| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
| ||||||||||||||
| ||||||||||||||
|
|
|
|
||||||||||||
|
||||||||||||||
From the *Department of Environmental Health Sciences, Department of Medicine, and Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland.
Address correspondence to Robert H. Brown, MD, MPH, Johns Hopkins School of Public Health, Room E7614, 615 N. Wolfe St., Baltimore, Maryland 21205. Address e-mail to rbrown{at}jhsph.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: Small, medium, and large airways (2–5, 5–8, >8 mm diameter) were analyzed by computed tomography in 15 asthmatic volunteers under baseline conditions and during infusion of lidocaine. Changes in luminal airway diameter and wall thickness from baseline to during lidocaine infusion, and the change in pulmonary function induced by lidocaine, were analyzed.
RESULTS: Lidocaine caused a significant decrease in the forced expiratory volume in 1 s pulmonary function measure (7 ± 2%, P = 0.006). There was also a small but significant decrease in the airway luminal diameter at total lung capacity during lidocaine infusion compared to baseline (–3 ± 0.5%, P < 0.001). Moreover, there was a significant correlation between the change in forced expiratory volume in 1 s and the change in airway luminal diameter at total lung capacity (r2 = 0.47, P = 0.01).
CONCLUSION: Lidocaine, which reduces airway responsiveness to drugs that cause bronchospasm through sensory nerve activation, did not reduce baseline airway tone. Instead, even when administered IV, lidocaine significantly increased airway tone and caused airway narrowing. Therefore, while the administration of lidocaine can prevent intubation-induced bronchospasm, the airways should be constantly monitored by auscultation even during IV lidocaine administration.
|
Introduction |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
We (9) have previously demonstrated that a major beneficial effect of inhaled anesthetics is to decrease baseline airway tone. One question that remains is whether one of the mechanisms by which IV lidocaine prevents bronchoconstriction is by altering baseline airway tone. Clearly, inhaled lidocaine has been shown to induce bronchoconstriction, and this has been attributed to an irritant effect (10–13). However, the effects of IV lidocaine on baseline airway tone have not been carefully examined. Therefore, we examined the effect of IV lidocaine on baseline airway tone in individuals with asthma. We have previously used high-resolution computed tomography (HRCT) to assess airway structure and its relationship to changes in pulmonary function under various conditions, in healthy and asthmatic individuals (14–16). In our continuing effort to determine the relationships between function and structure, we have also used HRCT in this study.
|
METHODS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
Study Design
Spirometry was performed using a portable spirometer (PDS, Inc., Louisville, CO), and lung volumes were measured in a body plethysmograph (MedGraphics, St. Paul, MN) with the subjects seated.
On the first visit, baseline HRCT scans were obtained at functional residual capacity (FRC) and total lung capacity (TLC). By controlling the amount of inspired air, lung volume at each scan series was maintained approximately constant at FRC, as previously described (14). To measure airway area at TLC, the subject was instructed to take a maximum deep inspiration.
On another day, an IV catheter was placed in the dorsum of the hand, and lidocaine (Abbott Laboratories, Abbott Park, IL) was administered via a dedicated infusion pump. Each subject received an initial loading dose of lidocaine (2 mg/kg by IV infusion over 30 min), followed by a continuous infusion of 4 mg/min. This dose has been shown to achieve median therapeutic concentrations (7). During maintenance infusion of lidocaine, HRCT scans were obtained at FRC and TLC. After completion of the scanning, and while the lidocaine infusion was maintained, spirometry was again performed with the subject seated.
HRCT Image Acquisition
HRCT scans were obtained in the supine position at FRC and TLC using a Somatom Plus scanner (Siemens, Iselin, NJ), with settings of 120 kVp, 170 mAs, and a 1 mm slice thickness. The rotation feed was set at 2 mm/s with a reconstruction interval of 1 mm. Images were reconstructed as a 256 x 256 matrix using a maximum zoom of 4.0 (12 cm field of view). These settings have been shown to provide accurate measurement of luminal size as small as 0.5 mm in diameter (17,18). One reference scan was taken approximately 6 cm above the diaphragm at FRC and TLC with the subject positioned supine in the computed tomography (CT) gantry to optimize location and registration. Approximately 61 contiguous segments were obtained caudally at FRC and TLC.
Image Analysis
The HRCT images were analyzed using the airway analysis module of the Volumetric Image and Display Analysis image analysis software package (Dept. of Radiology, Division of Physiologic Imaging, Univ. of IA, IA), as previously described and validated (19,20). The HRCT images were transferred to a UNIX-based Sun workstation. An initial isocontour was drawn within each airway lumen. The software program then automatically located the perimeter of the airway lumen by sending out rays in a spoke-wheel fashion to a predesignated pixel intensity level that defined the luminal edge of the airway wall. Intra- and interobserver accuracy and variability of the software program using this HRCT technique in phantoms, consisting of rigid tubes to measure known areas, has been shown by us (17) and by others (19) to be highly resistant to operator bias.
To measure airway wall thickness, the Volumetric Image and Display Analysis program displays a histogram of pixel intensity along a line that is drawn through the airway wall. The inflection points of increasing intensity represent the inner and outer edges of the airway wall. The line and points were selected manually. The program measures the distance in pixels between the two points. The software is capable of measuring fractions of a pixel, and therefore the measurements of wall thickness were not necessarily quantized to multiples of the pixel dimension. CT cannot partition water separated by microscopic boundaries. Thus, "wall thickness" is a term used in the broadest sense and includes the wall and any peribronchial cuff or luminal fluid. The airway wall measurements were only made at TLC. We were not able to measure wall thickness for all the airways because adjacent vessels obscured the wall landmarks.
Statistics
Pulmonary function measurements, i.e., the forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and lung volumes were compared baseline (first visit) and pre-lidocaine infusion, (second visit) using paired t-tests. In addition, the FEV1 and FVC pre-lidocaine infusion and during lidocaine infusion both measured on the same day were compared using paired t-tests. In addition, paired t-tests were used to separately compare the airway luminal diameters and the airway wall thicknesses at baseline and during lidocaine infusion.
The data were also analyzed by simple linear regression to describe the change in airway luminal diameter and the change in pulmonary function during lidocaine infusion relative to baseline; to describe the change in airway wall thickness and the change in pulmonary function during lidocaine infusion relative to baseline; and to relate the change in airway size with lung inflation from FRC to TLC and the change in pulmonary function. All analyses used JMP IN 5.1 software (SAS Institute, Cary, NC). Significance was accepted at a two-tailed level of P < 0.05.
|
RESULTS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
First, we examined the changes in pulmonary function at baseline and during lidocaine infusion. We found no significant difference between the baseline and pre-lidocaine measurements for FEV1 (P = 0.25), FVC (P = 0.66), FEV1/FVC (P = 0.28), TLC (P = 0.07), or residual volume (P = 0.24). These results demonstrate the stability in the subject's lung function between study days. There was a small but significant decrease in pulmonary function during lidocaine infusion compared to pre-lidocaine pulmonary function measurements. FEV1 decreased by 7% ± 7% (mean ± sd, P = 0.006) while FVC decreased by 3% ± 4% (P = 0.03), and FEV1/FVC decreased by 4% ± 4% (P = 0.01). Baseline FEV1 and FVC had no relationship to the lidocaine-induced changes (for FEV1, r2 = 0.11, P = 0.28 and FVC, r2 = 0.05, P = 0.51). Thus, IV lidocaine caused a small but significant decrease in pulmonary function in these individuals with asthma. However, the decrease in pulmonary function was not related to the underlying functional status of their airways.
Next, we examined the overall changes from baseline in airway luminal diameter and wall thickness, during lidocaine infusion, at FRC and TLC. At FRC, there was no overall significant change in the airway luminal diameter during lidocaine infusion compared to baseline airway diameter (–0.1% ± 6%, P = 0.77, Fig. 1). All airway sizes demonstrated similar relationships. When the airways were examined at full lung inflation (TLC), we found an overall small but significant decrease in the airway luminal diameter during lidocaine infusion compared to baseline (–3% ± 5%, P < 0.001, Fig. 1). Again, all airway sizes demonstrated similar effects. Airway wall thickness was examined only at TLC and no significant changes were observed during lidocaine infusion compared to baseline (1% ± 5%, P = 0.92).
|
We then examined the relationship between the change in airway luminal diameter and the change in pulmonary function during lidocaine infusion relative to baseline. We found a significant correlation between the change in the FVC and the change in airway luminal diameter at FRC (r2 = 0.48, P = 0.01, Fig. 2a), but not between the FEV1 and the change in airway luminal diameter at FRC (r2 = 0.30, P = 0.07). In contrast, we found a significant correlation between the change in FEV1 and the change in airway luminal diameter at TLC (r2 = 0.47, P = 0.01), as well as between the change in FVC and the change in airway luminal diameter at TLC (r2 = 0.40, P = 0.03, Fig. 2b). In other words, when lidocaine caused a decrease in airway diameter, lung function variables worsened.
|
We further tested the relationship between the change in airway luminal diameter and the change in pulmonary function during lidocaine infusion, relative to baseline, within each of the three airway size categories. We found a significant correlation between the change in FEV1 and the change in the small (r2 = 0.59, P = 0.001) and the medium (r2 = 0.50, P = 0.01), but not the large airways, at TLC. However, we did not find significant correlations between the change in FEV1 and the change in airways luminal diameter by size when scanning was conducted at FRC. Similarly, we found a significant correlation between the change in FVC and the change in the small (r2 = 0.49, P = 0.02) and the medium (r2 = 0.35, P = 0.04), but not the large airway luminal diameters, at TLC. Again, when scanning was conducted at FRC, we found significant correlations only between the change in FVC and the change in large (r2 = 0.60, P = 0.003) airways at FRC.
Next, we examined the relationship between the change in airway wall thickness and the change in pulmonary function during lidocaine infusion, relative to baseline, overall and within each of the three airway size categories. Overall, we found no correlation between either the change in FEV1 (r2 = 0.009, P = 0.76) or FVC (r2 = 0.13, P = 0.24) and the change in airway wall thickness. Furthermore, we found no significant correlations between the change in FEV1 and the change in airway wall thicknesses by airway size. Similarly, we found no significant correlations between the change in FVC and the change in airway wall thicknesses by airway size.
Finally, we asked the question whether lidocaine infusion had an impact on airway distensibility as measured by the change in airway diameter from FRC to TLC. We found a significant correlation between lidocaine-induced changes in airway distension and changes in FEV1 (r2 = 0.48, P = 0.01, Fig. 3a) or FVC (r2 = 0.42, P = 0.02, Fig. 3b). In other words, the larger the decrease in airway distensibility, i.e., the stiffer the airways with lung inflation during lidocaine infusion, the larger was the reductions in FEV1 and FVC. This analysis was also performed separately for each of the three airway size categories. We found a significant correlation between the lidocaine-induced change in FEV1 and the change in airway distension with lung inflation in the small (r2 = 0.63, P = 0.006) and the medium (r2 = 0.51, P = 0.009), but not the large (r2 = 0.12, P = 0.27) airways. Similar relationships were also found for FVC.
|
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
A second finding of this study is that the lidocaine-induced changes in pulmonary function measurements were strongly correlated with the observed changes in airway diameters, as measured by HRCT (Figs. 2a and b). These relationships were primarily driven by the changes in the diameter of small and medium-size conducting airways. A third finding is that IV lidocaine attenuated the ability of the airways to reach maximum airway size at maximum lung inflation (distensibility), similar to what is seen when methacholine is administered to individuals with asthma (15), suggesting that lidocaine, even when administered IV, causes a small but significant increase in airway tone (20).
We were initially surprised to see a decrease in FEV1 and FVC during the IV infusion of lidocaine. Lidocaine administered via aerosol can induce bronchoconstriction, possibly through an irritant effect (10–13). In one study, IV lidocaine also caused narrowing of canine airways (21). However, this occurred in dogs whose airways were instrumented with a bronchoscope, which could have induced an initial increase in tone. In the current study, there was no direct stimulation of the airways, either by an aerosol, or by instrumentation. Yet, our results clearly demonstrate that IV lidocaine can cause airway narrowing in subjects with asthma. Whether this also occurs in healthy individuals remains to be determined, but it would be of lesser clinical importance, because individuals who have no inflammatory airway disease rarely exhibit bronchoconstriction under normal intubation conditions.
One possible mechanism of the IV lidocaine-induced bronchoconstriction is through airway irritation. However, it is difficult to envision how systemic lidocaine can have an irritant effect on the airways, since airway sensory nerves interdigitate between epithelial cells, and their endings may not be readily accessible to a systemically administered drug. An alternative possibility is that systemic lidocaine may have a central nervous system effect that leads to reduced activity of the nonadrenergic, noncholinergic bronchodilatory system, the primary bronchodilatory mechanism of the human lung (22,23).
It is also unlikely that the change in position between the initial baseline measurement and the lidocaine measurement could account for the observed change in pulmonary function with lidocaine infusion. The initial pulmonary function measurements were performed with subjects in a seated position. Thereafter, a subject was supine on the CT scanner for approximately 40 min for the lidocaine infusion and scanning protocol. At the end of the scanning, the subject sat up again and the pulmonary function tests were repeated. When a subject's position changes from sitting to supine, FRC decreases by approximately 25%, whether measured by helium dilution (24) or body plethysmography (25). The decrease in lung volume in the supine position also increases airway resistance (24). However, this is unlikely to be the cause of the decrease in FEV1 that we observed in the subjects during the lidocaine infusion. Once the subjects returned to a seated position, the FEV1 should have returned to baseline, but this did not occur in all individuals.
To assure that there were no acute changes in disease severity between study days, lung function and lung volume measurements were performed at baseline (Visit 1) and repeated on the lidocaine infusion day (Visit 2) before the lidocaine infusion. We found no significant difference between the baseline and pre-lidocaine measurements for FEV1, FVC, FEV1/FVC, TLC, or residual volume. These results demonstrate the stability in the subject's lung function between study days, and that any changes between the pre-lidocaine infusion and during lidociane infusion were most likely caused by the lidocaine.
Furthermore, we did not observe any outliers driving the reported correlations (Figs. 2 and 3) and, therefore, there was no evidence that our findings were driven by a small number of subjects. When Figures 2 and 3 are examined, it becomes evident that all but one or two subjects had a decrease in their FEV1 and FVC during lidocaine infusion compared to the pre-lidocaine measurement.
In addition, there was significant diversity in the severity of asthma among the population in the current study. The disease diversity could be a confounder in the response to lidocaine. Because of this concern, we decided, as a first step, to address in the design of our study the question of whether disease severity, at least as assessed by baseline lung function, influenced the response to infused lidocaine. Use of this population was, therefore, the ideal approach at this early level of investigation. If we had found, for example, that only subjects with the most severe form of the disease experienced a detrimental effect with lidocaine infusion, we would have eventually designed a second study to exclusively evaluate this group. However, we found that baseline FEV1 and FVC had no relationship to the lidocaine-induced changes (for FEV1, r2 = 0.11, P = 0.28 and FVC, r2 = 0.05, P = 0.51). In other words, baseline lung function did not influence the response to lidocaine and, therefore, the obstructive reaction to the infused anesthetic is a phenomenon that depends on some aspect other than disease severity (assuming that lung function is a surrogate of severity).
In previous work, in individuals with mild asthma, the subjects were able to distend their airway much more than individuals with moderate to severe asthma in the current study (15). This may indicate a stiffer airway tree with increased disease severity. Alternatively, this may indicate greater air-trapping, higher lung volumes and, thus, less ability to expand the chest and lungs. In our previous study (15) we used methacholine to induce airway constriction, which limited the maximum size of the airways and decreased pulmonary function. While the current work was not planned to induce airway constriction, the current findings are consistent with those of the previous work, i.e., a decrease in the maximum size of the airways was associated with a decrease in pulmonary function.
As demonstrated in Figure 1, the reduction in baseline lung function outcomes limited the ability of the airways to reach maximum airway size at maximum lung inflation (TLC), indicating a stiffening of the airways (15,20,26,27). Furthermore, we found a strong correlation between the change in the maximum airway size of the airways with lung inflation from FRC to TLC and the decrease in pulmonary function (Figs. 2a and b). The relationships between the changes in pulmonary function and maximum airway diameter were even stronger when the medium and small size airways were considered. This likely reflects the fact that airway tone has a more potent effect on airways that are more easily narrowed, due to their structural characteristics, as well as the fact that resistance through the bronchial tree is far more dependent on medium and small size airways than can be measured by HRCT, compared to large airways (28).
A limitation of the current study is the lack of serum lidocaine levels in these asthmatic subjects. However, we (7) and others (8,29) have demonstrated that the dose we administered in the current study consistently produced serum levels of lidocaine in the therapeutic range for cardiac antiarrhythmic therapy. This same dose was also shown to decrease airway responsiveness to histamine in subjects with asthma (7). It might have been useful to test whether serum lidocaine levels were correlated with the increase or decrease in baseline airway tone. However, since previous investigations have not reported any association between serum lidocaine levels and effects on airway reactivity, it is unlikely that such an association would have been detected in this study.
In conclusion, these data suggest that lidocaine, which reduces airway responsiveness to drugs that cause bronchospasm through sensory nerve activation, did not reduce baseline airway tone. Instead, even when administered IV, lidocaine caused a small but significant amount of airway narrowing through a mechanism that is not clear. This airway narrowing was associated with a decrease in pulmonary function as measured by the FEV1 and FVC, the most commonly used measures to assess changes in a patient's asthma severity status.
Our data also suggest one possible reason why lidocaine is not always effective at preventing bronchospasm. Even when lidocaine was administered IV, and at the proper time and dose, the airway narrowing observed in our study could account for the frequently observed lack of efficacy. Even though it may prevent the intubation-induced bronchospasm, the initial airway narrowing and associated decrease in pulmonary function would be perceived as a treatment failure.
While the administration of lidocaine can prevent intubation-induced bronchospasm in some patients with asthma, it is not always effective. Future studies should focus on the structural changes in the airways that lead to this paradoxical response.
|
Footnotes |
|---|
Supported by NIH HL 62698 and PO10342.
Reprints will not be available from the author.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
