Guideline on management of the acute asthma attack in children by Italian Society of Pediatrics

Inhaled short-acting ß2 agonists are the first line treatment for acute asthma attack in children. Salbutamol is a useful medication that can be used in children of all ages. Inhaled via is the traditional route of administration [18]. Salbutamol given continuously via nebulizer was not associated with a better outcome with respect to frequent intermittent administration, in a systematic review, dating back to 2003 and including only one pediatric study [19, 20]. In 2013 Cochrane including 1897 children and 729 adults in 39 trials, Metered-Dose Inhalers (MDI) with spacer was considered the preferred option for delivering ß2 agonists in children with mild to moderate asthma attack [21].

Salbutamol dose to be administered through MDI with spacer should be individualized according to the asthma attack severity: 200–400 μg/dose (2–4 puffs/dose) could be sufficient in mild attacks. Children with severe asthma should receive frequent doses of nebulised bronchodilators (2.5 to 5 mg of salbutamol), driven by oxygen, given the risk of oxygen desaturation while using air-driven compressors. Once improving on two- to four-hourly salbutamol, patients should be switched to a MDI with spacer [16, 17, 22].

Literature data regarding iv short-acting ß₂ agonists use are poor. No consistent evidence favoring the use of iv short-acting ß₂-agonists for patients with acute asthma were evidenced in a 2012 Cochrane including 2 pediatric studies on children (one in ICU) [23].

Some authors suggest the use of iv salbutamol in addition of long-acting ß₂ agonists in children with severe asthma attack unresponsive to initial therapy [23]. The recommended dose is a single bolus of 15 μg/kg (diluition: 200 μg/mL for central iv line; 10–20 μg/mL for peripheral iv line) over 10 min, followed by continuous infusion of 0.2 μg/kg /min. Higher doses (1–2 μg/kg/min up to 5 μg/kg/min) can be administered in unresponsive children [2, 16]. Intravenous salbutamol should be given in the ICU with continuous ECG and twice daily electrolyte and lactate monitoring [17].

Ipratopium bromide induces a slower broncodilator response than ß₂ agonists, but the combination of the two medications produces a synergic effect. In severe attack the recommended nebulized dose is 125–250 μg/dose (in children < 4 years of age) to 250–500 μg/dose (in children ≥ 4 years of age), in combination with nebulized salbutamol. It should be administered frequently, up to 3 times every 20–30 min, within the first hour. The ipratropium dose should be tapered to 4 to 6 hourly or discontinued [17]. Once ipratropium bromide is discontinued, salbutamol dose should be tapered to one- to two-hourly thereafter according to clinical response.

A 2012 Cochrane review [24] including four trials on 173 children found that treatment failure on anticholinergics alone was more likely than when anticholinergics were combined with short-acting ß₂ agonists (OR 2.65; 95% CI 1.2 to 5.88). Authors concluded that inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations. In a subsequent 2013 Cochrane review [25], including 15 studies with 2497 children, the addition of an anticholinergic to a SABA significantly reduced the risk of hospitalization (RR: 0.73; 95% CI: 0.63 to 0.85). Fewer children treated with anticholinergics plus short-acting ß₂ agonists reported nausea and tremors compared to short-acting ß2 agonists alone; no significant group difference was observed for vomiting. Authors conclude that inhaled anticholinergics given in addition to β2-agonists are effective in reducing hospitalizations in children arriving in ED with a moderate to severe asthma exacerbation [25]. Only one study yielded a different result, however it should be noticed that MDI plus spacer was used [26]. It was a prospective, single-blinded, randomized, controlled, equivalence trial in a tertiary pediatric ED, including 347 children, and showing that the addition of ipratropium bromide was not significantly associated with a reduction in admission rates [26]. In a 2014 Cochrane review, including 4 studies on 472 children admitted to pediatric wards, no evidence of benefit for length of hospital stay nor other markers of response to therapy was noted when nebulised anticholinergics were added to short-acting β2-agonists [27].

Systemic steroids (SS) have been reported to be effective in the treatment of acute asthma attack in children, with no difference between oral or intravenously/intramuscle route of administration [28]. Therefore the oral steroids are preferable, in the absence of vomiting. Dexamethasone, prednisone, and prednisolone are equally effective even if dexamethasone is associated with a higher risk of vomiting [28]. A recent open randomized trial [29] and one meta-analysis including 6 pediatric studies [30] demonstrated no different efficacy between prednisone and dexamethasone in children with acute asthma attack. However, this meta-analysis concludes that “emergency physicians should consider single or 2-dose dexamethasone regimens over 5-day prednisone/prednisolone regimens for the treatment of acute asthma exacerbations”, due to easier administration and less side effects with dexamethasone [30]. A recent meta-analysis including 18 studies with a total of 2438 participants assessed the efficacy and safety of any dose or duration of oral steroids versus any other dose or duration of oral steroids for adults and children with an asthma exacerbation [31]. Literature data was not sufficient to discriminate whether shorter or lower-dose regimens are less effective than longer or higher-dose regimens, or indeed more adverse events are associated with the latter. Thus, authors underline that some regimen characteristics including palatability, regimen duration, and costs should be considered in order to improve adherence in individual patients [31]. Another recent meta-analysis, including 10 RCT in children, concluded that dexamethasone is likely to have less adverse effects than others corticosteroids, and similar efficacy in reducing hospitalizations and revisits [32].

Considering the time needed to induce gene expression and protein synthesis, the majority of pharmacological effects of steroid are not immediate, but are evident some hours after their intake. However, glucocorticoids can have rapid effects on inflammation which are not mediated by changes in gene expression [33]. Therefore their efficacy is optimized by an early use. Accordingly, an inverse association between time of administration and risk of hospitalization has been reported in a systematic review [34]. Steroid intake within the first hour from admission to the ED was associated with a significantly reduced time spent in the ED and a lower hospitalization rate [33].

The optimal duration of steroid therapy is unclear, some experts would suggest prolonging this therapy for 3 to 5 days, with no need to taper the dose at the end, particularly using molecules with short or intermediate half- life [34]. In a recent review acute single or recurrent systemic short-term (< 2 weeks) steroids in children with asthma exacerbations did not show any concern about short-term adverse effects [35].

However, it is important to underline the long-term risks caused by recurrent administration of oral steroids in children with asthma. Literature data report that children who require more than four courses of oral corticosteroids as treatment for underlying disease, including asthma, are at increased risk of fracture [36]. Furthermore, the CAMP study demonstrated that multiple oral corticosteroid bursts over a period of years can produce a dose-dependent reduction in bone mineral accretion and increased risk of osteopenia in children with asthma [37].

Six randomized controlled trials, overall including 1302 children, and 4 systematic reviews [38‐47] were evidenced through the literature search. Moreover other important studies, although published before 2009, have been considered [48]. Higher clinical efficacy of inhaled high-dose corticosteroids (ICS) with respect to the placebo was observed in one randomized controlled trials (RCT) [38]. The addition of nebulized high-dose budesonide was evaluated in adjunction to standard therapy without oral steroids in children with moderate-to-severe acute asthma exacerbation [38]. Complete remission rate was significantly higher (84.7% vs. 46.3%; P = 0.004) and need for oral corticosteroids was significantly lower (16.9% vs. 46.3%, P = 0.011) in the group receiving budesonide than in control group [38].

Two RCTs, whose results have been reported in three manuscripts [39‐41], showed that addition of high dose ICS to standard asthma attack therapy, including SS, was not associated with clinical improvement after one and 2 h. However, in one study, it was associated with a decreased admission rate of children with severe acute asthma [40].

Two randomized clinical trials compared the effectiveness of high-dose of ICS vs, SS [42, 43], the results showed that ICS and SS have the same efficacy to improve clinical symptoms. However, one study [38] showed that in the group treated with high doses of budesonide (800 μg/ 20 min) there was an increase in the percentage of children discharged from hospital after 2 h compared to the group treated with prednisolone (2 mg/kg).

A systematic review including eight studies published between 1995 and 2006 [44] showed no differences in the treatment with high-dose ICS or SS regarding admission rates, ED visits and rescue medications.

Two Cochrane reviews [45, 46], including both adult and pediatric studies, conclude that there is insufficient evidence that ICS treatment results in clinically important changes in pulmonary function or clinical scores when used in acute asthma in addition to SS [45, 46]. Therefore there is insufficient evidence that ICS therapy can be used in place of SS therapy when treating acute asthma [45, 46]. A 2012 Cochrane Review [47] evaluated the effectiveness of the ICS treatment after discharge from ED and concluded that ICS provides no additional benefit to standard therapy with SS in the post-discharge treatment of children with acute asthma. In conclusion, there was some evidence that high doses of ICS can be as effective as SS in the post-discharge treatment of children with acute asthma. However, it should be noticed that the settings where the trials have been performed - including specifically dedicated nurses and/or doctors - are difficult to replicate in the everyday practice in ED or ambulatory. In such situations, prudently, SS should be preferred. In addition, higher cost of ICS should be considered.

Several studies are available comparing the efficacy of aminophylline in different clinical settings (i.e. aminophylline compared to placebo when added to inhaled β2-agonists, or compared to iv salbutamol in more severe attacks) [49]. In a recent review results from 12 RCTs, involving 586 children, and comparing aminophylline with placebo or usual treatment were summarized [49]. Improvement in clinical severity scores was found in 3 RCTs but not confirmed in other six, while 2 RCTs showed improved lung function scores and two did not [49]. One trial showed that iv aminophylline reduced ICU admission rates, but no trial evidenced any benefit of aminophylline on length of hospital or ICU stay [49]. Seven out of these 12 trials have been included in a 2005 Cochrane review [50]. This review concluded that intravenous aminophylline improved lung function within 6 h of treatment, but did not appear to reduce symptoms or length of hospital stay, and there was insufficient evidence to evaluate its impact on ICU rates [50]. In conclusion, in the setting of moderate asthma attack, the association of aminophylline to inhaled β2 agonists and steroids in acute asthma does not offer substantial benefits [49, 50].

In the setting of severe asthma attacks data of the literature comparing iv salbutamol with iv aminophylline are poor [49, 51], and no substantial difference of efficacy emerges between the two drugs. In particular, iv aminophylline and salbutamol (or terbutaline) have been compared, head-to-head, in 4 RCTs including 202 children [49]. In three trials no different clinical severity scores were reported between iv salbutamol and iv aminophylline. Moreover no difference was observed in the one study reporting ICU admission rates and in two RCTs reporting length of hospital stay [49]. No study reported lung function outcomes. These paediatric studies have been included in a subgroup analysis in a Cochrane review [51], concluding that there was no consistent evidence to help decide between iv aminophylline and iv salbutamol as therapy of choice. In a recent study, a single i.v. dose of magnesium sulphate, added to inhaled β2 agonist and SS, was more useful and safe than iv aminophylline in 100 children with severe acute asthma [52]. In summary, the administration of iv aminophylline can be considered in addition to usual care in patients with impending respiratory failure and in those who have shown a good response to the drug in the past [2, 16, 17]. Serum levels measurements are needed, especially in patients already being treated with oral aminophylline [2, 16, 17]. Few studies are available regarding the use of low dose of aminophylline but further data are needed regarding this issue [53].

Epinephrine does not offer any advantages compared to β₂ agonist in the treatment of acute asthma and is associated with a greater risk of side effects, especially in hypoxemic patients. Epinephrine could be used if β₂agonists are not available [2, 16, 17].

The childhood experiences are still limited and related to the use of a single dose of 25–40 mg/kg iv. In a recent RCT of moderate quality [54] in 143 children with severe asthma, the intravenous administration of magnesium sulphate during the first hour was associated to a significant decrease in the number of patients who required mechanical ventilation. In a pharmacokinetic study [55] in 19 children with severe asthma, a bolus of magnesium sulphate (50–75 mg/kg), followed by continuous infusion (40 mg/kg/h) for 4 h, was safe and maintained appropriated levels of Mg in serum.

There are conflicting data about the use of nebulized MgSO4 in addition to β₂ agonists in asthma exacerbations [56, 57].

One RCT that included 508 children with severe acute asthma [58] compared the effect of nebulized magnesium sulphate to placebo. In the treated group there was a statistically significant improvement in asthma score after 60 and 240 min. However, the clinical relevance of this finding is uncertain. No serious adverse event was observed in 19% of patients in the Mg group and in 20% of the controls. Moreover, the study concludes there might be a role for nebulised MgSO4 in children with a severe exacerbation whose SaO2 in air after the first nebulised treatment remains below 92%, and in those with a shorter duration of symptoms [58]. Similarly a role of nebulised MgSO4 has been considered by other authors [59], but further studies are needed at this regard.

A recent RCT evaluated the effect of nebulized MgSO4, on FEV1 and PEF in children with asthma induced by acetylcholine [60]. The nebulized MgSO4 showed a wide bronchodilator effect but the rise in FEV1 and PEF was not superior to salbutamol. There is no evidence to support that the combination of salbutamol and magnesium sulphate displays a synergistic effect. No significant adverse event risk was reported.

A recent meta-analysis [61] including 5 studies (182 children) demonstrated that treatment with iv MgSO4 reduced the odds of admission to hospital by 68%. Adverse events have not been reported consistently with magnesium sulphate therapy.

A gas mixture containing helium / oxygen (Heliox) can decrease respiratory failure and improve ventilation in patients with airway obstruction. The use of this mixture is not indicated in mild-moderate asthma. It can be used as an alternative to oxygen in severe asthma not responding to the initial treatment [62].

According to results of a systematic review of 5 pediatric RCT (1996–2010) and 143 children, there are insufficient data to support the routine use of heliox in acute asthma. In particular, not benefits in terms of rate/length of hospitalization, nor percentage of children requiring intubation have been demonstrated [63]. However, it is a safe therapy, and some data suggest that it may be beneficial to patients with severely impaired lung function. A systematic review and meta-analysis [64], including 3 pediatric studies and 113 children, showed that heliox used as a vehicle to deliver β₂ agonist (compared to oxygen) was associated with improvement of acute asthma, especially in most severe attacks. It also was associated with reduced need for hospitalization [64].

Notably, to administer the heliox, a non-rebreathing high-flow system is needed. Heliox needs a high flow of oxygen to the appropriate sized particles.

A Cochrane review was available including 1470 adults and 470 children (aged 2–12), treated for acute asthma in ED and randomized to receive montelukast or placebo in addition to standard therapy [65]. No statistically significant difference was found in the risk of hospitalization with the use of oral montelukast in addition to standard therapy [65]. These results have been recently confirmed by Wang and colleagues in one trial comparing montelukast versus placebo in 117 children, aged 2 to 5 years, demonstrating no difference in PEF and lung function improvement [66].