Airway Anesthesia Alone Does Not Explain Attenuation of Histamine-induced Bronchospasm by Local Anesthetics: A Comparison of Lidocaine, Ropivacaine, and Dyclonine

Background: Lidocaine inhalation attenuates histamine-induced bronchospasm while evoking airway anesthesia. Because this occurs at plasma concentrations much lower than those required for intravenous lidocaine to attenuate bronchial reactivity, this effect is likely related to topical airway anesthesia and presumably independent of the specific local anesthetic used. Therefore, the authors tested the effect of dyclonine, lidocaine, and ropivacaine inhalation on histamine-induced bronchospasm in 15 volunteers with bronchial hyperreactivity.

Methods: Bronchial hyperreactivity was verified by an inhalational histamine challenge. Histamine challenge was repeated after inhalation of dyclonine, lidocaine, ropivacaine, or placebo on 4 different days in a randomized, double-blind fashion. Lung function, bronchial hyperreactivity to histamine, duration of local anesthesia, and lidocaine and ropivacaine plasma concentrations were measured. Statistical analyses were performed with the Friedman and Wilcoxon rank tests. Data are presented as mean +/- SD.

Results: The inhaled histamine concentration necessary for a 20% decrease of forced expiratory volume in 1 s (PC20) was 7.0 +/- 5.0 mg/ml at the screening evaluation. Lidocaine and ropivacaine inhalation increased PC20 significantly to 16.1 +/- 12.9 and 16.5 +/- 13.6 mg/ml (P = 0.007), whereas inhalation of dyclonine and saline did not (9.1 +/- 8.4 and 6.1 +/- 5.0 mg/ml, P = 0.7268). Furthermore, in contrast to saline and lidocaine, inhalation of both ropivacaine and dyclonine significantly decreased forced expiratory volume in 1 s from baseline (P = 0.0016 and 0.0018, respectively). The longest lasting and most intense anesthesia developed after dyclonine inhalation (48 +/- 13 vs. 28 +/- 8 [lidocaine] and 25 +/- 4 min [ropivacaine]).     

Lidocaine exerts its effect on induced bronchospasm by mitigating reflexes, rather than by attenuation of smooth muscle contraction

BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchoconstriction, as well as bronchoconstriction elicited by mechanical irritation. This effect could be mediated by direct effects on smooth muscle or by reflex attenuation. Therefore, we evaluated whether lidocaine attenuated the bronchial response of direct smooth muscle stimulation with methacholine. METHODS: In 15 volunteers with bronchial hyperreactivity, a methacholine challenge was performed following the inhalation of lidocaine, dyclonine (which does not attenuate bronchial reactivity) or saline on three different days in a randomized, double-blind fashion. Lung function, response to methacholine, and lidocaine and dyclonine plasma concentrations were measured. RESULTS: The inhaled methacholine concentration (PC20) necessary for a 20% decrease in the forced expiratory volume in 1 s (FEV1) was 8.8 +/- 6.1 mg/ml at the screening evaluation. The sensitivity to methacholine challenge (PC20) remained unchanged regardless of which solution was inhaled (9.1 +/- 7.5 mg/ml for lidocaine, 10.2 +/- 9.0 mg/ml for dyclonine and 9.8 +/- 8.3 mg/ml for saline; P = 0.58, means +/- standard deviation). Furthermore, the inhalation of all three solutions caused a significant decrease in FEV1 from baseline (P = 0.0007), with a significantly larger effect for dyclonine than lidocaine (P = 0.0153). CONCLUSIONS: Although both inhaled and intravenous lidocaine attenuates histamine-evoked bronchoconstriction, it does not alter the response to methacholine. Therefore, the attenuation of bronchial reactivity by lidocaine appears to be related solely to neurally mediated reflex attenuation, rather than to the attenuation of direct constriction of airway smooth muscle.     

Both Local Anesthetics and Salbutamol Pretreatment Affect Reflex Bronchoconstriction in Volunteers with Asthma undergoing Awake Fiberoptic Intubation

Background: Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a [beta]2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers.

Methods: Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured. Statistics: Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD.

Results: Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo in-halation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l;P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline.     

Lidocaine inhalation for local anaesthesia and attenuation of bronchial hyper-reactivity with least airway irritation. Effect of three different dose regimens

The inhalation of lidocaine attenuates bronchial hyper-reactivity but also causes airway irritation. However, how lidocaine dose and plasma concentration influence relationships are unknown. Accordingly, we evaluated the effects of three concentrations of lidocaine (1, 4, and 10%, total dose of 0.5, 2.0, and 5.0 mg kg-1, respectively) vs. placebo in 15 mild asthmatic patients, selected by their response to a histamine challenge (decrease in FEV1 > 20% to less than 18 mg mL-1 of histamine [PC20]). Baseline lung function, histamine-induced bronchoconstriction, topical anaesthesia, and lidocaine plasma concentrations were obtained. FEV1 following lidocaine inhalation showed the greatest decrease for the highest dose (from 3.79 +/- 0.15-3.60 +/- 0.15; P = 0.0012). Lidocaine inhalation increased baseline PC20 (6.1 +/- 1.3 mg mL-1) significantly (to 11.8 +/- 3.1, 16.1 +/- 3.3, and 18.3 +/- 4.5 mg mL-1, respectively) with no difference between the two highest doses. The duration of local anaesthesia was not significantly different between lidocaine concentrations of 4% and 10%. Thus, lidocaine inhalation, with increasing concentrations of the aerosolized solution, increases initial bronchoconstriction while significant attenuation of bronchial hyper-reactivity is not further enhanced with increasing concentrations from 4 to 10%. Plasma concentrations of lidocaine were always far below the toxic threshold. In conclusion, when local anaesthesia of the airways is required a lidocaine dose of 2.0 mg kg-1 as a 4% solution can be recommended for local anaesthesia and attenuation of bronchial hyper-reactivity with the least airway irritation.     

Airway anesthesia alone does not explain attenuation of histamine-induced bronchospasm by local anesthetics: a comparison of lidocaine, ropivacaine, and dyclonine

BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchospasm while evoking airway anesthesia. Because this occurs at plasma concentrations much lower than those required for intravenous lidocaine to attenuate bronchial reactivity, this effect is likely related to topical airway anesthesia and presumably independent of the specific local anesthetic used. Therefore, the authors tested the effect of dyclonine, lidocaine, and ropivacaine inhalation on histamine-induced bronchospasm in 15 volunteers with bronchial hyperreactivity. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. Histamine challenge was repeated after inhalation of dyclonine, lidocaine, ropivacaine, or placebo on 4 different days in a randomized, double-blind fashion. Lung function, bronchial hyperreactivity to histamine, duration of local anesthesia, and lidocaine and ropivacaine plasma concentrations were measured. Statistical analyses were performed with the Friedman and Wilcoxon rank tests. Data are presented as mean +/- SD. RESULTS: The inhaled histamine concentration necessary for a 20% decrease of forced expiratory volume in 1 s (PC20) was 7.0 +/- 5.0 mg/ml at the screening evaluation. Lidocaine and ropivacaine inhalation increased PC20 significantly to 16.1 +/- 12.9 and 16.5 +/- 13.6 mg/ml (P = 0.007), whereas inhalation of dyclonine and saline did not (9.1 +/- 8.4 and 6.1 +/- 5.0 mg/ml, P = 0.7268). Furthermore, in contrast to saline and lidocaine, inhalation of both ropivacaine and dyclonine significantly decreased forced expiratory volume in 1 s from baseline (P = 0.0016 and 0.0018, respectively). The longest lasting and most intense anesthesia developed after dyclonine inhalation (48 +/- 13 vs. 28 +/- 8 [lidocaine] and 25 +/- 4 min [ropivacaine]). CONCLUSION: Both lidocaine and the new amide local anesthetic ropivacaine significantly attenuate histamine-induced bronchospasm. In contrast, dyclonine, despite its longer lasting and more intense local anesthesia, does not alter histamine-evoked bronchoconstriction and irritates the airways. Thus, airway anesthesia alone does not necessarily attenuate bronchial hyperreactivity. Other properties of inhaled local anesthetics may be responsible for attenuation of bronchial hyperreactivity.     

Intravenous Lidocaine and Bupivacaine Dose-dependently Attenuate Bronchial Hyperreactivity in Awake Volunteers

Background: In standard textbooks, intravenous lidocaine is recommended for intubation of patients with bronchial hyperreactivity. However, whether and to what extent intravenous local anesthetics attenuate bronchial hyperreactivity in humans is unknown. Accordingly, nine awake volunteers with known bronchial hyperreactivity were subjected to an inhalational challenge with acetylcholine before and during intravenous infusion of lidocaine, bupivacaine, or placebo in a randomized, double-blinded fashion.

Methods: Baseline acetylcholine threshold concentrations were determined 3-5 days before initiation of the investigation. The response to the acetylcholine challenge was defined as hyperreactive, if forced expiratory volume in 1 s decreased by at least 20%. In addition, the acetylcholine threshold for a 100% increase in airway resistance was obtained by body plethysmography. On seven different days, the acetylcholine challenge was repeated at the end of a 30-min intravenous infusion period of three doses of lidocaine (1, 3, and 6 mg *symbol* min sup -1) or bupivacaine (0.25, 0.75, and 1.5 mg *symbol* min sup -1), during saline placebo infusion, respectively. Acetylcholine-threshold concentrations were presented with the respective plasma concentrations of the local anesthetic.

Results: The infusion of lidocaine and bupivacaine resulted in plasma concentrations (means+/-SD) of 0.29+/-0.11, 1.14 +/-0.39, and 2.02+/-0.5 micro gram *symbol* ml sup -1 for lidocaine and 0.11+/-0.04, 0.31+/-0.09, and 0.80 +/-0.18 micro gram *symbol* ml sup -1 for bupivacaine, respectively. Compared to baseline, the acetylcholine threshold for a 20% decrease of forced expiratory volume in 1 s as well as the threshold for a 100% increase in total airway resistance increased significantly with increasing plasma concentrations of both local anesthetics. Compared to placebo, acetylcholine threshold was almost quadrupled for lidocaine and tripled for bupivacaine with the highest plasma concentration of each local anesthetic.     

Both local anesthetics and salbutamol pretreatment affect reflex bronchoconstriction in volunteers with asthma undergoing awake fiberoptic intubation

BACKGROUND: Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a beta2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured. Statistics: Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD. RESULTS: Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo inhalation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l; P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline. CONCLUSION: In asthmatics, awake fiberoptic intubation evokes a more than 50% decrease in FEV1 following dyclonine inhalation. Using lidocaine for topical anesthesia the decrease in FEV1 is significantly mitigated (35%) and can be even further attenuated by salbutamol pretreatment. Therefore, combined treatment with lidocaine and salbutamol can be recommended for awake intubation while the use of dyclonine, despite its excellent and longer lasting topical anesthesia, may be contraindicated in patients with bronchial hyperreactivity.     

Prevention of Lidocaine Aerosol-induced Bronchoconstriction with Intravenous Lidocaine

Background: Lidocaine applied topically provokes bronchoconstriction in persons with hyperreactive airway disease. The authors questioned whether intravenous lidocaine would prevent lidocaine-aerosol induced bronchoconstriction. They compared the effects of lidocaine administered intravenously and by the aerosol route on baseline airway tone, and on the prevention of histamine-induced bronchoconstriction in five Basenji-Greyhound dogs.

Methods: Dogs were pretreated with either intravenous or aerosol lidocaine followed by histamine aerosol challenge. On separate days, dogs were pretreated with intravenous lidocaine, followed by aerosol lidocaine administration at similar doses. Airway caliber was assessed using high-resolution computed tomography. Data were analyzed by two-way analysis of variance. Serum lidocaine concentrations were obtained.

Results: Histamine alone decreased the airway area by 32 +/- 3%. Lidocaine administered intravenously or by the aerosol route significantly inhibited histamine-induced bronchoconstriction. There was no significant difference between the two routes in preventing histamine-induced bronchoconstriction. At the dose that inhibited histamine-induced bronchoconstriction, lidocaine administered by the aerosol route decreased baseline airway area by 27 +/- 3% (P <0.01), whereas intravenous lidocaine had no effect. Intravenous lidocaine prevented lidocaine aerosol-induced bronchoconstriction, and the combination of intravenous and aerosol lidocaine significantly dilated the airways by 20 +/- 5% (P < 0.01 compared with control).     

Changes in bronchial responsiveness to histamine at intervals after allergen challenge.

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.     

Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.     

Lidocaine inhalation attenuates the circulatory response to laryngoscopy and endotracheal intubation.

STUDY OBJECTIVE: To evaluate the effect of lidocaine inhalation on the circulatory response to direct laryngoscopy and endotracheal intubation. DESIGN: Prospective, randomized study. SETTING: Operating theater at a public hospital. PATIENTS: Eighty patients (ASA physical status I and II ages 25 to 45 years) scheduled for major abdominal surgery. INTERVENTIONS: In the first stage, 40 patients were randomly assigned to receive inhalation of either lidocaine 40 mg or a 0.9% solution of sodium chloride (placebo). In the second stage, the next 20 consecutive patients received inhalation of lidocaine 120 mg, and another 20 consecutive patients received intravenous (IV) lidocaine 1 mg/kg. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure rose significantly in the i.v. lidocaine group (21.2 mmHg; p < 0.05), the saline inhalation group (29.2 mmHg; p < 0.05), and the lidocaine 40 mg inhalation group (22.9 mmHg; p < 0.05), but not in the lidocaine 120 mg inhalation group (10.1 mmHg). The heart rate (HR) response to intubation with lidocaine inhalation was dose dependent. In the saline inhalation group, HR increased by 15.6 beats per minute (bpm) (p < 0.05); in the lidocaine 40 mg inhalation group, HR increased by 9.1 bpm (p < 0.05); and in the lidocaine 120 mg inhalation group, HR increased by only 3.1 bpm. CONCLUSION: Inhalation of lidocaine 120 mg prior to induction of anesthesia is an effective, safe, and convenient method to attenuate the circulatory response to laryngoscopy and endotracheal intubation.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.     

Concentration-effect Relations for Intravenous Lidocaine Infusions in Human Volunteers: Effects on Acute Sensory Thresholds and Capsaicin-evoked Hyperpathia

Background: Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation that can be regulated by systemically administered lidocaine. The authors extended these preclinical studies to human volunteers by examining the concentration-dependent effects of intravenous lidocaine on acute sensory thresholds and facilitated processing induced by intradermal capsaicin.

Methods: Fifteen healthy persons received a lidocaine or a placebo infusion. A computer-controlled infusion pump targeted sequential stepwise increases in plasma lidocaine concentration steps of 1, 2, and 3 micro gram/ml. At each plasma concentration, neurosensory testing (thermal and von Frey hair test stimulation) were performed. After completing the tests at the 3 micro gram/ml plasma lidocaine level, intradermal capsaicin was injected into the volar aspect of the left forearm, and the flare response and hyperalgesia to von Frey hair stimulation, stroking, and heat was assessed.

Results: The continuous infusion of lidocaine and placebo had no significant effect on any stimulus threshold. Although intravenous lidocaine resulted in a decrease in all secondary hyperalgesia responses, this was only significant for heat hyperalgesia. Intravenous lidocaine resulted in a significant decrease in the flare response induced by intradermal capsaicin.     

Lidocaine blood levels following aerosolization and intravenous administration.

STUDY OBJECTIVE: To determine whether, following aerosolization of lidocaine for topical airway anesthesia, intravenous (IV) lidocaine produces toxic lidocaine blood concentrations. DESIGN: Randomized, double-blind study. SETTING: University-affiliated hospital. PATIENTS: Forty healthy patients scheduled for outpatient surgery. INTERVENTIONS: The patients received in a randomized, double-blind manner aerosolized lidocaine or placebo followed 10 minutes later by IV lidocaine or placebo. MEASUREMENTS AND MAIN RESULTS: After completion of lidocaine or placebo aerosolization and 2 minutes following IV administration of either lidocaine or the placebo, venous blood samples were obtained. Lidocaine concentration was measured using a homogenous enzyme assay. The group receiving both aerosolized and IV placebo and the group receiving aerosolized lidocaine and an IV placebo had undetectable (less than 0.05 micrograms/ml) serum lidocaine levels. The groups that received either an aerosolized placebo or aerosolized lidocaine and IV lidocaine had similar serum lidocaine concentrations [3.34 +/- 0.46 vs. 3.24 +/- 0.55 micrograms/ml (mean +/- SEM); p greater than 0.05 by Mann-Whitney U test]. CONCLUSION: IV lidocaine can be safely administered following aerosolization of lidocaine in spontaneously breathing patients without producing toxic blood lidocaine concentrations.     

Propranolol inhalation challenge in relation to histamine response in children with asthma.

The relation between airway responsiveness to propranolol and histamine was studied in 32 asthmatic children. Propranolol and histamine were given by nebuliser to a maximum dose of 16 mg/ml and 32 mg/ml respectively and the response was measured as the provocative concentration of agonist causing a 20% fall in FEV1 (PC20). A PC20 histamine value of less than 32 mg/ml was obtained in 24 of the 32 children, of whom 15 had a measurable PC20 propranolol (less than 16 mg/ml). In these 24 children the geometric mean PC20 histamine was 4.5 mg/ml and 14.4 mg/ml respectively in those with and without a measurable PC20 propranolol (p = 0.023). There was a linear relationship between histamine and propranolol PC20 values (r = 0.60), and between PC20 histamine and FEV1 % predicted (r = 0.43), but not between PC20 propranolol and FEV1 % predicted (r = 0.38). In an open time course study in 12 children with asthma recovery of FEV1 after inhaled propranolol was incomplete in seven of the children after 90 minutes. When inhaled propranolol was followed by inhaled ipratropium bromide in a further 11 children FEV1 had returned to baseline in all children after 60 minutes. Thus propranolol inhalation can be used in children with asthma to assess the contribution of the beta adrenergic system to the regulation of bronchial smooth muscle tone. The test has several disadvantages in comparison with histamine provocation-long duration, the prolonged action of propranolol, and the fact that only the children with substantial hyperreactivity to histamine react to propranolol.     

Lack of Impact of Intravenous Lidocaine on Analgesia, Functional Recovery, and Nociceptive Pain Threshold after Total Hip Arthroplasty

Background: The analgesic effect of perioperative low doses of intravenous lidocaine has been demonstrated after abdominal surgery. This study aimed to evaluate whether a continuous intravenous low-dose lidocaine infusion reduced postoperative pain and modified nociceptive pain threshold after total hip arthroplasty.

Methods: Sixty patients participated in this randomized double-blinded study. Patients received lidocaine 1% (lidocaine group) with a 1.5 mg/kg-1 intravenous bolus in 10 min followed by a 1.5 mg [middle dot] kg-1 [middle dot] h-1 intravenous infusion or saline (control group). These regimens were started 30 min before surgical incision and stopped 1h after skin closure. Lidocaine blood concentrations were measured at the end of administration. In both groups, postoperative analgesia was provided exclusively by patient-controlled intravenous morphine. Pain scores, morphine consumption, and operative hip flexion were recorded over 48 h. In addition, pressure pain thresholds and the extent of hyperalgesia around surgical incision were systematically measured at 24 and 48 h.

Results: In comparison with the placebo, lidocaine did not induce any opioid-sparing effect during the first 24 h (median [25-75% interquartile range]; 17 mg [9-28] vs. 15 mg [8-23]; P = 0.54). There was no significant difference regarding the effects of lidocaine and placebo on pain score, pressure pain thresholds, extent in the area of hyperalgesia, and maximal degree of active hip flexion tolerated. Mean plasma lidocaine concentration was 2.1 +/- 0.4 [mu]g/ml.     

Relationship between the acid-induced cough response and airway responsiveness and obstruction in children with asthma.

BACKGROUND: In children with asthma little is known about the direct effect of the bronchoconstrictor and bronchodilator response on the cough threshold, or the relationship between bronchial responsiveness and the cough threshold. A study was undertaken to determine the effect of histamine-induced bronchoconstriction and salbutamol-induced bronchodilatation on the cough threshold in response to inhaled acetic acid, and to examine the relationship between the acetic acid cough threshold and bronchial hyperresponsiveness to histamine in children with asthma. METHODS: Nineteen children with asthma (16 boys) of mean (SE) age 10.6 (0.6) years were enrolled in the study. On day 1 each underwent a histamine inhalation challenge to determine the provocative concentration causing a fall in forced expiratory volume in one second (FEV1) of more than 20% (PC20) as an index of individual bronchial hyperresponsiveness. On day 2 the acetic acid cough threshold was determined before and just after the inhalation of the PC20 concentration of histamine, and then salbutamol (1 mg/m2) was inhaled to relieve the bronchoconstriction. Ten of the 19 patients (eight boys) of mean age 12.2 (0.7) years also tried acetic acid inhalation challenge just after salbutamol inhalation. RESULTS: There was no relationship between the bronchial responsiveness to histamine and acetic acid cough threshold in these patients. The acetic acid cough threshold after histamine inhalation was similar to that before histamine, although FEV1 decreased after histamine. In the 10 patients who also tried acetic acid inhalation challenge after salbutamol the cough threshold did not change. CONCLUSIONS: These findings suggest that acid-induced cough sensitivity and bronchomotor tone are independently regulated in children with asthma.     

Epidural Lidocaine Decreases Sevoflurane Requirement for Adequate Depth of Anesthesia as Measured by the Bispectral Index ® Monitor

Background: Epidural anesthesia potentiates sedative drug effects and decreases minimum alveolar concentration (MAC). The authors hypothesized that epidural anesthesia also decreases the general anesthetic requirements for adequate depth of anesthesia as measured by Bispectral Index (BIS).

Methods: After premedication with 0.02 mg/kg midazolam and 1 [mu]g/kg fentanyl, 30 patients aged 20-65 yr were randomized in a double-blinded fashion to receive general anesthesia with either intravenous saline placebo or intravenous lidocaine control (1-mg/kg bolus dose; 25 [mu]g [middle dot] kg-1 [middle dot] min-1). A matched group was prospectively assigned to receive epidural lidocaine (15 ml; 2%) with intravenous saline placebo. All patients received 4 mg/kg thiopental and 1 mg/kg rocuronium for tracheal intubation. After 10 min of a predetermined end-tidal sevoflurane concentration, BIS was measured. The ED50 of sevoflurane for each group was determined by up-down methodology based on BIS less than 50 (MACBIS50). Plasma lidocaine concentrations were measured.

Results: The MACBIS50 of sevoflurane (0.59% end tidal) was significantly decreased with lidocaine epidural anesthesia compared with general anesthesia alone (0.92%) or with intravenous lidocaine (1 %;P < 0.0001). Plasma lidocaine concentrations in the intravenous lidocaine group (1.9 [mu]g/ml) were similar to those in the epidural lidocaine group (2.0 [mu]g/ml).     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects.

BACKGROUND--It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS--Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS--Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS--Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.