Effect of Nebulized Lidocaine on Severe Glucocorticoid-Dependent Asthma

Effect of Nebulized Lidocaine on Severe Glucocorticoid-Dependent Asthma LOREN

W.

HUNT,

M.D.,

HARRY

A. SWEDLUND, M.D.,

AND GERALD

• Objective: To determine whether nebulized lidocaine is a useful therapy in patients with severe glucocorticoid-dependent asthma. • Design: We prospectively conducted an open study of the effects of administration of nebulized lidocaine four times daily in 20 patients with asthma who had side effects of exogenous hypercortisolism. • Material and Methods: The 18 women and 2 men, who were 19 to 71 years of age, all had severe asthma that necessitated both topical and systemic administration of glucocorticoids to control symptoms of airflow obstruction. Treatment consisted of nebulized lidocaine, 40 to 160 mg four times daily. Initially, all topical and systemic glucocorticoid regimens were maintained; if peak flow rates remained stable and symptoms of asthma were well controlled, orally administered glucocorticoid regimens were slowly reduced. Glucocorticoids are currently the most potent and consistently effective agents for reducing bronchial inflammation and symptoms in patients with bronchial asthma.':' The dosage and duration of glucocorticoid use, however, are limited by numerous adverse effects. 5 Patients with severe asthma often require therapy with large doses of glucocorticoids for protracted periods, and side effects of exogenous hypercortisolism that can be intolerable predictably develop. The use of inhaled glucocorticoids has reduced the requirement for systemically administered glucocorticoids.v' In many patients with severe asthma, however, inhaled glucocorticoids do not control the extraordinary degree of bronFrom the Division of Allergy/Outpatient Infectious Diseases and Internal Medicine (L.W.H., H.A.S.), Division of Pulmonary and Critical Care Medicine and Internal Medicine (L.W.H.), Department of Immunology (0.1.0.), and Allergic Diseases Research Laboratory (0.1.0.), Mayo Clinic Rochester, Rochester, Minnesota. This study was supported in part by Grants AI 15231 and AI 34577 from the National Institutes of Health, Public Health Service, and by the Mayo Foundation. Address reprint requests to Dr. L. W. Hunt, Division of Allergy, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.

Mayo Clin Proc 1996; 71:361-368

J. GLEICH, M.D.

• Results: Thirteen patients were able to discontinue oral use of glucocorticoids entirely, despite prolonged glucocorticoid dependence (mean 6.6 years and median 3 years for the 20 patients); 4 achieved reduction in their daily glucocorticoid requirement while maintaining control of symptoms of asthma (duration of glucocorticoid dependence for responders, mean 6.2 years and median 3.2 years). Three patients had no apparent response, as determined by their continued severe asthma symptoms and inability to reduce oral glucocorticoid requirements. • Conclusion: These results suggest that nebulized lidocaine is a useful therapy for chronic asthma, allowing reduction or elimination of oral glucocorticoid therapy. (Mayo Clin Proc 1996; 71:361-368)

I IL '" interleukin chial inflammation.s? For these reasons, physicians responsible for the care of patients with severe asthma are in desperate need of agents with the powerful anti-inflammatory activities of glucocorticoids but without their undesirable side effects. In a recent study of fluids obtained by bronchoalveolar lavage from symptomatic patients with asthma, we used a bioassay of eosinophil survival'? to detect eosinophil-active cytokines, interleukin (IL) 5, IL 3, and granulocyte-macrophage colony-stimulating factor. We found that several of the fluids contained a potent inhibitor of eosinophil survival, and we subsequently identified this inhibitor as lidocaine used for topical anesthesia during bronchoscopy." Furthermore, lidocaine potently inhibited cytokine-induced eosinophil survival and qualitatively and quantitatively mimicked the glucocorticoid inhibition of eosinophil survival noted by Wallen and associates." Because activated eosinophils are major effector cells in asthma,'>" this observation prompted the question of whether lidocaine, if regularly administered to the airway, has in vivo antieosinophil and glucocorticoidsparing properties in patients with severe asthma. Accordingly, in the hope of achieving corticosteroid-sparing effects, 361

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362

Mayo Clin Proc, April 1996, Vol 71

EFFECT OF NEBULIZED LIDOCAINE ON SEVERE ASTHMA

Table I.-Overview of Patients With Asthma Treated With Nebulized Lidocaine*t

Case

Age (yr) and sex

Duration of asthma (yr)

Nasal polyps:j:

I 2 3

44F 36F 33 F

4 4 22

No No Yes

4

65 F

34

Previous asthma Rx

Cat, mite

Manifestations of hypercortisolism O,OP,MP,P

Duration of steroid Rx (yr)f

Prednisone dose (mg) Initially

After

Duration of lidocaine Rx (mo)

Resolution of cushingoid appearance

°

0, OP, C, G, DM

0.5 1.2 3.2

40 55 45

0 4 0

18 6 14

All Some All

Yes

0, OP, DM, MP,

3.5

13

0

10

Some

0.8 1.0

6 60

4 24

Some All

24

All

5 6

63 F 30F

12 17

No No

7

37F

32

No

8 9

20F 41 F

8 22

No No

10

71M

32

No

11

21 F

21

No

12

56F

34

Yes

13 14 15 16

65 F 34F 42 F 60M

10 6 6

No No Yes Yes

17

18

67 F 47 F

50 18

Yes Yes

19

19F

9

No

20

40F

30

No

10

Positive skin tests§

Dog

MT,D, IVGG

Mite

BD

P,PUD O,OP,MP 0, OP, G

Cat, dog, weed, mite Mite Mite, cat, grass, mold Cat, dog, horse, grass Mite, grass, tree, weed, dog, horse

DF, TAO

O,P,PUD

8.5

30

0.5 10 q.o.d. 0

MT

MP,P MP

2.8 2.5

8 45

0 50

14 3

All None

DF

0, OP, DM, MP,

12.0

20

0

26

All

MT,DF, TAO

P,PUD O,OP,C,DM, MP,P

7.5

10

0

21

All

32.0

5-10

0

19

All

3.8 0.3 1.5 6.0

10 65 3-5 15

10 0 0 0

1.5 19 13 II

None All All All

25.0 16.0

10 12.5

10

2

5 I

None Some

1.0

10

0

6

All

1.8

5

0

5

All

0, OP, DM, MP,

P,PUD O,P,MP, PUD O,P O,P

Tree, weed, grass TAO Mite, weed, grass Mite, grass, tree, weed, cat, dog, roach

O,OP,C,MP O,OP,C, DM,MP O,P O,P

*BD = budesonide; C = cataracts; D = dapsone; DF = deflazacort; DM = diabetes mellitus; G = glaucoma; IVGG = intravenously administered y-globulin; MP = myopathy; MT = methotrexate; = obesity; OP = osteoporosis; P = psychiatric complications; PUD = peptic ulcer disease; q.o.d. = every other day; Rx = treatment; TAO = troleandomycin. tOf the 20 patients, 4 had occupational exposures: smoke and fire retardants in case 1, hairsprays and hairdressing products in case 9, barn and grain dust in case 10, and diesel exhaust in case 16. :j:All patients had rhinitis. §Skin reaction to at least one of several common allergens (for example, cat, dog, dust mite, pollens, mold). #Duration of continuous oral glucocorticoid maintenance therapy (mean, 6.6 years). Note that all patients were receiving topically administered glucocorticoids, including triamcinolone (16 or more sprays per day) and flunisolide (10 or more sprays per day).

°

we treated 20 patients who had symptoms of exogenous hypercortisolism with nebulized lidocaine.

PATIENTS AND METHODS Study Population.-Our study population consisted of 20 (18 female and 2 male) patients who underwent assessment and follow-up by the Division of Allergy/Outpatient Infectious Diseases or the Division of Pulmonary and Critical Care Medicine for severe, glucocorticoid-dependent asthma (that necessitated both topically and systemically administered glucocorticoids to control symptoms of airflow obstruction). All study patients were being treated with

prednisone orally. Each of the patients fulfilled the criteria for asthma established by the American Thoracic Society," had previous hospitalizations for status asthmaticus, had shown at least partial reversibility of pulmonary function abnormalities, and had no manifestations of other lung diseases, such as cystic fibrosis, pulmonary fibrosis, bronchiectasis, allergic aspergillosis, immunoglobulin deficiency, or emphysema. Nineteen patients were not active smokers nor had a prolonged history of cigarette smoking; one patient (case 14, Table 1) smoked one pack of cigarettes per day at the time of initial assessment. All patients had prominent side effects of exogenous hypercortisolism. Be-

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Mayo Clio Proc, April 1996, Vol 71

EFFECT OF NEBULIZED LIDOCAINE ON SEVERE ASTHMA

363

fore initiation of lidocaine treatment, systemic and topical administration of glucocorticoids was sufficient to control symptoms of asthma-that is, no patient was in the midst of an acute flare of airway obstruction when nebulized lidocaine therapy was initiated. If previous attempts to reduce or eliminate the oral use of glucocorticoids had failed, treatment with lidocaine was begun immediately. The patients were asked to perform frequent monitoring of their peak flow rates, particularly when symptoms of coughing, wheezing, or shortness of breath were present and periodically just before and after lidocaine treatments. Lidocaine Nebulization.-With use of a nebulizer (DeVilbiss Pulmo-aid), treatment with lidocaine was initiated in a dosage of 2 mL of a 2% solution (40 mg) four times daily, with allowance for an extra nebulization at night should the patient awaken with coughing or wheezing. After 2 to 4 weeks of treatment, some patients were asked to increase their lidocaine dosage to 3 mL four times daily, but most patients' regimens were changed to a 4% solution at a dosage of 2.5 mL (100 mg) four times daily, and one patient received 4 mL (160 mg) four times daily. All nebulizers were equipped with an on/off device or a Y-connector such that nebulization occurred only when the patient inhaled. This option facilitated maximal delivery of lidocaine to the patient's airway and prevented loss of medication into the surrounding air and room. If symptoms of coughing or chest tightness occurred after lidocaine nebulization, spirometry was performed before and 15 minutes after lidocaine nebulization. If no substantial decrease in airflow was observed (more than 12% reduction in forced expiratory volume in I second), the treatments were continued. Use of lidocaine was discontinued in one patient (case 17, Table I) because of subjective chest tightness; however, no airflow decline was observed after treatment, and results of a skin test to lidocaine were negative. All patients were asked to abstain from eating and drinking for 1 hour after treatment because lidocaine produces partial oropharyngeal and laryngeal topical anesthesia. Other Medications.-During therapy with lidocaine, the patients continued all nonglucocorticoid medications, including orally administered theophylline, at their prescribed dosages except for cromolyn sodium, which was discontinued at the start of the lidocaine treatment. P2-Agonist therapy or other bronchodilator treatment, such as ipratropium bromide, was used as "rescue" therapy every 4 hours as needed only during symptoms of coughing, wheezing, and shortness of breath and, if needed, before exercise. No patient was receiving oral132-agonist therapy. All topically and systemically administered glucocorticoids were initially maintained at their prior dosages, and all patients were treated with nebulized lidocaine for at least I week before a decrease in glucocorticoid dose was attempted. If

peak flow rates remained stable and unchanged and symptoms seemed well controlled, oral doses of glucocorticoids were cautiously and slowly reduced, as limited by the occurrence of corticosteroid-withdrawal side effects and in accordance with the duration and dosage of glucocorticoid treatment. Therapy with inhaled glucocorticoids was continued in all patients for the duration of the lidocaine treatment. Any patient previously involved in a trial of an agent or being treated with an agent, such as troleandomycin, methotrexate, or intravenously administered y-globulin, not yet considered standard treatment for asthma was allowed to continue the medication at the start of lidocaine therapy. If the symptoms of asthma were well controlled, all such treatments were discontinued within 2 weeks after initiation of therapy with nebulized lidocaine. Other medications, such as budesonide in one patient (case 6), were continued while the patient received lidocaine. Monitoring of Patients.-All patients performed daily monitoring of their peak flow rates, were scheduled for regular monthly follow-up visits for at least 5 months, had pulmonary function testing at least every 2 months, and were contacted every 2 to 4 weeks by telephone. Complete blood cell counts with differential leukocyte counts, serum chemistry group, and urinalysis were performed every 2 to 3 months, and serum lidocaine levels were measured on all patients both before and 15 minutes after inhaled lidocaine treatment at the initiation of therapy and if the dose was increased.

RESULTS A summary of information for the 20 patients treated with nebulized lidocaine for a mean of 12.2 months (median, 12; range, I to 26) is presented in Table 1. Their mean age was 44.6 years (median, 41.5; range, 19 to 71), and the mean duration of asthma was 19.1 years (median, 17.5; range, 4 to 50). All patients were glucocorticoid-dependent and had been treated with prednisone for a mean of 6.5 years (median, 3; range, 0.3 to 32). Their mean individual daily prednisone requirement was 24 mg (median, 13; range, 3 to 65). All patients had chronic rhinitis, seven had nasal polyposis, and eight were sensitive to aspirin. Eleven patients had positive results of allergy skin tests to common inhalant allergens. One patient was using budesonide aerosol, and five had previously achieved no reduction in corticosteroid dose with trials of troleandomycin or methotrexate. In addition, topically applied deflazacort had failed to be beneficial in three patients, as had intravenously administered y-globulin and dapsone in one each. All patients required rescue therapy with P2-agonists or ipratropium, and II patients were taking theophylline. In the past, treatment of all patients with cromolyn sodium had yielded no benefit

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364

EFFECT OF NEBULIZED LIDOCAINE ON SEVERE ASTHMA

Mayo Clin Proc, April 1996, Vol 71

in terms of control of symptoms or reduction of glucocorticoid dosage. The adverse effects from long-term use of glucocorticoids are also summarized in Table I. All but three patients had cushingoid habitus and prominent weight gain, and several had glucose intolerance, myopathy, osteoporosis, cataracts, glaucoma, mood alteration, or peptic ulcer disease. When the serum lidocaine level was determined, no measurable (more than 0.5 ug/ml.) blood levels were found in any patient within 15 minutes after a nebulized lidocaine treatment, including the patient who received individual nebulized doses of 160 mg. The clinical course of the patients after initiation of nebulized lidocaine therapy is shown in Table 1. During a mean of 12.2 months of treatment, the reduction in prednisone dose was striking; 17 of 20 patients were able to reduce the amount of prednisone needed by 80 to 100% of their initial maintenance dosage. The other three patients (cases 9, 13, and 17) had no noticeable improvement. Another patient (case 2) reduced the prednisone dosage from 55 mg to 4 mg daily. Subsequently, however, she became discouraged because of prominent glucocorticoid withdrawal effects, a recurrence of previously suppressed chronic urticaria, and three asthma flares that lasted 7 to 10 days each. She discontinued the lidocaine treatment and resumed the pretreatment prednisone regimen of 55 mg/day. Two patients (cases 5 and 9) were lost to follow-up; one (case 9) discontinued the nebulized lidocaine treatment because of apparent lack of response. Thirteen of 17 patients who responded to therapy with nebulized lidocaine were able to discontinue the oral use of glucocorticoids entirely and had concurrent resolution of many of the side effects of hypercortisolism. These patients, in general, resembled the overall group-with a mean age of 41.7 years (median, 40; range, 19 to 71), a mean duration of prior oral treatment with prednisone of 6.2 years (median, 3.2; range, 0.3 to 32), and a mean oral daily dose of prednisone of 21 mg (median, 13; range, 3 to 65). Pulmonary function spirometric flow-volume curves for three representative patients are shown in Figure 1. Two patients (cases 6 and 18) still required daily administration of prednisone but in decreased dosages; in these patients, better asthma control was achieved with the nebulized lidocaine.

In almost all patients, the factor limiting the rate of prednisone reduction was the occurrence of glucocorticoid withdrawal symptoms. Patients experienced profound side effects of deep aching of the extremities and long bones in conjunction with generalized myalgias, fatigue, listlessness, and occasional mood alteration (most commonly, depression). No side effects of nebulized lidocaine therapy were observed other than bitter taste and an occasional tendency toward regurgitation without nausea (reported by two patients within 1 hour after treatment). Accordingly, these patients were asked to abstain from eating or drinking for at least 3 hours after nebulized lidocaine treatments. Allergic reactions to lidocaine are extremely rare and did not occur in any of our patients. Because of subjective chest tightness after lidocaine nebulization, one patient (case 17) underwent skin tests to lidocaine; the results were negative. Lidocaine treatment was discontinued in this patient because of these symptoms and because no apparent benefit was derived from the treatment. No patient had a history of allergy to topically administered anesthetic agents. The bitter taste of the lidocaine did not cause any patient to discontinue treatment. Several of the patients had upper respiratory infections with exacerbations of asthma that necessitated use of increased doses of prednisone for 7 to 10 days as a "burst." In all patients, these episodes readily responded to prednisone; most impressively, these patients included those who in the past had required much larger doses for flares of asthma. These flares that necessitated glucocorticoid bursts did not affect the overall rate of withdrawal of prednisone therapy in these patients. DISCUSSION Our experience after treating 20 patients with severe glucocorticoid-dependent asthma from 1 to 26 months suggests that nebulized lidocaine in dosages of 40 to 160 mg four times daily has glucocorticoid-sparing effects. Of the 20 patients, 17 were able to reduce their oral prednisone doses by 80 to 100%. Thirteen patients were able to discontinue oral prednisone therapy, even though one of them had been dependent on such drugs for more than 3 decades. Results of pulmonary function tests remained stable or improved in all patients. Symptoms of glucocorticoid withdrawal were prominent and at times severe. In 17 patients, either all or

Fig. 1. Pulmonary function spirometric flow-volume curves determined in three patients: Top Panel, case 1; Middle Panel, case 3; Bottom Panel, case 7. Flow-volume curves on the left were determined during (cases 3 and 7) or 2 days after (case 1) a hospitalization for severe asthma. Flow-volume curves in the center were determined during outpatient follow-up visits 6 to 12 months after hospitalization and show normalization of pulmonary function while the patients were treated with their usual dosage of prednisone required to maintain control of asthma symptoms. Flow-volume curves on the right reflect pulmonary function during therapy with nebulized lidocaine from 4 to 8 months after discontinuation of prednisone treatment.

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EFFECT OF NEBULIZED LIDOCAINE ON SEVERE ASTHMA

Mayo Clin Proc, April 1996, Vol 71

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366

EFFECT OF NEBULIZED LIDOCAINE ON SEVERE ASTHMA

Mayo Clin Proc, April 1996, Vol 71

some of the physical appearances of hypercortisolism disappeared. Several patients continued to have occasional episodes of coughing and wheezing; in addition, upper respiratory infections led to occasional exacerbations. During these flares of asthma, some patients needed short-term oral treatment with glucocorticoids for as long as 7 to 10 days. No side effects of the nebulized lidocaine therapy were observed other than a bitter taste and an occasional tendency toward regurgitation of gastric contents in two patients. Because 9 of the 20 patients originally received 10 mg of prednisone or less, one might conclude that systemically administered glucocorticoids could be withdrawn. These patients, however, were also being treated maximally with inhaled glucocorticoids and had failed at least two attempts at withdrawal of prednisone. Overall for the 20 patients, the median time that prednisone had been given systemically was 3 years. Earlier studies reported that systemic toxic reactions to lidocaine are related to plasma concentrations. For example, serum lidocaine concentrations of 1.5 to 6.0 ug/ml, can cause anxiety, dizziness, or drowsiness, and levels in excess of 8 /-lg/mL can cause visual symptoms, tremors, twitching, or seizures.' None of our patients demonstrated these symptoms, and serum determinations immediately before and within 10 to 15 minutes after nebulized lidocaine treatments of 40 to 160 mg failed to show a measurable blood lidocaine level (all values were less than 0.5 ug/ml.). Reports in the literature indicate that nebulization of 10 mL of a 4% lidocaine solution (400 mg) resulted in serum concentrations of 1.5 to 4.5 ug/ml, 8 minutes later with no signs of toxicity." Direct tracheal and laryngeal spraying with 50 and 100 mg of lidocaine resulted in blood levels of only 1.5 ug/ml, at 10 and 15 minutes after spraying," and mean endobronchial lidocaine doses of 256 mg for bronchoscopy resulted in mean blood lidocaine levels of 3 /-lg/mLor less at 10, 15, and 30 minutes in 14 subjects.'? Finally, blood levels after lidocaine nebulization to the airway are extremely low; levels of less than 1.5 ug/ml. were noted in patients after nebulized doses as high as 400 to 500 mg. 20 ,2 1 In our study, all patients were given the first lidocaine nebulization under observation, and spirometry was performed before and after treatment; no reduction of peak flow or forced expiratory volume in 1 second was seen in any patient. Thus, our results differ from those previously reported" in normal persons after instillation of a 10% lidocaine solution. In addition, no patient reported worsening of coughing, wheezing, or chest tightness from the use of nebulized lidocaine. In one patient who reported chest tightness after lidocaine nebulization, results of spirometry were unchanged after two nebulizations under observation. Lidocaine is a potent suppressor of irritant-induced coughing and for many years has been used to achieve topical anesthesia of the airway for both bronchography-v"

and bronchoscopy.f-" Numerous reports have shown beneficial effects of lidocaine on a chronic and persistent cough'"" and cough induced by capsaicin," distilled water aerosol," or citric acid." In many of these experimental systems, cough and bronchoconstriction seemed to be separable effects. For example, lidocaine inhibited coughing but did not inhibit bronchoconstriction in patients with asthma induced by distilled water nebulization.F similar results were obtained after inhalation of leukotriene D4 in normal subjects." In primates, lidocaine at a concentration of 5% (but not at 1%) blocked bronchoconstriction induced by methacholine." In patients with asthma, inhalation of lidocaine at doses of 1 mg/kg inhibited exercise-induced bronchospasm.v The aforementioned effects were short-term observations, and we believe it unlikely that the improvement in our patients can be explained on this basis. On the basis of the discovery that lidocaine potently inhibits the in vitro activity of eosinophil-active cytokines, we assume that nebulized lidocaine has anti-inflammatory effects and blocks eosinophil survival in vivo in a manner similar to its ability to block cytokine-mediated eosinophil viability potently in vitro. Although lidocaine is metabolized in the liver, we are not aware that it affects hepatic glucocorticoid metabolism in a fashion similar to troleandomycin. That is, when glucocorticoid dosages were reduced in our patients, profound glucocorticoid withdrawal effects and loss of cushingoid features occurred. Likewise, the beneficial effect of lidocaine persists even after orally administered glucocorticoids have been withdrawn. Nonetheless, lidocaine is not a cure for asthma because exacerbations still occur. After discontinuing oral glucocorticoid therapy for 6 to 9 months, two of our patients (cases 1 and 3) subsequently stopped taking lidocaine, and they had only mild symptoms of asthma, usually after exercise. Later, both patients had flares of asthma and required 10 to 14 days of oral prednisone treatment; they resumed treatment with nebulized lidocaine and were able to discontinue prednisone therapy. Potential anti-inflammatory activities of lidocaine have not been addressed previously. In a recent study, an inhibitory activity against the neutrophil oxidant, hypochlorous acid, was found in bronchoalveolar lavage samples; subsequently, the inhibitory substance was identified as lidocaine used for topical anesthesia during the bronchoscopic procedure." Whether this apparent antioxidant mechanism might have potential therapeutic benefits was not investigated. If lidocaine has similar effects on the hypohalous system of inflammatory oxidants produced by the eosinophil, which in contrast to the neutrophil seems to generate hypothiocyanous acid," it suggests an additional potential mechanism of benefit in the treatment of asthma.

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Mayo Clio Proc, April 1996, Vol 71

Interestingly, three of our patients (cases 9, 13, and 17) had no measurable benefit from the nebulized lidocaine, as evidenced by persistent asthma; indeed, one patient (case 9) had an additional hospitalization with intubation and mechanical ventilation and no measurable reduction in her daily prednisone dosage of 40 to 50 mg. As shown by Wallen and colleagues," glucocorticoids are potent inhibitors of eosinophil survival, but the inhibitory effect can be overcome by increasing doses of eosinophil-active cytokines (IL 3, IL 5, and granulocyte-macrophage colony-stimulating factor). Thus, at least one mechanism of glucocorticoid resistance in asthma may be inflammation caused by high concentrations of these cytokines.

EFFECTOF NEBULIZED LIDOCAINE ON SEVEREASTHMA

6. 7.

8. 9. 10.

CONCLUSION The results in our current study suggest that regularly nebulized lidocaine is beneficial to patients with severe asthma and has glucocorticoid-sparing activity. The potential mechanisms of lidocaine activity are unknown, and our findings warrant further studies with double-blind, placebo-controlled trials. These trials will need to examine the effect of lidocaine on bronchial fluid eosinophil numbers and mediators and the effect on bronchial fluid cytokine levels. Blinding will be difficult in that inhalation of lidocaine always causes topical anesthesia of the larynx and pharynx. Additional in vitro studies of the ability of lidocaine to interfere with cytokine activation, increased survival, and degranulation of eosinophils and the potential blocking effects of lidocaine on eosinophil-generated reactive oxidant species will also be of interest.

11. 12. 13. 14. 15.

16.

ACKNOWLEDGMENT We thank Cheryl R. Adolphson and Linda H. Arneson for assistance with the preparation of the submitted manuscript.

17.

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23. 24. 25. 26.

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EFFECT OF NEBULIZED LIDOCAINE ON SEVERE ASTHMA

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TEXT BITES FROM OTHER JOURNALS

... high rates of compliance and cure can be achieved on a mass scale and in a short time by means of directly observed short-course chemotherapy and the WHO [World Health Organization] technical strategy for effective tuberculosis control. -Lancet 1996; 347:358-362 Heavy marijuana use is associated with residual neuropsychological effects even after a day of supervised abstinence from the drug. However, the question remains open as to whether this impairment is due to a residue of drug in the brain, a withdrawal effect from the drug, or a frank neurotoxic effect of the drug. -lAMA 1996; 275:521-527 The concomitant administration of losartan potassium, 50 mg, with 12.5 mg of hydrochlorothiazide once daily produced an additive reduction in trough sitting systolic and diastolic blood pressure and was well tolerated. -Arch Intern Med 1996; 156:278-285 Intensive therapy and the attendant risk for hypoglycemia were not associated with neuropsychological impairment in the DCCT [Diabetes Control and Complications Trial]. -Ann Intern Med 1996; 124:379-388 Passive smoking is associated with dose-related impairment of endothelium-dependent dilatation in healthy young adults, suggesting early arterial damage. -N Engl 1 Med 1996; 334:150-154

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