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Attenuation of isocapnic hyperpnoea-induced guinea-pig bronchoconstriction by chronic hypoxia.

Chronic hypoxia has been shown to augment the production of antioxidants in rat lungs and to reduce airway hyperreactivity in patients with asthma. This study investigated indirectly whether this increase in antioxidants occurs in guinea-pig lungs and whether the increased antioxidants affect hyperpnoea-induced bronchoconstriction (HIB). Guinea-pigs were divided into four groups: control (n=8); chronic hypoxia (n=7); capsaicin pretreatment (n=7); and capsaicin pretreatment plus chronic hypoxia (n=8). Control animals were not treated. Animals in the hypoxia group were intermittently exposed to an ambient pressure of 380 mmHg for 7 days. A five day pretreatment of capsaicin was used to deplete tachykinins. In the last group, animals were pretreated with capsaicin, followed by a seven day hypoxic exposure. On the day of the study, airway function was examined in the anaesthetized and paralysed animal. Fifteen minutes of hyperpnoea caused marked decreases in the maximal expiratory flow rate at 15% vital capacity, forced expiratory volume in one second, and dynamic respiratory compliance, indicating HIB. This HIB and plasma substance P levels were significantly attenuated by chronic hypoxia, capsaicin pretreatment, and capsaicin pretreatment plus chronic hypoxia. Furthermore, chronic hypoxia attenuated airway constriction induced by xanthine-xanthine oxidase. The results suggest that chronic hypoxia attenuates hyperpnoea-induced bronchoconstriction via a decrease in the oxygen radical-mediated release of tachykinins.

Animals↗

Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma.

Exercise-induced bronchoconstriction (EIB) is widely prevalent in asthmatic patients. Eosinophilic airway inflammation is considered to be a major factor in the pathogenesis of asthma. However, the effects of eosinophilic airway inflammation on EIB have been elucidated insufficiently. To examine the relationship between the severity of EIB and eosinophilic inflammation, sputum induction and exercise challenge were performed in 21 asthmatic patients. Significantly higher percentages of eosinophils and levels of eosinophil cationic protein (ECP) were found in induced sputum in EIB-positive asthmatics (median (range), eosinophils: 23.5 (11.0-61.0)%; ECP: 1,475 (74.8-17,701) ng x mL(-1)) than in EIB-negative asthmatics (eosinophils: 6.0 (1.0-41.5)% (p=0.006); ECP: 270.6 (10.8-7,700) ng x mL(-1) (p=0.049)). There was a significant correlation between the severity of EIB and the sputum eosinophil percentage (r=0.59, p=0.009) and the level of ECP (r=0.47, p=0.037). The area under the curve of the forced expiratory volume in one second for 30 min after exercise correlated with the percentage of eosinophils (r=0.60, p=0.008) and the level of ECP (r=0.45, p=0.04). There was no correlation between airway responsiveness to methacholine on the one hand and EIB, sputum eosinophils or ECP on the other. In conclusion, these results provide evidence that the severity of bronchoconstriction evoked by exercise is more closely related to eosinophilic airway inflammation than airway hyperresponsiveness to methacholine in asthmatic patients.

Adolescent↗

Effects of cysteine donor supplementation on exercise-induced bronchoconstriction.

PURPOSE: Reactive oxygen/nitrogen species (ROS/RNS) in resident airway cells may be important in bronchoconstriction following exercise. Glutathione (GSH) is a major lung antioxidant and could influence pathological outcomes in individuals with exercise-induced bronchoconstriction (EIB). This study examined the effects of supplementation with undenatured whey protein (UWP) in subjects exhibiting airway narrowing following eucapnic voluntary hyperventilation (EVH), a surrogate challenge for diagnosis of EIB. UWP is a cysteine donor that augments GSH production. METHODS: In a randomized, double-blind, placebo-controlled study, 18 EIB-positive subjects (age: 25.2 +/- 9.01 yr; weight: 77.3 +/- 18.92 kg; height: 1.7 +/- 0.09 m) with post-EVH falls of > or =10% in FEV1 received 30 g UWP (TX) or casein placebo (PL)/d. Subjects performed 6-min EVH challenges before and after 4 and 8 wk of supplementation. Exhaled nitric oxide (eNO) was measured serially before spirometry and at 1-wk intervals. Spirometry was performed pre- and 5, 10, and 15 min postchallenge. RESULTS: Subjects exhibited significant mean improvement in postchallenge falls in FEV(1) from 0 wk (-22.6 +/- 12.22%) with TX at 4 (-18.9 +/- 12.89%, P < 0.05) and 8 wk (-16.98 +/- 11.61%, P < 0.05) and significant mean reduction in post-EVH peak falls in FEF(25-75) from 0 wk (-40.6 +/- 15.28%) with TX at 4 (-33.1 +/- 17.11%, P < 0.01) and 8 (-29.7 +/- 17.42%, P < 0.05) wk. No changes in FEV(1) or FEF(25-75) were observed in the PL group at any time point. Mean eNO for PL and TX groups at 0, 4, and 8 wk (46.8 +/- 31.33, 46.5 +/- 35.73, 49.3 +/- 37.12 vs 35.2 +/- 26.87, 29.1 +/- 17.26, 34.7 +/- 21.11 ppb, respectively) was not significantly different. CONCLUSIONS: UWP may augment pulmonary antioxidant capacity and be therapeutically beneficial in individuals exhibiting EIB, as postchallenge pulmonary function improved with supplementation. The lack of significant change in eNO suggests that the pulmonary function improvements from UWP supplementation are independent of eNO.

Administration, Oral↗

[Effects of flutropium bromide, a new anti-asthma drug, alone or in combination with salbutamol, aminophylline and disodium cromoglycate on the acetylcholine induced bronchoconstriction].

Effects of flutropium bromide, a new bronchodilator with an anticholinergic action, alone or in combination with other antiasthma drugs were investigated in guinea pigs by using an index of inhibition of the acetylcholine (ACh)-induced bronchoconstriction. Single inhalation of flutropium bromide (0.0003%) into the airways of guinea pigs inhibited the ACh (i.v.)-induced bronchoconstriction without changing the fall in blood pressure induced by ACh. When salbutamol (3 micrograms/kg, i.v.), aminophylline (5 mg/kg, i.v.) or disodium cromoglycate (10 mg/kg, i.v.) was administered in combination with flutropium bromide (0.0003%), bronchodilation was enhanced as compared with single administration of the respective antiasthma drugs. From the above results, it is indicated that inhalation of flutropium bromide provides a more efficient bronchodilation in combination with other antiasthma drugs that possess different mechanisms of antiasthma effects.

Acetylcholine↗

Inhibitory effect of the newly synthesized pyridazinone derivative NZ-107 on bronchoconstriction induced by slow reacting substance of anaphylaxis in the guinea pig.

We have investigated the effect of a newly synthesized compound NZ-107, 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone, on bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A) in the guinea pig. Orally administered NZ-107 (10 mg/kg, 2 hr) inhibited antigen-induced SRS-A-mediated bronchoconstriction in sensitized guinea pigs. NZ-107 (2 mg/kg, i.v., 1 min) prevented the antigen-induced response about as well as the SRS-A antagonist FPL-55712 and rapidly reversed it. This rapid reversal by NZ-107 but not FPL-55712 also appeared with the leukotriene (LT) D4-induced contraction of the isolated trachea. NZ-107 more selectively inhibited the LTD4 response than those of histamine, acetylcholine and KCl. Compared to FPL-55712, NZ-107 was one-fifteenth less potent in inhibiting the LTD4 response, but two-fold more potent in inhibiting the LTC4 response. NZ-107 inhibited the LTD4 response of the trachea 10-fold more potently than that of the ileum (-log IC50: trachea 5.61, ileum 4.56). The combination of NZ-107 (1 microM) with the beta-agonist isoproterenol had no synergistic effect on the LTD4 response, but those of theophylline and papaverine had large effects. From these results, NZ-107 is a selective inhibitor of the SRS-A response and may be useful in the therapy of bronchial asthma and other diseases in which the LTs are thought to be involved.

Animals↗

Immunopharmacological studies on TBX, a new antiallergic drug (3). Inhibitory effects on histamine release from lung fragments and bronchoconstriction in guinea pigs.

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10(-7) to 10(-4) g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum. Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF, i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v.). However, high concentrations of TBX (more than 3 x 10(-4) g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10(-5) g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2 alpha-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction, possibly by interfering with mediator release.

Animals↗

Gastroesophageal reflux-induced bronchoconstriction. Is microaspiration a factor?

STUDY OBJECTIVE: To evaluate the role of microaspiration in gastroesophageal reflux-induced bronchoconstriction. DESIGN: Prospective study blinded to the subject. SETTING: Outpatient laboratory of a 908-bed university hospital. PARTICIPANTS: Thirty nonsmoking adults divided into two groups: asthmatics with reflux (AR), 20; and subjects with gastroesophageal reflux (R), 10. INTERVENTIONS: Dual esophageal pH probe placed. Esophageal infusions of normal saline solution, 0.1N hydrochloric acid, then normal saline solution, each lasting 18 min, were followed by two 20-min recovery periods. Subjects remained in the supine position throughout. Spirometry and specific airway resistance (SRaw) performed at baseline, after each esophageal infusion and recovery period. Proximal esophageal acid exposure, a requirement for microaspiration, was assessed by the proximal esophageal pH probe. RESULTS: Peak expiratory flow rate (PEF) decreased with esophageal acid in the AR group and did not recover immediately despite esophageal acid clearance with a significant main effect of subject groups (p < 0.021) by repeated measures analysis of covariance. This decrease in PEF was not associated with the presence of proximal esophageal acid exposure (p = 0.618). Specific airway resistance increased in the AR group with esophageal acid and worsened despite acid clearance, especially during the second recovery phase, with a significant phase (p < 0.009) and group by treatment effect (p < 0.009). The presence of proximal esophageal acid exposure was not associated with this deterioration in SRaw (p = 1.0). CONCLUSIONS: Esophageal acid infusions given in the supine position caused a decrease in PEF and an increase in SRaw in the asthma with reflux group, which did not improve despite acid clearance. These responses were not dependent on proximal esophageal acid exposure. Also, SRaw continued to worsen during the recovery phase in the AR group, which may represent a delayed bronchoconstrictor effect. These data suggest that microaspiration does not play a significant role in esophageal acid-induced bronchoconstriction.

Adult↗

The protective effect of salbutamol inhaled using different devices on methacholine bronchoconstriction.

STUDY OBJECTIVE: To determine the protective effect of salbutamol, 100 microg, inhaled by different devices (pressurized metered-dose inhaler [pMDI; Ventolin; GlaxoWellcome; Greenford, UK], pMDI + spacer [Volumatic; GlaxoWellcome], or breath-activated pMDI [Autohaler; 3M Pharmaceuticals; St. Paul, MN]) on bronchoconstriction induced by methacholine. DESIGN: Randomized, double-blind, cross-over, placebo-controlled study. PATIENTS: Eighteen subjects with stable, moderate asthma, asymptomatic, receiving regular treatment with salmeterol, 50 microg bid, and inhaled beclomethasone dipropionate, 250 microg bid, in the last 6 months, with high hyperreactivity to methacholine (baseline provocative dose of methacholine causing a 20% fall in FEV(1) [PD(20)] geometric mean [GM], 0.071 mg). Subjects were classified into two groups: subjects with incorrect (n = 5) pMDI inhalation technique, and subjects with correct (n = 13) inhalation technique. METHODS AND MEASUREMENTS: After cessation of therapy for 3 days, all subjects underwent four methacholine challenge tests, each test 1 week apart, each time 15 min after inhalation of salbutamol, 100 microg (via pMDI, pMDI + spacer, or Autohaler), or placebo. The protective effect on methacholine challenge test was evaluated as the change in the PD(20), and expressed in terms of doubling doses of methacholine in comparison with placebo treatment. RESULTS: The PD(20) was significantly higher after salbutamol inhalation than after placebo inhalation, but no significant difference was observed among the three different inhalation techniques. Only when salbutamol was inhaled via pMDI + spacer, PD(20) was slightly but not significantly higher (pMDI GM, 0.454 mg; pMDI + spacer GM, 0.559 mg; and Autohaler GM, 0.372 mg; not significant [NS]) than other inhalation techniques. Similar results (mean +/-SEM) were obtained with doubling doses of methacholine (pMDI, 2 +/- 0.47; pMDI + spacer, 3 +/- 0.35; and Autohaler, 2.4 +/- 0.40; NS). No significant difference was found among techniques when subjects with correct or incorrect inhalation technique were separately considered. CONCLUSIONS: Our data show that the protective effect of salbutamol, 100 microg, on methacholine-induced bronchoconstriction is not affected by the different inhalation techniques, although inhalation via pMDI + spacer tends to improve the bronchoprotective ability of salbutamol. These data confirm the clinical efficacy of salbutamol, whatever the device, and the patient's inhalation technique.

Adolescent↗

Exhaled nitric oxide as a predictor of exercise-induced bronchoconstriction.

INTRODUCTION: Exercise-induced bronchoconstriction (EIB) is present in 40 to 90% of patients with asthma. Exhaled NO (eNO) levels have been correlated with bronchial hyperresponsiveness to methacholine, and have correlated with the degree of decrease in FEV(1) with exercise. The purpose of our study was to examine whether eNO measurements prior to or after exercise could be used as a surrogate marker of exertional bronchoconstriction in a population referred specifically for the evaluation of EIB. METHODS: We studied 50 consecutive subjects without a history of asthma who were referred for the clinical evaluation of EIB. eNO levels were measured prior to exercise challenge and every 5 min for a total of 30 min after exercise. Forced expiratory flows were measured prior to and serially after exercise challenge. RESULTS: Seven subjects had a decrease in FEV(1) of > or = 15% with exercise. The mean eNO level prior to exercise was 41 parts per billion (ppb) [median +/- SD, 23 +/- 42.2 ppb] in the EIB group and 25.6 ppb (median, 19.95 +/- 18.47 ppb) in the group without EIB. A receiver operator characteristic curve yielded a value of 0.636. When using an eNO level of < 12 ppb, the sensitivity, specificity, negative predictive value, and positive predictive value for EIB were 1.0, 0.31, 0.19, and 1.0, respectively; therefore, no one with a baseline eNO of < 12 ppb demonstrated EIB. CONCLUSIONS: No subjects with very low pre-exercise eNO levels (< 12 ppb) demonstrated bronchial hyperresponsiveness to exercise. eNO measurement may obviate the need for bronchoprovocation testing in patients who complain of exertional dyspnea.

Adult↗

Attenuation of the metabisulfite-induced bronchoconstrictive response by pretreatment with cromolyn.

In a retrospective analysis of 1,544 patients who underwent provocative challenge with metabisulfite at the National Jewish Center between 1983 and 1987, an abnormal airway response to metabisulfite was found in 52 patients, an incidence of 3.4 percent. There was no relationship between this abnormal airway responsiveness to metabisulfite and the degree of airway obstruction present, or the degree of airway reactivity as assessed by the response to inhaled bronchodilator or exercise testing. In a pilot study, we found that the administration of cromolyn sodium prior to metabisulfite challenge markedly attenuated the abnormal bronchoconstrictive response in nine of ten patients. We conclude that a metabisulfite-induced bronchoconstrictive response cannot be predicted on the basis of the degree of airway obstruction or airway reactivity and that pretreatment with cromolyn sodium may attenuate the abnormal response.

Adolescent↗

The effect of caffeine on exercise-induced bronchoconstriction.

The effect of caffeine on exercise-induced bronchoconstriction was examined in ten patients with bronchial asthma. Placebo and caffeine 3.5 mg/kg and 7 mg/kg were given two hours before exercise. Spirometry was taken at one and two hours following caffeine and at 5, 15, and 30 minutes following exercise. Caffeine significantly improved baseline FEV1 and prevented exercise-induced bronchoconstriction only at a dose of 7 mg/kg. Caffeine was well tolerated by the patients. These data suggest that only high doses of caffeine significantly prevent a postexercise drop in FEV1.

Adult↗

The participation of the subepithelial airway receptor in the bronchoconstriction of monkeys.

In order to elucidate the mechanism of the bronchial response of monkeys to constrictive stimuli, the effects of pretreatment with aerosolized lidocaine, atropine, and isoproterenol were studied. Treatment with aerosolized lidocaine and atropine not only extinguished the cough reflex, but also decreased bronchial susceptibility to aerosolized methacholine. Moreover, the pretreatment with lidocaine blocked the histamine challenge, but atropine did not. The aerosolized lidocaine decreased the bronchoconstriction induced with methacholine, but not with histamine. Pretreatment with over 1% of isoproterenol did not extinguish the cough reflex. However, this dose of isoproterenol did suppress an increase in Rrs due to the challenge of both methacholine and histamine. Isoproterenol also decreased the bronchoconstriction due to the previous challenge by both methacholine and histamine. The antagonistic effects of lidocaine, atropine, and isoproterenol on the broncho-constriction of monkeys are discussed in relation to the subepithelial receptor.

Aerosols↗

Perception of bronchoconstriction in chronic asthma.

Twenty-nine asthmatic children were studied to assess their ability to detect the severity of their bronchoconstriction. First (STEP 0): each child was asked if he "felt asthma," inviting him to give a self-estimated obstruction score (SEOS) from 0 (no asthma) to 3 (severe asthma) and a baseline FEV1 was recorded. Then (STEP 1): methacholine was administered to all except 9 children with an FEV1 less than 80% of predicted who received saline nebulization and a second SEOS was recorded. Finally: salbutamol aerosol was administered and a third SEOS and FEV1 were obtained (STEP 2). Spearman's correlation coefficients r between SEOS and FEV1 were for the overall population -0.602, -0.517, and -0.104 at STEP 0, STEP 1, and STEP 2, respectively. The r values reduction during the trial can be due either to a decrease of children's concentration during the study or to a real difficulty in recognizing repeated changes in airway status. Some children tend to underestimate their bronchospasm. For these patients an accurate assessment of the severity of the bronchoconstriction requires an objective measurement during acute changes in asthmatic children.

Aerosols↗

[Allergen-induced bronchoconstriction in asthma: antagonistic effect of a synthetic anticholinergic drug (author's transl)].

In ten allergic patients, the effect of inhaltion of increasing quantities of grass pollen on specific airways resistance (SRaw, measured by plethysmography) was estimated after preliminary inhalation of a placebo and of a synthetic anticholinergic drug (SCH 10000). After placebo, the inhalation of grass pollen induced in all cases a bronchoconstriction (mean increase of SRaw : 170 %). After SCH 1000, and for the same quantity of pollen inhaled, seven patients were entirely protected against the bronchoconstrictor effect of the allergen ; for the whole group, the observed bronchoconstriction was significantly lower (p less than 0.01, mean increase of SRaw : 60 %). The possible mechanisms of this protection are discussed. The results suggest that SCH 1000 could be used as a preventive drug in pollinic asthma.

Adult↗

Ventilatory capacity, working capacity and exercise-induced bronchoconstriction in a population sample of subjects with bronchial asthma or chronic bronchitis.

We have studied a representative population sample comprising 185 persons, aged 35-54 years, having certain respiratory symptoms and considered to have chronic bronchitis and/or bronchial asthma. There were 86 with bronchial asthma (without chronic bronchitis), 69 with chronic bronchitis (without asthma) and 30 with both chronic bronchitis and bronchial asthma. Fifty-one of the 116 asthmatics had reaginic bronchial allergy. In the groups with chronic bronchitis or bronchial asthma, the mean ventilatory capacities were slightly below the normal, being 89 and 91%, respectively, of the predicted values for FEV1 and 85 and 87% of those for MVV40. In the group of persons with both diseases, the mean FEV1 was 77% and the mean MVV40 84% of that predicted. Of the 21 persons with a mean FEV1 below 70% of that predicted 10 had both asthma and bronchitis. Exercise-induced bronchoconstriction, defined as a 15% fall of PEF after exercise, occurred in 22 of the 116 asthmatics and in one of the 69 persons with chronic bronchitis without bronchial asthma. In the asthmatics there was a significant correlation between resting PEF or the difference in PEF before and after orciprenaline inhalation on the one hand, and exercise-induced bronchoconstriction on the other hand. This was taken as an indication of increased bronchial hyperreactivity.

Adult↗

Allergic bronchoconstriction and its drug-induced reversal in anesthetized, ovalbumin-sensitized cats.

Cats, once thought to possess little immunological responsiveness, have recently been shown to manifest a wide range of immunologic reactions. Sensitization of cats with ovalbumin rendered the animals capable, after a latency period of 40 to 60 days, of anaphylactic shock upon intravenous challenge. Physiologically the response is characterized by bronchoconstriction as evidenced by an increase in airways resistance. This response was ameliorated by intravenous administration of either aminophylline or isoproterenol. Other reactions elicited upon challenge were dyspnea, cyanosis, and in some instances death. The parameters of the allergic response corresponded with those reported in previous studies of other experimental models of allergic bronchoconstriction.

Airway Resistance↗

Improvement of fog and exercise-induced bronchoconstriction after local and subcutaneous immunotherapy in mite asthma.

We compared the changes of non-specific bronchial hyperreactivity to methacholine, UNDW and exercise in 2 groups of patients with mite asthma treated with local immunotherapy (LIT group: 12 patients) and subcutaneous immunotherapy (SIT group: 8 patients) for 1 year. Bronchial challenges were done 1 week before the beginning and 1 week after the end of 1 year of treatment. The results showed a reduction of bronchial hyperreactivity to methacholine in the LIT group (PD 20FEV1 before: 223 +/- 193, after: 434 +/- 548) but not in the SIT group (PD 20FEV1: before: 143 +/- 188, after: 125 +/- 121) but the difference was not statistically significant. Exercise-induced bronchoconstriction completely disappeared in all the patients of LIT group (8/8) although only in 2 out of 4 patients of SIT group. Water-induced bronchoconstriction improved in 66% of LIT group (4/6) compared with none of SIT group (0/4). We conclude that, with the protocol of the present study, LIT is able to improve, more than SIT, non-specific bronchial hyperreactivity evaluated with osmotic stimuli as exercise and UNDW but not with pharmacologic stimuli as methacholine.

Administration, Inhalation↗

[Transient increase of bispectral index in a patient with bronchoconstriction after endotracheal intubation].

A 62-year-old woman (148 cm, 48.5 kg) with a history of bronchial asthma underwent an emergency appendectomy. Ten days before the operation she developed symptoms of wheezing while under asthma medication. An endotracheal tube (7 mm) was inserted after the induction of general anesthesia with intravenous injection of fentanyl 100 micrograms, propofol 100 mg and vecuronium 10 mg under Sellick's maneuver. Anesthesia was maintained with 1% sevoflurane with oxygen 6l-min-1 just after intubation, but bilateral lung sound soon became weaker and ventilation difficult. Based on a diagnosis of bronchoconstriction, we started hyperventilation with 3% sevoflurane. Ventilation returned to normal after about 5 minutes. Percutaneous O2 saturation was maintained at 100% during this episode, but the BIS transiently rose to 82. Anesthesia was maintained with 2% sevoflurane and 50% nitrous oxide balanced with oxygen, and 250 mg aminophylline was administered. Upon completion of the operation, the endotracheal tube was removed without any events. The patient gave no sign of awareness during the operation. When severe bronchoconstriction prevents the absorption of anesthetics from the lung alveoli, additional intravenous anesthetics should be administered to maintain stable amnesia.

Anesthesia, General↗