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General Articles: Research Report

Alkalinization of Intracuff Lidocaine: Efficacy and Safety

Estebe, Jean-Pierre, MD, PhD*‡; Gentili, Marc, MD, PhD; Le Corre, Pascal, PharmD, PhD†‡; Dollo, Gilles, PharmD, PhD†‡; Chevanne, François, BSc†‡; Ecoffey, Claude, MD*‡

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doi: 10.1213/01.ANE.0000180995.24211.89
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An 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 (5–9). 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 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 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%, Astra-Zeneca, 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 37°C 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 I–II) 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 2–3 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 μg · kg−1 · h−1, and atracurium 0.6 mg/kg were used for anesthesia. Tracheal intubation was performed using tracheal tube (Murphy™, Allegiance, Malaysia, low volume, high pressure; PVC cuff) 6.5–7.0 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 4.5–5.5 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 μg · kg−1 · h−1 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 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 α = 5% with a type II error of β = 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 Student’s 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.

Figure 1.
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).
Table 1
Table 1:
In Vitro pH Evaluation of Solutions with 2 mL of 2% Lidocaine and Various Concentrations and Various Volumes of Sodium Bicarbonate

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).

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

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 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).

Figure 2.
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).
Table 3
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

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 ETT-induced 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 (5–9). 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 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 μg/mL) (10–12), which is smaller than when L-HCl was used topically (0.43–1.5 μg/mL) (20) or IV (2–3 μg/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 μg/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 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 patient’s 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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