Atrovent (ipatropium) and Atropine for Asthma ============================================= - good for sicker asthmatics [Schuh S, 1995] [Stoodley, R.G., S.D. Aaron, and R.E. Dales, The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a metaanalysis of randomized clinical trials. Ann Emerg Med, 1999. 34(1): 8-18.] - works well for kids (6-18), too, and may decrease admission rate (20% vs. 32% in a study of 90 kids). [Sutherland, E.R. and R.M. Cherniack, Management of chronic obstructive pulmonary disease. N Engl J Med, 2004. 350(26): p. 2689-2697.] [Qureshi F. Efficacy of nebulized ipratropium in severely asthmatic patients. Ann Emerg Med 1997;29:205-211.] and this difference was maintained in a larger study [Zaritsky A, Qureshi F. Ipratropium does indeed reduce admissions to hospital with severe asthma [letter; comment]. Bmj 1999; 318:738.] [Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. N Engl J Med 1998; 339:1030-5.] [Qureshi F, Zaritsky A, Lakkis H. Efficacy of nebulized ipratropium in severely asthmatic children. Ann Emerg Med 1997; 29:205-11.] Just as in the case of the use of magnesium for acute exacerbations of asthma there is no consensus in the literature with regards to any possible synergistic effect of beta-agonists and anticholinergics. Some studies have found benefit (1,2,3,4), while others have not (5). In acute exacerbations of COPD there is (6), there is not (7) and there might be (but not after 24 hours) (8) value to using both drugs together. In any case the response, if any, to ipratropium is not a near instantaneous one as it is for beta-agonists. Rather a period of time (1 - 2 hours) is necessary to see improvement. As an aside, the literature continues to insist that there is no difference between using MDI and nebulized medication for acute asthma. My experience is otherwise. H. Louzon MD (1) Beck R [Use of ipratropium bromide by inhalation in the treatment of acute asthma in children. Clinical experience] Arch Pediatr 1995;2 Suppl 2():145S-148S ABSTRACT: Clinical experience. Anticholinergic drugs, notably atropine, have long been known to be potent bronchodilators, but their use was limited by systemic absorption and significant side effects. Ipratropium bromide has no systemic anticholinergic action, but maintains the local anticholinergic action on the tracheobronchial tree. In 1984, we observed that in children with acute asthma, treated aggressively with frequent doses of nebulized beta 2 adrenergics, a significant degree of airway obstruction remained, and did not improve with further doses of beta 2 agonists. We postulated that vagal bronchomotor tone might contribute to this problem and that further improvement could be obtained with the use of ipratropium bromide. Ipratropium was shown to be useful in pediatric asthma in the early 1980s. There appeared to be an age difference in the response to the medication. A dose-response curve for nebulized ipratropium was determined. The optimal dose was found to be > 75 micrograms. Repeated studies and extensive experience demonstrated safety and few side effects. In 1984 we studied the effect of adding ipratropium after one hour of treatment with a regimen of frequent nebulized salbutamol in children with acute asthma. We found a slight but significant further improvement in FEV1, beginning one hour after administration of ipratropium. Further studies confirmed these findings, when using two doses of combined ipratropium/fenoterol an hour apart or every 40 minutes for three doses. One study using ipratropium every eight hours failed to show a change, confirming the need to use the medication more frequently. For the past six years, we have been using a protocol that incorporates ipratropium in the treatment of acute asthma in children.2+ (2) Schuh S, Johnson DW, Callahan S, Canny G, Levison H Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma. J Pediatr 1995 Apr;126(4):639-45 ABSTRACT: OBJECTIVE: The objective of this trial was to determine the efficacy of frequent nebulized ipratropium added to high-dose albuterol therapy in children with severe asthma. METHODS: One hundred twenty children (5 to 17 years) of age) with severe acute asthma (forced expiratory volume in 1 second (FEV1), < 50% of the predicted value) were enrolled into a randomized double-blind three-arm placebo-controlled trial comparing three groups: group 1, three doses of nebulized ipratropium bromide within 60 minutes (250 micrograms/dose); group 2, one dose of ipratropium; group 3, no ipratropium. All patients were also treated with three doses of nebulized albuterol within 60 minutes (0.15 mg/kg per dose). Pulmonary function and clinical measures were assessed every 20 minutes for up to 120 minutes. RESULTS: The groups were comparable at baseline. At 120 minutes, the mean percentage of predicted FEV1 improved from 33.4% to 56.7% in group 1, from 34.2% to 52.3% in group 2, and from 35.4% to 48.4% in group 3 (p = 0.0001). The differences between groups were larger in those children with a baseline FEV1 < or = 30% of the predicted value: FEV1 increased from 24.5% to 50.9% in group 1, from 25.0% to 39.8% in group 2, and from 25.9% to 36.5% in group 3 (p = 0.0001). In group 1, 38% of the patients were hospitalized after the study, 44% in group 2, and 46% in group 3 (p value not significant). However, in patients with FEV1 < or = 30%, the hospitalization rates were 27% in group 1, 56% in group 2, and 83% in group 3 (p = 0.027). There were no toxic effects attributable to ipratropium. CONCLUSION: The addition of repeated doses of nebulized ipratropium to frequent high-dose albuterol therapy in patients with acute severe asthma is both safe and more effective than albuterol alone; its use in patients with very severe asthma may reduce hospitalizations. (3) Delacourt C, de Blic J, Lebourgeois M, Scheinmann P [Value of ipratropium bromide in asthma crisis in children] Arch Pediatr 1994 Jan;1(1):87-92 ABSTRACT: Ipratropium bromide is a synthetic derivative of atropine with little absorption when used in inhalation, and therefore little secondary effects. The authors review its pharmacological properties and therapeutic efficacy in the treatment of asthma in children. Combined nebulized inhalation of ipratropium bromide and beta 2 sympathomimetic results in a more efficient and more sustained bronchodilatation than beta 2 sympathicomimetic alone in the treatment of acute asthma in children. Ipratropium bromide should be usefully introduced in the therapeutic scheme of acute asthma in children. Further studies will be necessary in order to determine its efficacy and tolerance in infants. (4) Louw SJ, Goldin JG, Isaacs S Relative efficacy of nebulised ipratropium bromide and fenoterol in acute severe asthma. S Afr Med J 1990 Jan 6;77(1):24-6 ABSTRACT: In a double-blind, randomised, controlled clinical trial of 145 patients with acute asthma, the efficacy of nebulised 4-hourly ipratropium bromide plus 4-hourly fenoterol (group I, 50 patients), 2-hourly fenoterol (group II, 50 patients) and 4-hourly fenoterol (group III, 45 patients) was assessed. All patients received an optimal infusion of aminophylline and 81 patients (27 in each group) received hydrocortisone for clinical indications. It was found that cholinergic side-effects in group I were not more common than in group II. Tremor was more common in group II. Assessment of bronchodilator efficacy was confined to the 81 patients whose therapy included hydrocortisone. Peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity were expressed as a percentage of predicted for each individual and the mean values for each group plotted. It was found that the response rate, as assessed by the area under the curve, was significantly more rapid in group I compared with both group II (P less than 0.001) and group III (P less than 0.005). These findings were consistent for all three lung function measurements. However, there was no significant difference in the responses between group II and group III. It is concluded that adding ipratropium bromide to conventional regimens is likely to benefit patients with acute asthma. (5) Summers QA, Tarala RA Nebulized ipratropium in the treatment of acute asthma [see comments] Chest 1990 Feb;97(2):425-9 ABSTRACT: The efficacy of ipratropium and salbutamol was determined in 117 patients with acute asthma who presented to an emergency department to determine whether the order of administration of the two agents affects the improvement in peak flow rates. Patients were given two nebulized treatments at an interval of one hour in a randomized, double-blind design. They received either 5 mg nebulized salbutamol followed by 0.5 mg ipratropium, ipratropium followed by salbutamol, or both drugs administered together followed by nebulized saline. Ipratropium was an effective bronchodilator when given as the first agent. Simultaneous administration with salbutamol was as effective as sequential administration. At one hour after treatment, there was no difference in peak flow between the combination of drugs and either drug given alone. Ipratropium given after salbutamol was not superior to saline solution given after the combination of drugs. Our data do not suggest a substantial therapeutic effect from addition of ipratropium to salbutamol in the immediate treatment of acute asthma. (6) Fernandez A, Munoz J, de la Calle B, Alia I, Ezpeleta A, de la Cal MA, Reyes A Comparison of one versus two bronchodilators in ventilated COPD patients. Intensive Care Med 1994;20(3):199-202 ABSTRACT: OBJECTIVE: To compare the bronchodilating effect of a single drug, ipratropium bromide (IBr), with that of its combination with fenoterol (IBr+F). DESIGN: The study was triple blind and randomized. SETTING: Medical-surgical intensive care unit. PATIENTS: 12 patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation for severe respiratory failure. INTERVENTIONS: Before administering each drug, peak airway pressure (Ppeak), end inspiratory pressure (Pei), resistive pressure (Pres), and auto positive--end expiratory pressure (auto-PEEP) were measured. Inspiratory system resistance (Rins) and dynamic respiratory system compliance (C) were calculated. Arterial pH and blood gas determinations were made. These measurements were repeated 60 min after administration of each therapeutic regimen. For ipratropium bromide alone the dose was 0.04 mg. When the combination of drugs was used, the doses were 0.04 mg for ipratropium bromide and 0.1 mg for fenoterol. MEASUREMENTS AND RESULTS: With the combination of both drugs, all the pressures in the airway, as well as the auto-PEEP and the Rins were significantly reduced (p < 0.05) with respect to baseline values. With ipratropium bromide alone, no significant changes were observed either in the pressures or in the inspiratory resistance. No significant changes were observed either in the pH or blood gases with any of the treatments. The combination of both drugs produced significantly reduction in Pei and auto-PEEP when compared with ipratropium bromide alone. CONCLUSIONS: The combination of both drugs is more effective than ipratropium bromide alone at the doses used in this study. (7) Kuhl DA, Agiri OA, Mauro LS Beta-agonists in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Ann Pharmacother 1994 Dec;28(12):1379-88 ABSTRACT: OBJECTIVE: To critically evaluate the following issues regarding the use of beta-agonists in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD): (1) optimal dose, (2) use of nebulizer (NEB) versus metered-dose inhaler-spacer devices (MDISs), (3) comparison with anticholinergic agents, and (4) use in mechanically ventilated patients. The patient populations addressed are limited primarily to emergency department (ED) and intensive care/acute care settings. DATA SOURCES: English-language journal articles published between 1977 and 1993. STUDY SELECTION: Nine studies were evaluated that included beta-agonists alone or in combination with other bronchodilators in the treatment of acute exacerbation of COPD. Many of the studies contained design flaws or were limited in size, making interpretation difficult. In studies containing both asthma and COPD patients, focus was restricted to analysis of COPD patients when possible. DATA EXTRACTION: Performed subjectively by the authors. Studies were evaluated for methodologic strengths and weaknesses. DATA SYNTHESIS: Dosing studies in patients with stable disease show a relationship between dose and the various pulmonary function tests (PFTs). Dose also correlates with duration of action and incidence of adverse effects. Four studies compared NEBs versus MDISs. Studies revealed significant improvement in PFTs for both treatments, with no significant difference between groups noted. Five studies compared various combinations of beta-agonists and ipratropium. Both ipratropium and beta-agonists caused statistically significant increases in PFTs from baseline. Combination therapy provided no further increase in spirometry compared with that of single-agent therapy. One study did report an early discharge from the ED with the addition of ipratropium. Most studies did not use large doses of beta-agonists or evaluate the effect of repeated doses. Many studies allowed concomitant therapy. Most did not include outcome measurements, such as ED length of stay, admission rates, hospital stay, or incidence of relapse. CONCLUSIONS: Dose-response studies in patients with stable disease suggest that doses of albuterol powder up to 1 mg may be tolerated safely, although use of repeated larger doses has not been well studied. Beta-agonists given by MDIS or NEB are equally effective in this setting. There is no apparent advantage to combined use of beta-agonist and ipratropium in the acute setting. Future research in this area should evaluate the use of larger or repeated doses of beta-agonists in the acute setting. Optimizing concurrent therapy and evaluating various patient outcomes should receive special attention in further investigations. (8) Patrick DM, Dales RE, Stark RM, Laliberte G, Dickinson G Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy. Chest 1990 Aug;98(2):295-7 ABSTRACT: Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy. For kids check out Osmond MH. Acad Emerg Med 1995;2:651-656. A meta-analysis of 6 studies. Concludes that addition of ipra will increase FEV1 overall, may be harmful in the real sickies and produces no measurable clinical improvement. (R McNamara, MD)