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Atrovent and Asthma Beyond the Emergency Department

Posted March 20th, 2008 by lasaj
in
Author Name(s):
Javier J. Lasa, MD and Amy Cohen, MD
Reviewer Name:
Angela Ellison, MD
Clinical Question:

Does nebulized ipratropium bromide (Atrovent) have a clinically significant effect in treating moderate to severe asthma exacerbations in hospitalized pediatric patients?

Background:

Ipratropium bromide is an anti-cholinergic derivative of atropine with documented bronchodilatory effects in combination with beta-agonist therapy. (Gross, 1984)   In the acute emergency department setting, the beneficial effects of atrovent in combination with albuterol and corticosteroids has been well documented in several studies of both pediatric and adult patients. In addition, one study of the inpatient management of adults with asthma has been published demonstrating inconsistent improvements in clinical outcomes with the addition of ipatropium bromide to beta agonist therapy.   These studies are summarized below:  

  • Schuh, et al. - Pediatrics 1995
    • Objective – to study the efficacy and safety of the addition of three doses versus one dose of nebulized atrovent added to frequent albuterol in comparison to albuterol alone in the ED.   Type of Study: Randomized, double blind three arm trial comparing 3 doses of atrovent in 1 hour, 1 dose of atrovent in 1 hour, or no atrovent added to 3 doses of nebulized albuterol.   Study population: Children 5-17 years old in ED with an acute asthma exacerbation who were able to perform PFTs.  Primary outcome: difference in the change of percentage predicted FEV1 between the 3 groups.  Significant differences between the 3 groups were found and were especially marked in subjects with severe baseline status ( you may want to add in the numbers for the change in predicted FEV1 between the groups here, p= 0.0001); differences in the rate of hospitalization were only significant for subjects with FEV1 <30% predicted p=0.027.
  • Qureshi, et al. – NEJM 1998
    • Objective: To determine if rates of hospitalization decreased with the addition of ipratropium to albuterol in the ED.  Type of Study: randomized, double-blind, placebo controlled; albuterol given every 20 minutes x3 doses, steroids given with second dose, 500ug of ipratropium or NS given with doses 2 and 3.  Study population: 2-18yo with known history, acute exacerbation (wheezing, worsening of symptoms, increased difficulty breathing, deteriorating peak flow).  Primary outcome: rate of hospitalization between the 2 groups. Secondary outcomes included peak flow, asthma score, pulse rate, respiratory rate, and oxygen saturation.  Overall, the rate of hospitalization was lower for subjects treated with atrovent (27.4 vs 36.5; p=0.05); there was no significant difference for subjects with moderate asthma exacerbation; for patients with a severe exacerbation, rates were 37.5 vs 52.6%; p=0.02.  Also noted that the asthma score improved significantly more in the treated group (p =0.05, 0.01 for severe flares).
  • Zorc, et al. – Pediatrics 1999
    • Objective: To determine if atrovent given with albuterol in the ED reduces time to discharge, number of treatments before discharge and rate of hospitalization.  Type of study: randomized, double blind; subjects were given albuterol every 20min x3 doses and one dose of prednisone; 1ml of the study drug (IB or NS) was given with each of the first 3 albuterol treatments.  Study population: Age  >12 months with critical ED assessment.  Primary outcome: Fewer subjects in the atrovent group were admitted, but did not reach statistical significance, there was only a trend toward reduction (p=0.3); a significant difference in favor of the atrovent group was found for time to discharge (28min difference, p =0.001).
  • Salo, et al. – J of Emerg Med 2006
    • Objective:  To examine the effects of adding ipratropium bromide (IB) to continuous albuterol in an emergency room setting for adults with acute asthma exacerbation.  Type of Study: Randomized, double blind trial of adults (>18yo) with acute asthma exacerbation (PEFR<70% predicted, clinical history, prior history) randomized to receive either continuous albuterol (15mg plus isotonic saline) alone or with ipratropium bromide (2mg plus albuterol plus isotonic saline).  All subjects received prednisone.  Vitals, PEFR and physical exam documented at pre-treatment, 60 minutes and 120 minutes post-treatment.  Primary outcome: mean change in PEFR from pre-treatment and post-treatment times.  Secondary outcome: admission rate.  Out of 166 eligible subjects, only 37.9% (66) were enrolled with median age 35 years old. There was no statistically significant change in mean improvement in PEFR and no statistically significant difference between in admission rates between groups.
  • Brophy, et al. – Thorax 1998
    • Objective: To determine whether continued administration of ipratropium bromide beyond the first few hours after admission to hospital would aid recovery and, if so, to determine the optimal duration of treatment.  Type of Study: Randomized, double-blind, placebo-controlled trial of adults (>18 yo) admitted to hospital with acute asthma exacerbation who all received nebulized salbutamol(S) and 500mcg ipratropium bromide (IB) every four hours.  Subjects were randomized to one of three groups: I) Regimen of S + IB every four hours for first twelve hours then converted to S only with placebo until end of study (60 hours), II) Regimen of S + IB every four hours for first 36 hours then converted to S only with placebo until end of study, III) Regimen of S + IB every four hours for entire study period (60 hours).  Primary outcome: Change in FEV1 between groups during hospital stay.  Secondary outcomes:  PEFR values measured throughout treatment period and at end of each treatment, duration of stay, and symptom scores (five symptoms graded on analog scale 0-10: cough, chest tightness, shortness of breath, early morning wheeziness, general well-being).  Between 19% and 34% of subjects in each group received systemic corticosteroids (groups III and II respectively, 22% in group I).  Out of 106 subjects enrolled, only 86 completed the study.  There were no statistically significant differences between groups in any FEV1, rate of change of symptoms, and the time to greatest PEFR.  Median duration of hospital stay was 5.4 days in group I, 4.1 days in group II, and 4 days in group III (p<0.05 w/CI 0.3-2.4).  Authors concluded nebulized IB resulted in clear advantage in reducing LOS if given every four hours with albuterol for at least 36 hours. Note that group II, with shorter LOS, had highest percentage of subjects receiving steroids.



To our knowledge, the role of ipratropium bromide in the treatment of children hospitalized with asthma exacerbations following emergency department treatment has not been well studied.  We have used this Clinical Appraisal Tool to better elucidate the little data present in the current literature surrounding longer duration therapy with ipratropium bromide for children hospitalized with moderate to severe asthma exacerbations.

Clinical Bottom Line:
    • There is no evidence that the addition of inhaled ipratropium bromide to standard inhaled beta-agonist therapy for hospitalized pediatric patients with moderate to severe asthma exacerbation (with or without early intensive treatment in the emergency department) significantly reduces length of stay or improves pulmonary function tests.
    • There is no clear adult or pediatric patient dosing schedule or regimen for inhaled ipratropium bromide in hospitalized patients with asthma exacerbations.
    • Further studies are required to demonstrate the efficacy of inhaled ipratropium bromide as an adjuvant therapy for moderate to severe asthma in hospitalized pediatric patients receiving inhaled beta-agonists and corticosteroid therapy.
Summary of Key Evidence:
  • Craven et al. conducted a randomized, double-blind, placebo-controlled trial of 210 patients (out of eligible 491) at a tertiary care pediatric hospital (Rainbow Babies and Childrens Hospital, Cleveland, Ohio, USA). Subjects aged 11 months to 17 years were entered into the hospital’s Asthma Care Algorithm (ACA) from clinics or the emergency department and followed phase-wise progression from treatment every 2 hours (I), 3 hours (II), 4 hours (III), and 6 hours (IV) before being discharged home.  All subjects received standard treatment with nebulized albuterol and systemic corticosteroids.  They were then randomized to receive either nebulized ipratropium bromide (IB) or nebulized isotonic saline with each nebulized albuterol treatment.Primary outcomes were hospital length of stay (LOS) and ACA progression (time to phase IV from initiation of ACA).  Subgroup analysis examined performance based on age with stratification at age 6 due to a sensitivity analysis which showed the cut point at which the 2 groups were the most different.  The study was also powered to 80% based on a goal of 15% reduction of LOS with data provided by a historical cohort of ACA admissions. 
    • Overall, older subjects (>6 years) showed a trend toward shorter LOS and more rapid ACA-P but without any statistical significance.  Routine administration of repeated doses of IB to hospitalized subjects with acute asthma exacerbation was shown to be safe but produced no clinical benefit beyond that provided by aggressive therapy with beta agonists, systemic corticosteroids, and as-needed IB. 
    • There were many strengths of this clinical trial including randomization, blinding, the wide age range of subjects and use of a standardized protocol. However, the authors did note that sample size for the older subjects was small and may have limited their ability to determine significant differences in outcomes among those subjects.  In addition, significant selection bias may have been present as only 43% of eligible patients enrolled in the study.  Other factors which may have contributed to the lack of contributing to statistically insignificant outcomes included the possible dilution of clinical efficacy by including subjects in the control group who were "intensified".  Subjects who failed to progress along the ACA received an "intensification regimen" of subcutaneous epinephrine and a one time dose of nebulized IB.  Lastly, this study's results are inconsistent with a previous large ED trials that found enhanced clinical efficacy from IB in children <5 years old.  
  • Goggin et al. also performed  a randomized, double-blind, placebo-controlled trial with subjects aged 1-18 years who presented with moderate to severe asthma exacerbation (requiring albuterol at least every 2 hours, FEV1 25-80% or asthma score of 3-9).  Eighty subjects (N=80) were enrolled in the study and received nebulized albuterol (0.15 mg/kg/dose, max of 5mg) every 0.5 to 2 hours, with spacing to every 4 hours once improved clinically.  The dosing of the study drug (1 ml nebulized ipratropium vs 1 ml nebulized isotonic saline) matched that of the albuterol. All subjects were also treated with corticosteroids for at least 5 days.The subjects were then stratified by age (>=5yrs vs <5yrs) and by number of ipratropium doses administered in the ED (<=3 vs >3 – cutoff determined by a prior double-blind, randomized controlled trial – Schuh, et. al.).  Primary outcome was measurement of asthma severity during the first 36 hours of hospitalization based on an asthma score (reliability of scoring - Parkin, et al.).The score was measured at baseline and every 6 hours following until either discharge or 36 hours.  Secondary outcomes included oxygen saturation, heart rate, FEV1. 
    • In both groups, there was no significant difference in asthma score over time (p = 0.07).  In secondary outcomes, there were also no significant differences.  No subjects presented to the ED or for readmission within 72 hours. Subgroup analysis of the group receiving 3 or fewer doses in the ED, showed a significant difference in the asthma score over time favoring the ipratropium group (p = 0.04).  There was no difference in the remaining subgroups.
    • Limits to this study include most subjects enrolled were younger than 5 years and only 15 were able to perform spirometry.In addition, these results may not be generalizable to patients in intensive care units or those who have not received intensive combination bronchodilator treatment in the ED. 
    • The sample size of 80 gave greater than 90% power to detect a difference in clinical asthma score as small as 0.9 and a length of stay as small as 12.5 hours.  It was then concluded that adding nebulized ipratropium bromide to nebulized beta agonist and corticosteroid treatment in hospitalized asthmatic patients does not confer any benefit.

Search Strategy:

((("ipratropium"[TIAB] NOT Medline[SB]) OR "ipratropium"[MeSH Terms] OR atrovent[Text Word]) AND ("asthma"[MeSH Terms] OR asthma[Text Word])) AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract])) AND hospitalized[All Fields] AND (Randomized Controlled Trial[ptyp] AND ("infant"[MeSH Terms] OR "child"[MeSH Terms] OR "adolescent"[MeSH Terms]))

References:

1) Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis. 1984 May;129(5):856-70. [Penn Proxy]

2) Zorc JJ, Pusic MV, Ogborn CJ, Lebet R, Duggan AK. Ipratropium bromide added to asthma treatment in the pediatric emergency department. Pediatrics. 1999 Apr;103(4 Pt 1):748-52. [Penn Proxy]

3) 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 Oct 8;339(15):1030-5. [Penn Proxy]

4) Salo D, Tuel M, Lavery RF, Reischel U, Lebowitz J, Moore T. A randomized, clinical trial comparing the efficacy of continuous nebulized albuterol (15 mg) versus continuous nebulized albuterol (15 mg) plus ipratropium bromide (2 mg) for the treatment of acute asthma. J Emerg Med. 2006 Nov;31(4):371-6. [Penn Proxy]

5) Brophy C, Ahmed B, Bayston S, Arnold A, McGivern D, Greenstone M. How long should Atrovent be given in acute asthma? Thorax. 1998 May;53(5):363-7. [Penn Proxy]

6) Goggin N, Macarthur C, Parkin PC. Randomized trial of the addition of ipratropium bromide to albuterol and corticosteroid therapy in children hospitalized because of an acute asthma exacerbation. Arch Pediatr Adolesc Med. 2001 Dec;155(12):1329-34. [Penn Proxy]

7) Craven D, Kercsmar CM, Myers TR, O'riordan MA, Golonka G, Moore S. Ipratropium bromide plus nebulized albuterol for the treatment of hospitalized children with acute asthma. J Pediatr. 2001 Jan;138(1):51-58. [Penn Proxy]

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