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Ureteral calculi: What should you consider before intervening?
THE SIZE OF THE CALCULI, their location, and complicating factors such as infection should all be considered.
Most ureteral calculi smaller than 5 mm pass spontaneously, as do approximately half of calculi between 5 and 10 mm. Calculi larger than 10 mm are unlikely to pass without intervention. Distal calculi are more likely to pass spontaneously than calculi in mid- or proximal ureteral locations; most spontaneous passage occurs within 4 to 6 weeks (strength of recommendation [SOR]: A, prospective cohort studies).
All patients with calculi complicated by such factors as obstruction, infection, renal injury, or a single kidney require surgical consultation (SOR: C, expert opinion).
Medical expulsion therapy with alpha-blockers (usually tamsulosin) and nifedipine improves passage rates, including for some calculi larger than 10 mm (SOR: A, meta-analysis of prospective cohort studies).
Evidence summary
A meta-analysis of 5 prospective cohort studies evaluated the rate of spontaneous passage of ureteral calculi according to size. Calculi smaller than 5 mm passed spontaneously in 68% of patients (5 studies, N=224). Calculi between 5 and 10 mm passed spontaneously in 47% of patients (3 studies, N=104).1
A prospective cohort study evaluated spontaneous passage rates of ureteral calculi by size in 172 patients who were diagnosed by unenhanced helical computed tomography.2 Investigators found spontaneous passage rates of 87% for 1-mm calculi, 76% for 2- to 4-mm calculi, 60% for 5- to 7-mm calculi, 48% for 7- to 9-mm calculi, and 25% for calculi larger than 9 mm.
Spontaneous passage rates differed significantly for calculi 1 to 4 mm in size compared with calculi 5 to 7 mm in size (P<.001) and for calculi 5 to 7 mm in size compared with calculi 8 mm or larger (P<.001). Calculi in either the distal ureter or ureterovesicular junction were more likely to pass that those in the mid- or proximal ureter (75% to 79% vs 48% to 60%; P<.001).
Most smaller calculi pass in 4 to 6 weeks
Another prospective cohort study (N=75) found that most calculi pass spontaneously within 4 to 6 weeks. In 95% of patients, calculi passed within 31 days (2 mm or smaller), 40 days (2-4 mm), or 39 days (4-6 mm).3
Some cases require prompt surgery
The American Urological Association (AUA) expert panel recommends early surgical intervention, regardless of calculus size, under the following circumstances: obstruction with high-grade hydronephrosis, infection, impending renal deterioration, intractable pain, nausea and vomiting, or obstruction in a solitary or transplanted kidney.1
Medical expulsion therapy trumps waiting for distal calculi to pass
A meta-analysis comparing rates of calculus passage found that medical expulsion therapy was more effective than expectant management for patients with distal ureteral calculi. Sixteen RCTs (N=1235) evaluated alpha-antagonists (mostly tamsulosin), and 9 RCTs (N=686) evaluated nifedipine. Treat ment periods for medical expulsion therapy ranged from 30 to 60 days.
Alpha-antagonists increased expulsion rates over expectant management for calculi ranging in size from 3 to 18 mm with a mean diameter greater than 5 mm (relative risk [RR]=1.59; 95% confidence interval [CI], 1.44-1.75; number needed to treat [NNT]=3). The mean time until passage ranged from 2.7 to 14.2 days. Nifedipine also increased expulsion rates for calculi with a mean diameter larger than 5 mm, ranging in size from 3.9 to 12.8 mm (RR=1.50; 95% CI, 1.34-1.68; NNT=4).4
Recommendations
The Joint European Association of Urology/ AUA Nephrolithiasis Guideline Panel recommends observation with periodic evaluation for patients newly diagnosed with ureteral calculi smaller than 10 mm.1 Patients may be offered medical expulsion therapy to facilitate calculus passage. Surveillance should be maintained until calculi pass; intervention should be considered if calculi don’t pass spontaneously within about 30 days.
The Panel states that patients with ureteral calculi larger than 10 mm could be observed (with or without medical expulsion therapy); however, most cases will require surgical intervention.1
Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the United States Army or the US Army Service at large.
1. European Association of Urology/American Urology Association Nephrolithiasis Guideline Panel. 2007 Guideline for the management of ureteral calculi. Available at: www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=uc. Accessed August 16, 2010.
2. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to calculus size and location as revealed by unenhanced helical CT. Am J Roentgenol. 2002;178:101-103.
3. Miller OF, Kane CJ. Time to calculus passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-691.
4. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-563.
THE SIZE OF THE CALCULI, their location, and complicating factors such as infection should all be considered.
Most ureteral calculi smaller than 5 mm pass spontaneously, as do approximately half of calculi between 5 and 10 mm. Calculi larger than 10 mm are unlikely to pass without intervention. Distal calculi are more likely to pass spontaneously than calculi in mid- or proximal ureteral locations; most spontaneous passage occurs within 4 to 6 weeks (strength of recommendation [SOR]: A, prospective cohort studies).
All patients with calculi complicated by such factors as obstruction, infection, renal injury, or a single kidney require surgical consultation (SOR: C, expert opinion).
Medical expulsion therapy with alpha-blockers (usually tamsulosin) and nifedipine improves passage rates, including for some calculi larger than 10 mm (SOR: A, meta-analysis of prospective cohort studies).
Evidence summary
A meta-analysis of 5 prospective cohort studies evaluated the rate of spontaneous passage of ureteral calculi according to size. Calculi smaller than 5 mm passed spontaneously in 68% of patients (5 studies, N=224). Calculi between 5 and 10 mm passed spontaneously in 47% of patients (3 studies, N=104).1
A prospective cohort study evaluated spontaneous passage rates of ureteral calculi by size in 172 patients who were diagnosed by unenhanced helical computed tomography.2 Investigators found spontaneous passage rates of 87% for 1-mm calculi, 76% for 2- to 4-mm calculi, 60% for 5- to 7-mm calculi, 48% for 7- to 9-mm calculi, and 25% for calculi larger than 9 mm.
Spontaneous passage rates differed significantly for calculi 1 to 4 mm in size compared with calculi 5 to 7 mm in size (P<.001) and for calculi 5 to 7 mm in size compared with calculi 8 mm or larger (P<.001). Calculi in either the distal ureter or ureterovesicular junction were more likely to pass that those in the mid- or proximal ureter (75% to 79% vs 48% to 60%; P<.001).
Most smaller calculi pass in 4 to 6 weeks
Another prospective cohort study (N=75) found that most calculi pass spontaneously within 4 to 6 weeks. In 95% of patients, calculi passed within 31 days (2 mm or smaller), 40 days (2-4 mm), or 39 days (4-6 mm).3
Some cases require prompt surgery
The American Urological Association (AUA) expert panel recommends early surgical intervention, regardless of calculus size, under the following circumstances: obstruction with high-grade hydronephrosis, infection, impending renal deterioration, intractable pain, nausea and vomiting, or obstruction in a solitary or transplanted kidney.1
Medical expulsion therapy trumps waiting for distal calculi to pass
A meta-analysis comparing rates of calculus passage found that medical expulsion therapy was more effective than expectant management for patients with distal ureteral calculi. Sixteen RCTs (N=1235) evaluated alpha-antagonists (mostly tamsulosin), and 9 RCTs (N=686) evaluated nifedipine. Treat ment periods for medical expulsion therapy ranged from 30 to 60 days.
Alpha-antagonists increased expulsion rates over expectant management for calculi ranging in size from 3 to 18 mm with a mean diameter greater than 5 mm (relative risk [RR]=1.59; 95% confidence interval [CI], 1.44-1.75; number needed to treat [NNT]=3). The mean time until passage ranged from 2.7 to 14.2 days. Nifedipine also increased expulsion rates for calculi with a mean diameter larger than 5 mm, ranging in size from 3.9 to 12.8 mm (RR=1.50; 95% CI, 1.34-1.68; NNT=4).4
Recommendations
The Joint European Association of Urology/ AUA Nephrolithiasis Guideline Panel recommends observation with periodic evaluation for patients newly diagnosed with ureteral calculi smaller than 10 mm.1 Patients may be offered medical expulsion therapy to facilitate calculus passage. Surveillance should be maintained until calculi pass; intervention should be considered if calculi don’t pass spontaneously within about 30 days.
The Panel states that patients with ureteral calculi larger than 10 mm could be observed (with or without medical expulsion therapy); however, most cases will require surgical intervention.1
Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the United States Army or the US Army Service at large.
THE SIZE OF THE CALCULI, their location, and complicating factors such as infection should all be considered.
Most ureteral calculi smaller than 5 mm pass spontaneously, as do approximately half of calculi between 5 and 10 mm. Calculi larger than 10 mm are unlikely to pass without intervention. Distal calculi are more likely to pass spontaneously than calculi in mid- or proximal ureteral locations; most spontaneous passage occurs within 4 to 6 weeks (strength of recommendation [SOR]: A, prospective cohort studies).
All patients with calculi complicated by such factors as obstruction, infection, renal injury, or a single kidney require surgical consultation (SOR: C, expert opinion).
Medical expulsion therapy with alpha-blockers (usually tamsulosin) and nifedipine improves passage rates, including for some calculi larger than 10 mm (SOR: A, meta-analysis of prospective cohort studies).
Evidence summary
A meta-analysis of 5 prospective cohort studies evaluated the rate of spontaneous passage of ureteral calculi according to size. Calculi smaller than 5 mm passed spontaneously in 68% of patients (5 studies, N=224). Calculi between 5 and 10 mm passed spontaneously in 47% of patients (3 studies, N=104).1
A prospective cohort study evaluated spontaneous passage rates of ureteral calculi by size in 172 patients who were diagnosed by unenhanced helical computed tomography.2 Investigators found spontaneous passage rates of 87% for 1-mm calculi, 76% for 2- to 4-mm calculi, 60% for 5- to 7-mm calculi, 48% for 7- to 9-mm calculi, and 25% for calculi larger than 9 mm.
Spontaneous passage rates differed significantly for calculi 1 to 4 mm in size compared with calculi 5 to 7 mm in size (P<.001) and for calculi 5 to 7 mm in size compared with calculi 8 mm or larger (P<.001). Calculi in either the distal ureter or ureterovesicular junction were more likely to pass that those in the mid- or proximal ureter (75% to 79% vs 48% to 60%; P<.001).
Most smaller calculi pass in 4 to 6 weeks
Another prospective cohort study (N=75) found that most calculi pass spontaneously within 4 to 6 weeks. In 95% of patients, calculi passed within 31 days (2 mm or smaller), 40 days (2-4 mm), or 39 days (4-6 mm).3
Some cases require prompt surgery
The American Urological Association (AUA) expert panel recommends early surgical intervention, regardless of calculus size, under the following circumstances: obstruction with high-grade hydronephrosis, infection, impending renal deterioration, intractable pain, nausea and vomiting, or obstruction in a solitary or transplanted kidney.1
Medical expulsion therapy trumps waiting for distal calculi to pass
A meta-analysis comparing rates of calculus passage found that medical expulsion therapy was more effective than expectant management for patients with distal ureteral calculi. Sixteen RCTs (N=1235) evaluated alpha-antagonists (mostly tamsulosin), and 9 RCTs (N=686) evaluated nifedipine. Treat ment periods for medical expulsion therapy ranged from 30 to 60 days.
Alpha-antagonists increased expulsion rates over expectant management for calculi ranging in size from 3 to 18 mm with a mean diameter greater than 5 mm (relative risk [RR]=1.59; 95% confidence interval [CI], 1.44-1.75; number needed to treat [NNT]=3). The mean time until passage ranged from 2.7 to 14.2 days. Nifedipine also increased expulsion rates for calculi with a mean diameter larger than 5 mm, ranging in size from 3.9 to 12.8 mm (RR=1.50; 95% CI, 1.34-1.68; NNT=4).4
Recommendations
The Joint European Association of Urology/ AUA Nephrolithiasis Guideline Panel recommends observation with periodic evaluation for patients newly diagnosed with ureteral calculi smaller than 10 mm.1 Patients may be offered medical expulsion therapy to facilitate calculus passage. Surveillance should be maintained until calculi pass; intervention should be considered if calculi don’t pass spontaneously within about 30 days.
The Panel states that patients with ureteral calculi larger than 10 mm could be observed (with or without medical expulsion therapy); however, most cases will require surgical intervention.1
Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the United States Army or the US Army Service at large.
1. European Association of Urology/American Urology Association Nephrolithiasis Guideline Panel. 2007 Guideline for the management of ureteral calculi. Available at: www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=uc. Accessed August 16, 2010.
2. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to calculus size and location as revealed by unenhanced helical CT. Am J Roentgenol. 2002;178:101-103.
3. Miller OF, Kane CJ. Time to calculus passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-691.
4. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-563.
1. European Association of Urology/American Urology Association Nephrolithiasis Guideline Panel. 2007 Guideline for the management of ureteral calculi. Available at: www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=uc. Accessed August 16, 2010.
2. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to calculus size and location as revealed by unenhanced helical CT. Am J Roentgenol. 2002;178:101-103.
3. Miller OF, Kane CJ. Time to calculus passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-691.
4. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-563.
Evidence-based answers from the Family Physicians Inquiries Network
What is the preferred treatment for a child with mild persistent asthma?
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Evidence-based answers from the Family Physicians Inquiries Network