
Cuff pressure was recorded with initial pressure less
than 30 cm H2O (Mallinckrodt, Seelscherf 1, Germany). If an air leak was recorded during the surgery
1 mL of NaHCO3 (8.4% or 1.4%) was added for liquid
groups or 1 mL of air was added in the control group.
The anesthesiology team, unaware of the experimental
protocol, delivered anesthesia. Ventilation was controlled to maintain an end-tidal CO2 of 4.55.5 kPa,
and no gastric tube was inserted. Patients were in the
supine position. Any member of the surgical or anesthesia team applied topical anesthesia or vasoconstrictor to the larynx when indicated. Maintenance anesthesia included: air/O2 (50%/50%), sevoflurane (1 to
1.2%), and sufentanil 0.35 g kg1 h1 until surgical
closure and dressing (time T0). Patients were then
administered 100% oxygen and placed in the recovery
room.
When all of the tracheal extubation criteria were met
(return of neuromuscular function confirmed using
train-of-four peripheral nerve stimulation, ability to
follow verbal commands, regular spontaneous ventilation), tracheal extubation was performed just after
suctioning at the discretion of the physician in charge
of the patient. Time of spontaneous ventilation time
(time between emergence of spontaneous breathing
and extubation) was recorded. The gas and liquid
volumes withdrawn from ETT cuffs at extubation
were recorded. Cough and restlessness were checked
before extubation, excluding cough on suctioning and
extubation times. A blinded nurse evaluated the sore
throat in the recovery room with a visual analog scale
(VAS, 0 10 cm) after extubation (at 30 min and 1, 2, 3,
6 and 24 h). Other complaints of throat discomfort,
such as hoarseness, bucking, dysphonia, and dysphagia, were systematically evaluated as present or absent. Impairment of swallowing reflex was evaluated
by oral intake of a glass of water 15 min after extubation. Hemodynamic variables and postoperative nausea and vomiting were also recorded for 2 to 4 h as
routine control in the recovery room.
Sample-size calculation was based on our previous
studies (10 12); our primary efficacy variable was the
incidence of sore throat as measured by VAS. We

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ANESTH ANALG
2005;101:1536 41

Figure 1. Percentage of lidocaine release in vitro as a function of time, from

the cuff filled with 40 mg of lidocaine
hydrochloride (2 mL 2%) and additional 3 mL of sodium bicarbonate at
8.4% and 1.4% concentrations (n 2
for each concentration).

postulated that if the alkalinized L-HCl had only a

volume effect avoiding the overinflation phenomena,
no effect could be recorded if ventilation was controlled without N2O (null hypothesis) and the results
would be equivalent to the air group data. We estimated that using alkalinized L-HCl would decrease
the rate of sore throat by 25%30% as evaluated by
VAS compared with the air group (alternative hypothesis) (11,12). Based on these estimates, we calculated a
sample size that would permit a type I error of 5%
with a type II error of 5% and power of 95%.
Enrollment of 20 patients in each group was required.
Patients were withdrawn from the study when the
trachea was not intubated on the first attempt. Results
are presented as mean sd. Data were analyzed using
the analysis of variance followed by unpaired Students t-test with Bonferroni correction for parametric
data. Kruskal-Wallis and Mann-Whitney U-tests were
used for nonparametric data. Statistical significance
was defined as P 0.05. Patient randomization was
performed using a computerized list and the same
investigator performed the filling protocol of ETT but
was excluded from all other periods (i.e., anesthesia,
intubation, and extubation time).

Results
Concerning the effect of various concentrations of
NaHCO3, there was a slight tendency for a slower
release when the smaller concentration (1.4%) of
NaHCO3 was used compared with the larger concentration NaHCO3 (8.4%) (Fig. 1). At 3 h, 15% of L-HCl
was released throughout the ETT cuff when 1.4% of
NaHCO3 was added, versus 25% when 8.4% of
NaHCO3 was used. At 6 h 36% of L-HCl was released
throughout the ETT cuff when 1.4% of NaHCO3 was

added versus 45% when 8.4% of NaHCO3 was used.

In vitro pH determination is summarized in Table 1.
Sixty patients participated in the study and none was
excluded (i.e., all patients were tracheally intubated at
first attempt). There was no statistically significant difference among groups regarding surgery and anesthesia
characteristics (Table 2). There were no problems with
endotracheal intubation or cuff inflation. During controlled ventilation, no air leak was recorded. Compared
with the control group there was a slight but not significant difference in the initial volume of the solution
injected into the cuff (3.9 0.6 mL, 4.3 0.5 mL, 4.1
0.4 mL for groups air, large dose, and small dose, respectively; P 0.08). There was no significant difference
among groups in ETT cuff pressure recording. The volume withdrawn at extubation time was not significantly
different among groups (3.4 0.8 mL, 3.5 0.5 mL, and
3.4 0.5 mL for groups air, large dose, and small dose,
respectively).
Compared with group air, group large dose and
group small dose had significant reductions in sore
throat (mean end-point for efficacy) during the 24-h
postoperative period (P 0.0001)(Fig. 2). The difference was not significant between the two alkalinized
L-HCl groups. This increase in ETT tolerance was
confirmed by the analysis of secondary and safety
end-points (Table 3). There was a significant prolongation of spontaneous ventilation time and the time to
tracheal extubation. The good tolerance of the ETT
was associated with less cough and restlessness before
suctioning and extubation. No difference was recorded in cough reflex at extubation time. Neither
laryngospasm, nor depression of the swallowing reflex, was recorded. Based on postoperative nausea and
vomiting and hoarseness the control group (air-filled
cuff) displayed less tolerance (Table 3). There was no

ANESTH ANALG
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Table 1. In Vitro pH Evaluation of Solutions with 2 mL of 2% Lidocaine and Various Concentrations and Various
Volumes of Sodium Bicarbonate
1.4% NaHCO3

pH

8.4% NaHCO3

2 mL

3 mL

4 mL

6 mL

2 mL

3 mL

4 mL

6 mL

7.44

7.47

7.59

7.63

7.95

7.99

8.07

8.09

Table 2. Demographic Patient Data for the Air Group, Lidocaine Alkalinized Groups with 8.4% or 1.4% of Sodium
Bicarbonate

Group size

Air
(n 20)

8.4% NaHCO3 2% lidocaine

2 mL
(n 20)

1.4% NaHCO3 2% lidocaine

2 mL
(n 20)

Age (yr)
Weight (kg)
Height (cm)
Female/male
Smoking (%)
Surgery (min)
Sufentanil (g/kg/h)

47 13
62 7
165 6
17/3
40
58 13
0.34 0.03

48 15
64 8
166 9
15/5
35
56 8
0.36 0.02

48 12
65 10
167 9
15/5
35
57 6
0.35 0.04

Figure 2. Visual analog scale (VAS, 0 100 mm) scores of sore throat
during the first postoperative days for air group (group air; black
symbol), lidocaine alkalinized groups with 8.4% (group large dose;
gray symbol) or 1.4% (group small dose: open symbol) of sodium
bicarbonate (n 20 for each group). *P 0.0001 group air versus
liquid groups (large or small dose).

difference between liquid groups. There was a trend

of reduced hypertension and tachycardia in the control group and the alkalinized L-HCl groups but it was
not significant (Table 3).

Discussion
This is the first study in which the ETT cuff filled with
alkalinized L-HCl was evaluated in anesthetized patients with controlled ventilation without N2O. Our
results showed a significant improvement of the ETTinduced emergence phenomena from general anesthesia when alkalinized L-HCl was used instead of air to

fill the ETT cuff. VAS scores for sore throat were
similar before surgery (Fig. 2). Although thyroid surgery was responsible for pain in the cervical area,
patients clearly reported a decrease of VAS scores for
sore throat in the two alkalinized L-HCl groups.
The incidence of coughing and sore throat on emergence from general anesthesia in the presence of ETT
has been estimated to range from 38% to 96% (8,15). In
our control group, coughing was reported in 70% of
patients and sore throat was evaluated at 30 15 mm
using the VAS. These results were in agreement with
previous studies (8,10 12,15). Our data confirmed the
lack of increased cuff pressure and cuff volume after
air inflation without N2O (4,16). It has been reported
that the overinflation occurring during general anesthesia was attributable to an increase in temperature
and, most importantly, because of more rapid NO2
diffusion into the cuff than out from the cuff (1,13,16).
This overinflation of the ETT cuff has been associated
with damage to the pharyngeal mucosa and recurrent
laryngeal nerve palsy (17). The lack of hyperpressure
is probably one advantage of liquid filling of ETT cuffs
(18,19). However, despite the absence of overinflation
in our control group, filling the cuff with alkalinized
L-HCl allowed a significant improvement of ETT cuff
tolerance. The effect on thyroid surgical pain could not
be excluded. However, surgical pain (i.e., pressure
threshold) was not specifically evaluated.
It has been reported that L-HCl injected alone had a
slow diffusion rate across the ETT cuff (1% of release
during the 6-hour period) (11). For a clinical effect,
large doses of L-HCl (200 to 500 mg) were believed to
be required (59). In addition to the potential adverse
effect of these large doses in case of rupture, there was
no real advantage compared to saline (4). The use of

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Table 3. Secondary End-points of Endotracheal Tube-induced Emergence Phenomena: Time of Spontaneous Ventilation
Before Extubation (T0 Isoflurane and Propofol Were Stopped), Cough Effort and Restlessness Before Extubation,
PONV, Dysphonia, and Hoarseness After Extubation. Hemodynamic Data 5 Minutes After Extubation: Systolic and
Diastolic Arterial Blood Pressure and Cardiac Frequency for Air Group, Lidocaine Alkalinized Groups with 8.4% or 1.4%
of Sodium Bicarbonate

Spontaneous ventilation time (min)

Cough effort (%)
Restlessness (%)
PONV (%)
Dysphonia (%)
Hoarseness (%)
AP systolic (mmHg)
AP diastolic (mmHg)
Cardiac frequency (beats/min)

Air
(n 20)

8.4% NaHCO3 2% lidocaine

2 mL
(n 20)

1.4% NaHCO3 2% lidocaine

2 mL
(n 20)

4.5 2
70
30
85
5
75
128 39
80 10
94 18

12 3
5
0
30
5
40
119 15
74 11
89 20

11 4*
5
5
40
5
20
123 19
73 11
85 17

Values are mean sd or %.

PONV postoperative nausea and vomiting; AP arterial blood pressure.
* P 0.0001.

alkalinized local anesthetics into the ETT cuff offers

the advantages of minimal stress response to smooth
tracheal extubation and cough-free emergence. We
previously reported that alkalinization of L-HCl allowed the diffusion of 65% of the neutral base form of
L-HCl through the hydrophobic structure of the PVC
cuff within a 6-hour period and showed that the use of
a small dose (40 mg) of alkalinized L-HCl markedly
improved ETT tolerance during the first postoperative
day (11,12). It appears that only the hydrophobic neutral form of L-HCl was able to diffuse across a membrane, while for charged alkalinized L-HCl only a
permeation phenomenon occurred. Following the
Henderson-Hasselbach equation (i.e., the ratio between ionized and nonionized species being a function of both the pK of the substance and the pH of the
dissolving medium) the addition of NaHCO3 to alkalinized L-HCl alkalinizes the L-HCl solution. This provides the corresponding hydrophobic base and allows
the diffusion of this uncharged form through the hydrophobic PVC wall of the cuff more readily than the
alkalinized L-HCl and allows for the best release profile observed with the lidocaine base (10). In line with
this concept of alkalinization, we have previously reported that the amount of L-HCl diffusing across the
ETT cuff in the presence of NaHCO3 was proportional
to the dose of L-HCl applied (20 40 mg) (10). Our in
vitro and in vivo studies showed no cuff rupture or
obstruction (10 12).
No significant difference was reported between the
use of 8.4% and 1.4% NaHCO3 to alkalinized L-HCl
for VAS scores for sore throat (mean total clinical
volume 4 0.5 mL; 2 mL 2% of lidocaine and 2
0.5 mL of NaHCO3). Those clinical data were confirmed by our in vitro results showing a similar release
profile of L-HCl from the cuff. There was no significant difference in the release of L-HCl with a different

brand of ETT high-pressure-low-volume PVC cuff

(unpublished data). The slight difference of L-HCl
release observed as a function of NaHCO3 concentration in our in vitro results seems to have no clinical
effect. This slight delay of release with the small concentration of NaHCO3 could be useful for long duration surgery. Based on pH in vitro evaluation, we
report an increase of pH with the NaHCO3 concentration (i.e., at the same volume) and an increase of pH
with NaHCO3 volume (Table 1) without beneficial
clinical effect. We have previously reported, in a pharmacokinetic study, that diffusion with 8.4% NaHCO3
gives a very small maximal plasma concentration of
L-HCl (Cmax 0.08 g/mL) (10 12), which is smaller
than when L-HCl was used topically (0.431.5 g/mL)
(20) or IV (23 g/mL) (21,22). We have also shown, in
vitro, that variation in volumes of 8.4% of NaHCO3 (1
to 7 mL) injected into the cuff had no effect on the
diffusion of 40 mg L-HCl (11); in this study we have
shown that the concentration of NaHCO3 had no clinical effect on the L-HCl diffusion.
If alkalinization of L-HCl improved cuff tolerance
during the evaluation period, the local anesthetic effect did not depress the swallowing reflex, indicating
palsy of the vocal cords, consistent with our earlier
report (11,12). The decrease in cough before tracheal
extubation should not be attributed to a depression of
cough reflex during the suction-extubation act. It
probably results from an increase in ETT tolerance
attributable to a local effect rather than a systemic
effect because it was reported at intubation time with
a high level of plasma L-HCl after IV administration
(2 mg/kg given lidocaine levels 3 g/mL) (22). The
efficacy of IV or topical administration of L-HCl appears to be short-acting. To reduce sore throat at extubation time requires local application of L-HCl (with

ANESTH ANALG
2005;101:1536 41

a specific device) (20), IV administration before extubation (15), or large doses of local application of L-HCl
at intubation time for short-duration surgery
(90 min) (23). Prolongation of the time of spontaneous ventilation must be seen as an improvement of
ETT tolerance rather than as an adverse effect. Because
of the experimental anesthetic protocol, similar for
each group (i.e., maintenance of anesthesia until dressing), a prolongation of the time of spontaneous ventilation was observed. However, differences in recovery
room stay were not observed overall. In our clinical
practice, the increase of ETT tolerance allows for earlier reduction of anesthesia and spontaneous ventilation at the end of surgery. Quiet tracheal extubation
without sore throat was easily obtained in the recovery room and allowed a decrease in adverse effects, as
previously observed (i.e., postoperative nausea and
vomiting) (10 12).
As in our previous studies with N2O (10 12), this
study performed in a clinical setting without N2O for
controlled ventilation confirmed that alkalinized
L-HCl (i.e., base L-HCl) injected into the cuff, instead
of air, was clinically effective and safer in reducing
postoperative sore throat. Using a solution close to the
physiological pH and a small dose of L-HCl (40 mg)
reduces the risks of local anesthetic vascular absorption and mucosal irritation in case of ETT rupture,
although ETT rupture has never been reported. Conversely, some cases of cuff rupture have been reported
when L-HCl was used as lubricant or for local anesthesia (24). Hence, the current findings support the
use of a 1.4% NaHCO3 concentration to refill the cuff
of the ETT.
We conclude that there is a decrease in sore throat
during the postoperative period when the cuff is inflated with a small dose of alkalinized L-HCl (i.e.,
small dose of L-HCl:40 mg and small dose of
NaHCO3:1.4%) rather than with air when ventilation
is controlled without N2O. This technique is also applicable for the indirect effects of tracheal extubation,
including restlessness, hoarseness, and dysphonia.
Such a drug delivery system should be considered in
clinical practice to improve a patients tolerance of
anesthesia (with and without N2O) and intensive care
and, most importantly, in the case of cardiovascular
disease, intracranial or intraocular hyperpressure, or
hyperreactive pulmonary disease.

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