|Year : 2008 | Volume
| Issue : 5 | Page : 536
Diffusion of Lidocaine Buffered to An Optimal pH Across the Endotracheal Tube Cuff-An in-Vitro Study
VV Jaichandran1, N Angayarkanni2, Coral Karunakaran2, IM Bhanulakshmi1, V Jagadeesh1
1 Department of Anaesthesiology, Vision Research Foundation, Chennai 600 006, India
2 Department of Biochemistry, Vision Research Foundation, Chennai 600 006, India
|Date of Acceptance||15-Jun-2008|
|Date of Web Publication||19-Mar-2010|
V V Jaichandran
Department of Anaesthesiology, Sankara Nethralaya, Vision Research Foundation, 18, College Road, Chennai 600 006
Source of Support: None, Conflict of Interest: None
Diffusion of lidocaine across the endotracheal tube (ETT) cuff helps in smooth emergence of patients from general anaesthesia by preventing ETT-induced cough to occur. Buffering enhances the rate of diffusion from ETT cuff. The aim of this in-vitro study was to determine the optimal pH at which maximum diffusion of lidocaine occurs across the ETT cuff. Fifteen 8.0 mm ID Portex ETT's were divided into three groups. In each group, the cuffs were filled with 6ml of 2% lidocaine buffered to a pH of 7.4 (Group I), 7.6 (Group II) and 7.8 (Group III). They were then immersed in 20ml distilled water in a water bath set at 38 0 C. The lidocaine diffused was measured using high performance liquid chromatography every half hour interval for up to five hours. There was a significant increase in the onset of diffusion in Group II compared to Groups I and III (P< 0.0001), but the minimum concentration of lidocaine (C m , 155µg.ml -1 ) that is required for blocking the cough receptors was obtained across the ETT cuff by all the three groups at 90 minutes (P >0.05). At 300 minutes, maximum diffusion occurred in both the Groups I and II, which was significantly higher compared to Group III (P <0.05). In spite of the above findings, the present study concluded lidocaine buffered to a pH of 7.4 as the optimal pH for the practical reason that solution in Group I was non-precipitating in nature and hence both filling as well as withdrawing the solution from the cuff was easier in this group, unlike that happened in the Groups II and III.
Keywords: Lidocaine, Cough.
|How to cite this article:|
Jaichandran V V, Angayarkanni N, Karunakaran C, Bhanulakshmi I M, Jagadeesh V. Diffusion of Lidocaine Buffered to An Optimal pH Across the Endotracheal Tube Cuff-An in-Vitro Study. Indian J Anaesth 2008;52:536
|How to cite this URL:|
Jaichandran V V, Angayarkanni N, Karunakaran C, Bhanulakshmi I M, Jagadeesh V. Diffusion of Lidocaine Buffered to An Optimal pH Across the Endotracheal Tube Cuff-An in-Vitro Study. Indian J Anaesth [serial online] 2008 [cited 2020 Oct 24];52:536. Available from: https://www.ijaweb.org/text.asp?2008/52/5/536/60670
| Introduction|| |
Diffusion of lidocaine across the endotracheal tube (ETT) cuff may enable the cuff to serve as a reservoir for local anaesthetic and subsequent anaesthesia of underlying tracheal mucosa, by blocking the cough receptors or rapidly adapting stretch receptors (RARs). , Only the non-ionized base form of the drug diffuses across the hydrophobic polyvinyl chloride walls of the ETT cuff. , Increasing the pH of the solution can predictably increase the percentage of the non-ionized fraction of the drug. Addition of bicarbonate resulted in a 63-fold increase in the diffusion of lidocaine across the ETT cuff.  Huang et al filled the ETT cuff with lidocaine buffered to a pH of 7.34+0.11 and were able to significantly reduce ETT-induced coughing following emergence from general anaesthesia with a minimum surgical time of 2 hours.  As the pKa value of lidocaine is 7.8, by buffering to more than 7.4 the present study attempts to evaluate whether it is possible to promote more rapid diffusion across the cuff so as to obtain the minimal blocking concentration (C m ) of lidocaine for cough receptors(155µg.ml -1 )  at the earliest time interval possible, so that this technique can be employed for surgeries of less than 2 hours duration.
| Methods|| |
Fifteen Portex high volume, low pressure ETT's (Portex Limited, United Kingdom) of size 8.0 mm ID were divided into three groups (n=5). 6ml each of 2% lidocaine of HPLC grade (Loxicard 2%; Neon Laboratories Limited, Mumbai, India), buffered to pH values 7.4, 7.6 and 7.8 was used to fill the cuff of the ETT in Groups I, II and III respectively. Freshly prepared 7.5%sodium bicarbonate was used for buffering the lidocaine. The pH was measured using calibrated digital pH meter (ELICO, Hyderabad, India). After filling the cuff of the endotracheal tubes with the buffered lidocaine, rubber bands were put around the cuff to maintain the pressure at 25cm of H 2 O, measured using a cuff manometer, [Figure 1]. They were then immersed in 20ml distilled water in a temperature regulated water bath set at 38 0 C. An aliquot of 100µl of distilled water around the cuff was drawn at every half hour interval for up to 5 hours with the help of a micropipette. 20µl aliquots were injected into the C18 column for detection of lidocaine concentration using High Performance Liquid Chromatography (HPLC).
| HPLC Analysis|| |
Lidocaine analysis was carried out using Prominence, Shimadzu liquid chromatographic system consisting of a binary pump (Shimadzu model LC-20 AT, Shimadzu Corporation, Kyoto, Japan) with a 20µl loop and UV/VIS photo diode array detector (Model SPDM20 A). A reversed phase C18 analytical column, [Figure 2],(Zorbax 3.5 µm, 75 x 4.6mm Agilent, USA) was used. Isocratic elution was performed using acetonitrile - phosphate buffer, pH 5.9 (20:80 v/v) as the mobile phase at a flow rate of 1ml.min -1 under ambient temperature (25 0 C). UV detection was carried out at 210 nm.
Stock lidocaine solution was diluted using mobile phase in the range of 100-1000µg.ml -1 . This was stored at 4 0 C and used within 1 week of preparation.
In each set of experiments, 100µl solution was taken at half hour interval up to 5 hours and stored at 4 0 C. The HPLC system was calibrated with lidocaine standard prior to the analysis of samples. Intra-assay variation of lidocaine was found to be 11.8µg.ml -1 . [Figure 3] illustrates the HPLC elution profile showing lidocaine standard peak with a retention time of 6.8 minutes.
Based on the study done by Haung et al  , we conducted this pilot study, with a similar sample size (n=5) to determine whether diffusion is influenced by filling the ETT cuff with buffered lidocaine. One-way ANOVA was used for data analysis. Bonferroni posthoc multiple comparisons tests was used for the groups. Statistical significance was defined as P<0.05. SPSS 13.0 version was used for statistical analysis.
| Results|| |
The mean pH values of the lidocaine solution used to fill the cuff of endotracheal tubes, the volume of sodium bicarbonate required for buffering and the concentration of lidocaine diffused across the cuff walls in the three Groups, I, II and III are shown in [Table 1]. The mean initial pH value of the lidocaine solution was 6.55+0.17.
Onset of diffusion of lidocaine was highly significant in Group II (62.46+11.35µg.ml -1 ) compared to Groups I (8.45+0.56µg.ml -1 ) and III (17.07+1.52µg.ml 1) , (P<0.0001). At the end of 60 minutes lidocaine diffused significantly across the cuff in both the Groups I (83.43+4.94µg.ml -1 ) and II (85.43+8.02µg.ml -1 ) compared to Group III (55.76+6.73µg.ml -1 ), (P<0.01). The C m of lidocaine that is needed for blocking RAR was attained by all the Groups at 90 minutes, (p>0.05). At 300 minutes maximum lidocaine concentration across the cuff was detected in both the Groups I (863.94+5.08µg.ml -1 ) and II (856.88+22.82µg.ml -1 ), which was significantly higher compared to Group III (815.02+12.54µg.ml -1 ), (P<0.05).
| Discussion|| |
In early in vitro studies done by Dollo et al  and Estebe et al  , diffusion of lidocaine across the cuff was studied using low-volume, high pressure Rusch armoured ETT. In the above studies, concentration of lidocaine diffused across the cuff wall was measured using spectrophotometer. Later on, Huang et al  and Estebe et al  , found diffusion to occur across the cuff of high-volume, low-pressure Mallinckrodt ETT. But for the detection of lidocaine across the cuff, the former investigators used gas chromatograph equipped with flame ionization detector (GC-FID) where as the latter investigators used the spectrophotometer technique. In our study, high-volume, low-pressure Portex ETT was used and the lidocaine diffused was measured using HPLC method.
Dollo et al  filled the low-volume, high pressure ETT cuff with varying volumes of lidocaine 2% (1-2ml) along with 8.4% sodium bicarbonate (8-9ml), where as Estebe et al  filled the high-volume, low pressure ETT with a fixed dose of 2ml of 2% lidocaine with varying volume of 8.4% sodium bicarbonate (8-15ml). With high-volume, low pressure cuffs, the lidocaine release profile seemed to be slightly less than that obtained with low-volume, high-pressure cuffs - 50% lidocaine diffused in 5 hours with the former and 3 hours with the latter  .
Huang et al study  determined the effect of warming, buffering, or warming with buffering on lidocaine diffusion across the ETT cuff. Hence four preparations of lidocaine 4% were used for filling the cuff of Mallinckrodt ETT as lidocaine at 24 0 C, lidocaine warmed to 38 0 C, lidocaine buffered to a pH of 7.34+0.11 and lidocaine buffered to the same pH warmed to 38 0 C. It was concluded that buffering with or without warming, but not warming alone, produced rapid lidocaine diffusion from the ETT cuffs. Unlike the earlier studies ,,, , Huang et al also determined the time interval at which the minimum concentration of lidocaine for blocking RAR was obtained across the cuff walls. It was found that, through manipulation by buffering with or without warming, lidocaine in ETT cuffs may exert its RAR blocking effect within 120 - 180 minutes after its application  .
Similarly in the present study we too focussed on the minimum time interval at which RAR blocking effect was obtained by lidocaine across the cuff, but by utilizing the effect of buffering alone. Hence the pH of lidocaine solution was raised from 6.55+0.17 to values between 7.40+0.01 to 7.82+0.01 by buffering with 7.5% sodium bicarbonate in volumes ranging from 0.6+0.08 to 2.70+0.20 ml. Onset of diffusion of lidocaine across the cuff was found to be rapid in Gr II compared to the other groups. The increased fraction of the non-ionised form of the drug in Gr II perhaps would account for the rapid onset of diffusion across the ETT cuff. Though lidocaine buffered to a pH of 7.4 initially showed a slow onset of diffusion, after the first 30 minutes interval diffusion was faster, and at 300 minutes it attained the maximum with a lidocaine concentration of 863.94+5.08µg.ml -1 across the cuff. However the C m of lidocaine that prevents activation of the stretch receptors (RAR) for the cough reflex was attained by all the three groups at 90 minutes. While buffering lidocaine, solutions precipitated three out of five times (3/5 times) for pH 7.6 (Group II) and all the five times (5/5 times) for pH 7.8 (Group III), such precipitation was not encountered at all when lidocaine was buffered to a pH of 7.4 (Group I). Additionally, in both the Groups II and III difficulty was encountered in both filling as well as in withdrawing the solution from the ETT cuff, as the precipitated particles occluded the port in the pilot balloon. Hence, though maximum diffusion occurred in both the Groups I and II, the present study concludes that lidocaine buffered to a pH of 7.4 is the optimal pH as diffusion was rapid after the first 30 minutes interval, C m of lidocaine for blocking RAR was obtained well at 90 minutes, diffusion was maximum at 300 minutes and the solutions did not precipitate. Hence, both filling as well as withdrawing the solution from the cuff was easier in this group.
Based on the above findings, we propose by filling the ETT cuff with 6 ml of 2% lidocaine buffered to a pH of 7.4, adequate concentration of lidocaine can be obtained across the cuff by diffusion to block the cough receptors in the tracheal mucosa at the end of 90 minutes. This in turn can increase the ETT tube tolerance as well as decrease or prevent ETT-induced coughing during emergence from general anaesthesia. In a previous in vivo study by Huang et al, filling the ETT cuff with 5ml of 4% lidocaine buffered to a similar pH, ETT-induced cough during emergence from general anaesthesia was found to be reduced in patients with surgical duration of 120 minutes  .
The total amount of lidocaine used for filling the ETT cuff by Huang et al was 200mg (5ml of 4% lidocaine) , . In our study, only 120mg of lidocaine (6ml of 2%lidocaine) was used. This lesser amount of lidocaine used, further reduces the chances of lidocaine toxicity from occurring in case of any cuff rupture or leak. Though Dollo et al  and Estebe et al  , used only 40mg of lidocaine, they used more than 8ml of 8.4% sodium bicarbonate in their study. Further Estebe's in vitro study concluded that the lower the sodium bicarbonate injection volume, the greater the release of lidocaine across a low-pressure, high-volume cuff  . This in turn correlates with the findings obtained in our study  , as we used only 0.5ml to 2.90ml of 7.5% sodium bicarbonate.
Although cuff failures have been reported for polyvinyl chloride ETT's sprayed and lubricated with lidocaine solution  , no cuff in our in vitro study showed any apparent defect or ruptured. As in Huang's study each cuff was also tested rigorously for leakage at the end of the study and all remained intact.
The C m of lidocaine for blocking the RAR was obtained at 90 minutes interval indicating thereby that this technique may not be beneficial for shorter procedures. Since diffusion of lidocaine is also time-dependent, the longer the surgical procedure, a better effect would be seen in preventing coughing during emergence from general anaesthesia. An in vivo study, with our findings as a background, is therefore needed to evaluate the effect of diffused lidocaine on the cough receptors.
Filling the ETT cuff with 6ml of 2% lidocaine and 0.6ml of 7.5% sodium bicarbonate can produce adequate diffusion of uncharged base form of the drug across the cuff walls. This technique can be used to prevent ETT-induced coughing following emergence from general anaesthesia with a minimum surgical time of 90 minutes.
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[Figure 1], [Figure 2], [Figure 3]