Non-cAMP-mediated bronchial arterial vasodilation in response to inhaled beta-agonists.

We studied the dose-dependent effects of inhaled isoetharine HCl, a beta-adrenergic bronchodilator (2.5, 5.0, 10.0, and 20.0 mg), on bronchial blood flow (Qbr) in anesthetized sheep. Isoetharine resulted in a dose-dependent increase in Qbr. With a total dose of 17.5 mg, Qbr increased from baseline values of 22 +/- 3.4 (SE) to 60 +/- 16 ml/min (P < 0.001), an effect independent of changes in cardiac output and systemic arterial pressure. To further study whether synthesis of endogenous nitric oxide (NO) affects beta-agonist-induced increases in Qbr, we administered isoetharine (20 mg) by inhalation before and after the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Intravenous L-NAME (30 mg/kg) rapidly decreased Qbr by approximately 80% of baseline, whereas L-NAME via inhalation (10 mg/kg) resulted in a delayed and smaller (approximately 22%) decrease. Pretreatment with L-NAME via both routes of administration attenuated bronchial arterial vasodilation after subsequent challenge with isoetharine. We conclude that isoetharine via inhalation increases Qbr in a dose-dependent manner and that beta-agonist-induced relaxation of vascular smooth muscle in the bronchial vasculature is partially mediated via synthesis of NO.

Isoetharine versus albuterol for acute asthma: greater immediate effect, but more side effects.

PURPOSE: To compare the magnitudes of the immediate effects of the nebulized beta-agonists isoetharine and albuterol in the treatment of acute severe asthma. PATIENTS AND METHODS: Fifty-one adults presenting with severe asthma exacerbations (forced expiratory volumes in the first second of exhalation [FEV1] <40% of predicted) to the emergency department were randomized (double-blind) to receive hourly inhaled nebulization treatment with either isoetharine (5 mg) or albuterol (2.5 mg). The FEV1 was measured immediately before and after each nebulized treatment. Any side effects were recorded. RESULTS: Immediately after the first nebulized treatment, the isoetharine group improved its mean FEV1 (+/-SEM) by a significantly greater amount than did the albuterol group: 60% +/- 11% versus 39% +/- 5%, respectively (P <0.05). One hour later the mean FEV1 were equivalent. This pattern repeated itself after the second hourly treatment. The two groups did not differ in any outcome parameters (FEV1 at discharge, number of nebulized treatments required, the number of inpatient admissions, number of clinical relapses after discharge). More patients treated with isoetharine had side effects (36% versus 4% for albuterol, P <0.01), 1 of whom required discontinuation from the study. CONCLUSIONS: Both medications were equally effective in alleviating bronchospasm. The immediate effect of isoetharine was significantly greater, but equalized that of albuterol within an hour after treatment. There were more side effects with isoetharine.

Elevation of breath ethanol measurements by metered-dose inhalers.

STUDY OBJECTIVE: Metered-dose inhalers (MDIs) may contain as much as 38% ethanol. We evaluated the effects of ethanol-containing MDIs on breath alcohol testing. DESIGN: Prospective, single-blind, crossover, controlled study. PARTICIPANTS: Three healthy male volunteers 29 to 36 years old. INTERVENTION: We studied three brands: Tornalate, (38% ethanol), Bronkometer, (30% ethanol), and Alupent, (0% ethanol). The effects of each MDI on breath and blood ethanol measurements were evaluated separately. Two puffs of each brand of MDI were administered. Breath ethanol measurements were obtained at baseline and .25, .5, 1, 2, 3, 5, and 10 minutes after MDI use. Blood ethanol measurements were obtained at baseline and 1 and 10 minutes after MDI use. RESULTS: Overall, Tornalate had the highest breath ethanol readings, with a mean ethanol level of 189 mg/dL recorded just after MDI use. Breath ethanol levels subsequently decreased rapidly over time. Mean breath ethanol concentrations were lower after the use of Bronkometer and undetectable after the use of Alupent. Blood ethanol levels were undetectable at all times tested. CONCLUSION: MDIs may cause elevations of breath alcohol above the legal criteria for intoxication. These effects are transient and may be prevented by a 10-minute interval between the use of an MDI and breath alcohol testing.

Inhaled albuterol powder for pulmonary function testing.

To assess the role of albuterol powder in testing for reversibility of airflow obstruction during routine pulmonary function testing, spirometric data from subjects with baseline FEV1/FVC less than 70 percent and FEV1 less than 80 percent predicted who received inhaled albuterol powder (n = 42) were compared with those who received isoetharine aerosol via metered dose inhaler (n = 49). Prebronchodilator lung function was comparable for the albuterol and isoetharine groups. With albuterol powder, 14 (33 percent) of 42 subjects showed reversibility of airflow obstruction (defined as a 15 percent or greater improvement in either FEV1 or FVC) as compared with 30 (61 percent) of 49 subjects with isoetharine aerosol. The significantly (p less than 0.01) lower rate of improvement with albuterol powder was especially prominent in subjects with moderate airflow obstruction (FEV1/FVC of 45 to 59 percent). These data do not support the substitution of inhaled albuterol powder for isoetharine aerosol in assessing for reversibility of airflow obstruction during routine pulmonary function testing.

Decreased duration of emergency department treatment of chronic obstructive pulmonary disease exacerbations with the addition of ipratropium bromide to beta-agonist therapy.

STUDY OBJECTIVES: To determine the benefit of the addition of ipratropium bromide to beta-agonist therapy of acute exacerbations of chronic obstructive pulmonary disease. DESIGN: The trial was randomized and double blinded. SETTING: The study was conducted in the emergency department of Parkland Memorial Hospital, a busy, inner-city, county hospital. INTERVENTIONS: Patients were treated in the medicine emergency department with either the standard regimen of nebulized isoetharine, 0.5 mL of a 1% solution (5.0 mg) diluted to 2.0 mL with normal saline every hour (control group) or with the same regimen plus ipratropium bromide, 54 micrograms (three puffs) after the first isoetharine treatment and 36 micrograms (two puffs) after the second and fourth (experimental group). A placebo metered-dose inhaler used in the same manner as the ipratropium blinded the study to both the patients and medical personnel. MEASUREMENTS AND MAIN RESULTS: The group treated with the addition of ipratropium (30) was discharged from the ED an average of 91 minutes (P less than .05) sooner than the control group (25) and required on the average one less isoetharine treatment (P less than .05). The pulmonary functions tested, forced expiratory volume in the first second, and the forced vital capacity were the same in the two groups initially and on discharge, as identical discharge criteria were used in each group. CONCLUSION: The addition of ipratropium to standard beta-agonist treatment of chronic obstructive pulmonary disease exacerbations shortens the duration of treatment required in the ED.

A controlled trial of nebulized isoetharine in the prehospital treatment of acute asthma.

Acute asthma is a potentially life-threatening disorder, recognizable to the prehospital care provider. While therapies are available to the prehospital care provider for treating acute asthma, no previous controlled studies have been performed demonstrating the treatment in the field is efficacious and safe. The authors conducted a controlled trial of the prehospital use of nebulized isoetharine in an urban emergency medical services system. Fifty-two patients with acute asthma were studied. Patients were initially evaluated with a peak flow meter. Half of the patients received isoetharine, while the control group received basic life support only. There was no difference in baseline values. Peak expiratory flow increased from 138 L/min to 148 L/min in the control group, while it increased from 149 L/min to 218 L/min in the treatment group (P less than .001). The authors conclude that paramedic treatment of acute asthma with nebulized isoetharine is effective in improving pulmonary function and clinical status during transport.

Combination of atropine and isoetharine aerosol therapy in pediatric acute asthma.

Seventeen hospitalized children with acute asthma, ages 7 to 15 years, were studied to determine the efficacy of simultaneous administration of atropine sulfate and isoetharine. Combination therapy was superior in 11/17 (65%) patients while isoetharine alone was superior in 4/17 (23%) patients (P = .037). We conclude that simultaneous administration of combination therapy is safe and beneficial in some children with acute asthma.

Longitudinal response of pulmonary function to bronchodilators in cystic fibrosis.

Previous studies have found that between 0 and 95% of patients with cystic fibrosis (CF) have a significant response to bronchodilators. These studies have been limited by small numbers and the measurement of response at one point in time. We analyzed the response to bronchodilators of patients with CF in a longitudinal and cross-sectional manner using pulmonary function data from 1980 to 1988. Overall, the proportion of patients with a positive response to bronchodilators was relatively large but not consistent over time. Of 573 tests in 127 persons, a positive response occurred in 68 tests of 51 patients. A negative response occurred in 19 tests of 17 patients. Only nine patients had a positive response in more than one third of their tests. The cross-sectional analysis showed variability similar to previous cross-sectional studies. Although a large proportion of patients with CF had a response to bronchodilators, the response was not consistent and may have been related to the number of tests performed. Continued longitudinal testing is necessary for valid decisions for bronchodilator use and for documenting the length, variability, and clinical significance of these responses.

Hypokalemia induced by inhaled bronchodilators.

Since parenteral beta 2-adrenergic stimulation can induce hypokalemia, we postulated that administration of beta 2 adrenoreceptor agonists by inhalation could induce the same. We administered the usual clinical doses of three commonly used bronchodilators to each of six subjects receiving assisted mechanical ventilation in line with the ventilator: two beta 2-adrenoreceptor agonists, metaproterenol, 5 percent solution, and isoetharine, 1 percent solution; and the anticholinergic agent atropine as a control. Each bronchodilator was nebulized over 10 to 15 minutes in random order, four hours apart, and given to every subject. Plasma potassium was measured at five-minute intervals and arterial blood gases at 15-minute intervals, for a total of 50 minutes after administration of each bronchodilator. Following administration of each drug, plasma potassium showed an average decline. The mean decline in plasma potassium from baseline was statistically significant for metaproterenol (p = 0.04) and atropine (p = 0.001) but not for isoetharine (p = 0.09). Although there were no statistically significant differences among the declines in plasma potassium induced by the three drugs, metaproterenol caused the greatest decline (-0.6 mEq/L).

Effect of a beta-agonist nebulization on lung function in neonates with increased pulmonary resistance.

Pulmonary resistance is elevated early in preterm infants who later develop chronic lung disease. This early increase in pulmonary resistance may play a role in the development of severe bronchopulmonary dysplasia (BPD). A beta-2-agonist (isoetharine HCl) was used as an aerosol in 13 preterm infants with elevated pulmonary resistance. Their birthweight ranged from 880 to 1630 g, their gestational age from 27 to 34 weeks, and their post natal age from 3 to 18 days. All infants had required mechanical ventilation for respiratory distress syndrome and therefore were at risk to develop BPD. Pulmonary mechanics were measured before and 30 minutes after aerosol treatment, determining inspiratory and expiratory flow with a pneumotachometer and esophageal pressure through a water-filled feeding tube. The treatment was well tolerated with no significant changes in blood pressure, heart rate, or respiratory rate. Pulmonary resistance decreased significantly from 130 +/- 35 cm H2O/L/sec to 89 +/- 24 cm H2O/L/sec after the treatment. Dynamic lung compliance increased in 11 of the 13 infants. It is concluded that beta-2-agonist nebulization is effective in reducing the early increase in pulmonary resistance that occurs in preterm infants who are at risk of developing BPD. This effect may be due to relaxation of bronchial smooth muscle, to improved mucociliary transport, and to a reduction in peribronchial edema.

Effect of a treatment protocol on the efficiency of care of the adult acute asthmatic.

A treatment protocol for patients with acute bronchospasm was introduced to an adult emergency department in an attempt to decrease treatment time and potentially decrease need for admission. The charts of all patients seen in a control year (before any protocol was in place) and the first three years of the protocol were reviewed. All care was given by medical housestaff. The first year after the protocol was introduced showed no change in either admission rate or stay in the ED. During this time, however, the protocol was used only 33% of the time. In the following two years, the protocol was used 93% of the time, and the admission rate decreased from 36.4% to 23.3% (P less than .02). The length of stay for all patients seen fell from a mean of 3.6 hours to 2.8 hours (P less than .005). The length of stay for those discharged fell from an average of 4.3 hours to 3.6 hours (P less than .02). Among the patients admitted, there was also a less striking but similar decrease from 3.0 hours to 2.4 hours. An organized treatment protocol was effective in increasing the efficiency of care given by the housestaff. The routine use of the protocol was not immediate and required time for acceptance by the housestaff.

Therapy of acute asthma: I. Evaluation of successive bronchodilator treatments.

Ninety-one children with acute asthma were studied to determine the extent of incremental improvement in pulmonary function afforded by successive doses of subcutaneous epinephrine, and by a bronchodilator aerosol in those patients refractory to epinephrine. A significant proportion of patients (69%), as expected, responded to the first injection. Among those who did not respond to the first injection a significant proportion (30%) responded to the second injection. Markedly fewer patients responded to subsequent bronchodilator treatments, including aerosols, if they did not improve significantly after the first two treatments. Patients with higher initial peak flow rates (PEFR) generally required fewer epinephrine injections, and achieved higher maximal PEFR than those with lower initial PEFR. Most asthmatic patients who required hospital admission had lower initial peak flow rates, were less responsive to epinephrine injections, and achieved lower maximal rates than those who could be discharged home.

Nebulized isoetharine and fenoterol in acute attacks of asthma.

Nebulized, selective beta 2-adrenergic agents were shown to be a safe and effective alternative to subcutaneous epinephrine chloride in the treatment of acute asthma attacks. Results of a trial of nebulized 1% isoetharine hydrochloride and 0.5% fenoterol in 40 patients with acute attacks of wheezing is reported. Both groups showed significant improvement on forced expiratory volume in one second (FEV1), maximum expiratory flow at 25% and 50% vital capacity but those who received fenoterol therapy showed more significant bronchodilation after one hour. Based on clinical criteria and the ability to raise and maintain for four hours an FEV, by 15% above baseline, ten (50%) of the patients who received isoetharine and 16 (80%) of the patients who received fenoterol therapy were successes. Mild side effects were encountered in eight patients of each treatment group. Fenoterol therapy was significantly more effective and had a longer duration of action.

Isoetharine-isoproterenol: a comparison of effects in childhood status asthmaticus.

Eighteen children in status asthmaticus, six to 14 years of age, were systematically studied to compare the efficacy of aerosolized isoetharine and isoproterenol. The studies were conducted in a randomized, double-blind fashion. Five inhalations of 1% isoetharine and 0.5% isoproterenol were administered via a wall-mounted air/O2 nebulizing unit. Pulse, respiratory rate, blood pressure, FVC, PEFR, FEV1 and FEF25-75 were measured at the patient's bedside. Isoetharine produced significantly less cardiac side effect and tended to produce a greater improvement in pulmonary function than did isoproterenol. In addition, no change from baseline was noted in any of the parameters at 120 minutes following treatment with either medication.

The clinical significance of volume-adjusted maximal mid-expiratory flow (Iso-volume FEF25-75%) in assessing airway responsiveness to inhaled bronchodilator in asthmatics.

The clinical significance of Iso-volume FEF25-75% in assessing airway responsiveness to an inhaled bronchodilator was evaluated in 167 asthmatics who presented with variable degrees of airway dysfunction. Iso-volume FEF25-75% identified responsiveness in one patient (5%) out of 20 of the most dysfunctional asthmatics, in three (20%) out of 15 of the least dysfunctional asthmatics and over-all in four (8%) out of 47 asthmatics not showing significant responsiveness via the FEV1. Over-all, FEV1 identified significant responsiveness in more patients (68.6%) than did the Iso-volume FEF25-75% (61%). The authors conclude that the Iso-volume FEF25-75% adds little to the FEV1 in the assessment of obviously dysfunctional asthmatics, the FEF25-75% as conventionally measured is a relatively useless post-bronchodilator measurement and that the FEV1 remains the single best spirometric test with which to assess airway responsiveness in asthmatics.