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EVIDENCE BASED MANAGEMENT OF SEVERE ASTHMA

IN THE EMERGENCY DEPARTMENT

Suzanne Schuh, MD, FRCP(C), FAAP, ABPEM

Professor of Paediatrics

Staff Paediatrician & Research Director

Division of Paediatric Emergency Medicine

Associate Scientist, Research Institute

Hospital for Sick Children

University of Toronto

1

Monitoring and Oxygenation

Recognition of high-risk patients with an acute asthma exacerbation is essential. Risk factors

include previous life threatening episodes requiring ICU admission, recent multiple ED visits,

poor compliance with therapy, excessive use of short-acting 2 agonists, and/or signs of severe

respiratory distress such as difficulty talking/feeding, excessive fatigue, marked suprasternal

retractions/nasal flare, grunting, or a feeble respiratory effort [1, 2]. The degree of accessory

muscle use has been shown to correlate most closely with the severity of airway obstruction and

with oxygen saturation [3].

Children with transcutaneous oxygen saturation of 90% or less usually require supplemental

oxygen. However, adequate oxygenation does not always indicate adequate ventilation and must

always be interpreted in the context of the child’s degree of respiratory distress. A recent study

by Keahey et al showed that while the initial saturation of 88% or less signals subsequent

hospital admission, this test of little value of predicting hospitalization in the majority of children

with acute asthma [4]. Arterial blood gases are rarely necessary but should be done if the child

presents in extremis and/or deteriorates on intensive therapy. A low pH with CO2 values above

40 mmHg with a rising trend and rising oxygen requirements often serve a supplementary

evidence for ICU monitoring and/or for strong consideration for artificial airway placement.

Bedside spirometry may be useful in children over six years of age in whom there is question

regarding diagnosis, in those with discrepancy between history and objective findings, in patients

with suspected poor compliance with treatment and in those with past severe attacks who present

2

with relatively mild respiratory distress. In general, FEV1 less than 50 percent predicted value

indicates severe disease.

The goals of ED therapy are to relieve hypoxemia, to reverse airway obstruction and to prevent

early relapse.

2 Agonists

A short acting 2 agonist such as salbutamol (albuterol) is considered the first-line treatment for

acute asthma, both for stabilization in the ED and for several days after discharge. Despite long

experience with 2 agonists in the ED, there are unanswered questions such as which drug should

be used, whether to use nebulization or MDI/VHC for delivery and what is the most appropriate

dose for each method of therapy.

The nebulization route represents the preferred method of administration of 2 agonists in

pediatric EDs. Approximately 80% of airway dilatation occurs within five minutes and peak

effect within 30 minutes of therapy [5]. Compared to oral or IV administration, following

aerosolization a given degree of bronchodilation is achieved with greater efficacy and with fewer

side effects [6]. Several studies have shown efficacy and safety of frequent or continuous

administration of nebulized 2 agonists in severe disease [7]. A useful regime includes

salbutamol 0.15 mg/kg/dose (up to 5 mg) q20 minutes until a clinical response is achieved;

hourly administration is given to children with less severe disease [8]. However, many clinicians

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use adult doses of salbutamol for pre-school and school-aged children and half the adult dose for

infants and toddlers without evidence of toxicity. Side effects are usually mild and well

tolerated. They include hyperactive, skeletal muscle tremor, tachycardia and hypokalemia [9].

Arrhythmias are very rare. Potassium monitoring and supplementation may be considered in

children with prolonged frequent administration of 2 agonists (usually inpatients) and/or those

with underlying diuretic therapy.

A theoretical advantage of using levalbuterol is that it contains pure bronchodilating R-albuterol

whereas the conventional albuterol also contains an equal amount of S-albuterol, which was

thought to have deleterious effects [10]. However, a recent work shows that S-albuterol is likely

inactive [11]. Furthermore, the substantial cost of levalbuterol has not been shown to be offset

by other savings such as hospitalizations and conventional albuterol therefore remains the

preferred choice.

In severe cases, albuterol can be given either by back-to-back (frequent) nebulizations or

continuously. To date no pediatric study has conclusively demonstrated that continuous delivery

offers substantial advantages such as lower hospitalization rate or greater improvement in

pulmonary function, although one study suggests more improved clinical scores in children

receiving continuous therapy [12]. However, children on continuous nebulization therapy may

go unobserved for longer periods of time whereas frequent intermittent therapy dictates

numerous re-evaluations. For now therefore frequent intermittent therapy is likely preferable.

4

Recent evidence suggests that approximately 75% of pediatric emergency physicians use

nebulizers in delivering 2 agonists in stabilization of children with acute asthma, including those

with severe disease [13]. The main advantage of nebulizers includes their ability to deliver

supplemental oxygen. However, the dose and particle characteristics of the aerosol generated

depend on technical factors, which vary greatly among different nebulizers [14, 15]. Lung

deposition from conventional nebulizers in children ranges from 0.7% in infants to 6.5% in older

children [16-18]. The new designs of nebulizers such as breath enhancement greatly increase the

efficiency of nebulizers [19, 20]. The main disadvantages of nebulizers include their bulkiness,

time required for inhalation, requirement for an electrical source, need for maintenance and their

cost. Also, the lung deposition may be 60% lower when the child is crying [21].

In contrast to nebulizers, the advantages of using MDI’s include greater efficiency of delivery

[22], speed of administration [23, 24], improved cost-effectiveness [25], and greater portability.

Their disadvantage is that aerosol discharge and inhalation must be coordinated to achieve

effective treatment. VHC’s with a mask or a mouthpiece have to be used with MDI’s for

effective aerosol delivery, so that precise coordination between actuation and inhalation is not

necessary. The VHC’s also help ensure that the ratio of the amount of the drug deposited in the

lung (desirable) to that deposited in the upper airway (undesirable and associated with more

systemic absorption and side effects) is maximized [26]. New VHC’s such as the Aerochamber

allow reliable provision of bronchodilators to infants during tidal breathing [27] and overcome

the problem of hand-breath coordination and aerosol delivery to those young children who are

dyspneic. The use of the VHC’s increases the drug deposition to the lower airways by 15-20%

[28], with a corresponding ten-fold decrease in oropharyngeal deposition [29]. Although the

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mouthpiece avoids nasal filtering of the drug and therefore ensures enhanced drug delivery into

the lower airways by 50% [30], in infants and pre-school children pressurized MDI’s can be used

only with a VHC and mask. Mouthpieces are better than masks in school-aged children since

they increase the drug deposition in the lung at least two-fold [31] due to avoidance of nasal

filtering. Five to six tidal breaths should be taken between MDI actuations to empty the VHC.

Delivery of the drug is much higher if the VHC is washed with detergent and allowed to air dry

(no towel) to reduce electrostatic charge and enhance delivery significantly [32].

In recent years, there has been increasing tendency to use MDI to administer 2 agonists to

children of post-infancy age with acute asthma in the acute care setting. In a critical review of

bronchodilator therapy of severe acute asthma in children, Amirav concluded that MDI is as

effective as nebulizer for relieving bronchospasm using five to six times lower doses of 2

agonists [33]. Outpatient studies of children of post-infancy age have established that MDI’s

have efficacy comparable [34-36] or superior [23, 37-40] to that of nebulizers. The single

systematic review of this issue found children treated with MDI to have similar hospitalization

rates, to spend less time in the ED and to suffer fewer side effects than those given nebulizers

[41]. A survey by Tien et al shows that, despite the aforementioned evidence, only 10 to 21% of

pediatric emergency physicians use MDIs in the ED, almost exclusively for mild disease [13].

However, only pediatric studies with mean age of two years and older were included,

presumably because of paucity of relevant information in young infants.

The appropriate dose of albuterol to be given via MDI/VHC is still being determined. Previous

pediatric studies have found the equivalent dose of 2 agonists via MDI vs nebulizer to range

6

from 1:1 [38] to 1:7 [40]. An ED study of school-aged severely asthmatic children showed that

this population requires 600 mcg to 1000 mcg of salbutamol per dose to achieve improvement

comparable to those given standard salbutamol doses via nebulizer [42]. A recent CME review

article by Scarfone suggests using a starting dose of 0.5 puffs of albuterol per kilogram weight

with a maximum of 10 puffs [43], resulting in an MDI to nebulizer dose ratio of albuterol of 1:3

and allowing proportionately greater dosing for your children and infants in whom the drug

delivery into the lungs is less efficient.

With regard to a continuous versus intermittent therapy, there is no evidence in pediatric

literature of a difference in hospitalizations or in lung function between these regimes [12].

Furthermore, Scarfone’s review article points out that continuous therapy poses a danger of

prolonged periods during which children may go unobserved [43]. Therefore, intermittent

therapy is currently appropriate for most children with severe disease.

Anti-cholinergic Agents

A recent meta-analysis concluded that the addition of ipratropium bromide to nebulized 2

agonists has an additive effect in improving lung function in children with severe acute asthma

[44]. A recent study has also demonstrated reduced hospitalization rate with the use of

ipratropium in severe disease [45]. A minimum of three consecutive doses of ipratropium (250

mcg/dose) mixed with albuterol is recommended in severe asthma in the early hours of therapy

[46]. Ipratropium bromide is very safe and virtually free of side effects [46]. It is not indicated

in mild to moderate exacerbations [8].

7

Corticosteroids

The anti-inflammatory activity of corticosteroids, which takes 12-24 hours to take full effect,

happens due to indirect block of the phospholipase alpha-2 activity [47]. However,

corticosteroids also exhibit upregulation of adrenergic receptors as well as mucosal

vasoconstriction with decrease in airway edema [48] as early as 2-4 hours after administration

[49, 50]. Corticosteroids given orally are readily absorbed from the gastrointestinal tract with 15

minutes and appear to be as effective as intravenous preparations [51].

A short course of oral corticosteroids is indicated in all cases of moderate to severe acute asthma.

Evidence suggests that oral corticosteroids decrease the rate of hospitalizations from the ED

within four hours in severe asthma exacerbations [52] and also decrease relapse rates following

acute asthma episodes [53-55]. Those children who do need hospital admission stay in hospital

for a shorter period of time if they receive systemic corticosteroid therapy [56]. Corticosteroids

should be commenced in appropriate cases in the ED as soon as possible, either before or after

the first inhalation of bronchodilators. Useful regimes in the ED include prednisolone or

prednisone 2 mg/kg in the first dose and 1 mg/kg/dose q24 hours for four subsequent doses [57].

The biologic half-life of these corticosteroids is approximately 12-36 hours [58] and they have to

be administered every 24 hours. Due to poor taste and large volumes, prednisone and

prednisolone are often poorly tolerated by young children. Literature suggests incidence of

vomiting of prednisone to be 3-15% [49, 59, 60], which often necessitates repeating the dose.

For this reason, a more practical approach may include administration of oral dexamethasone.

Dexamethasone syrup can be prepared from the IV preparation according to our recipe.

8

Dexamethasone has a long biologic half-life of up to 48 hours [61]. Other advantages of

dexamethasone include six times lower equivalent dose compared to prednisone [58] and

pleasant taste. A recent study shows that two doses of oral dexamethasone (0.6 mg/kg/dose)

provide similar efficacy as five doses of prednisone (2 mg/kg/dose in the ED and 1 mg/kg/dose

for four daily doses after discharge), with improvement compliance and fewer side effects [62].

According to an accompanying editorial, EDs should consider this protocol for asthma

management [63]. Numerous children with asthma are treated with systemic corticosteroids

without any problems. However, if possible duration of corticosteroid therapy should be

minimized since frequent high dose or prolonged corticosteroid therapy can cause adrenal

suppression [64] and has been associated with rare cases of opportunistic infections [65].

Can children with acute asthma exacerbations be stabilized with inhaled corticosteroids? A

recent systematic review of seven trials, two of which were pediatric, concluded that at present

there is insufficient evidence that inhaled corticosteroids alone are as effective as systemic

corticosteroids and that further research is necessary in this area [66]. The studies on this subject

have yielded disparate results. A pediatric study by Scarfone suggested that nebulized

dexamethasone exerts comparable benefit to oral prednisone in the ED within four hours of

therapy [49]. However, nebulized dexamethasone is absorbed systemically and the benefit may

therefore relate to this property. A recent study with 100 children with severe asthma

exacerbations favors the use of oral prednisone as compared to inhaled fluticasone (2 mg/dose)

during the initial four-hour stabilization period in the ED, with hospitalization rate of 31% in the

fluticasone group and 10% in the prednisone group [67]. While most physicians agree that

systemic steroids are preferred to inhaled corticosteroids for stabilization of severe acute asthma,

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little work has been done with examining the role of inhaled corticosteroids in children with

milder disease.

Inhaled corticosteroids have been shown to prevent asthma exacerbations [68] and they are

therefore recommended following stabilization of moderate to severe attacks. A useful regime

includes fluticasone propionate 100-150 mcg bid via MDI/VHC for a 4-6 week period.

Magnesium

Children with severe disease who do not respond to the aforementioned treatment often benefit

from IV administration of magnesium sulfate. Magnesium appears to be involved in regulation

of the receptor adenylate cyclase complex [69]. Magnesium is a calcium antagonist, and also

functions as a cofactor in enzyme systems involving sodium and potassium flux across cell

membranes [69]. These properties contribute to its role as a smooth muscle relaxant, block in

cholinergic neuromuscular transmission and stabilization of mast cells [70, 71]. Recent studies

of children with severe acute asthma showed significantly greater improvement in spirometry in

those receiving 25 mg/kg of IV magnesium sulfate as compared to placebo 30 minutes after

infusion [72]. An even earlier and greater effect on pulmonary function and a lower

hospitalization rate has been achieved in children receiving 40 mg/kg IV magnesium sulfate

versus placebo [73]. Likely candidates for magnesium include critically ill children, especially

those who do not respond well to systemic corticosteroids and frequent 2 agonist nebulizations.

Many of these patients are also candidates for care in the ICU. The above results suggest that IV

magnesium should be considered in children with poor response to the initial triad of nebulized

10

2 agonists in an attempt to decrease hospitalization rate. No side effects were identified in the

previous magnesium trials.

Respiratory Failure

Although a vast majority of children respond to the above therapy, a few develop increasing

fatigue with progressive hypoxemia and hypercapnia. Infants tend to be at an increased risk of

respiratory failure compared to their older counterparts due to their small airway, compliant rib

cage and larger concentration of mucous glands in the respiratory tree [74]. Provision of 100%

oxygen and continuous cardiopulmonary monitoring in a resuscitation room with frequent

reassessments is essential. Aggressive nebulized bronchodilator therapy with

back-to-back/continuous albuterol administration should be provided and may avert the need for

ventilation in some cases [75]. Several doses of ipratropium bromide added to the salbutamol at

20-minute intervals may also be helpful. Intravenous corticosteroids need to be given. A trial of

IV magnesium sulfate is warranted [73]. Children unresponsive to this intervention should be

started on intravenous salbutamol infusion. In our experience, this intervention sometimes

obviates the need for intubation and ventilation but research into this therapy is very limited [76,

77]. Intravenous salbutamol is usually given in the ICU setting but can be commenced in the ED

if necessary. The initial loading dose is 1 mcg/kg/minute for 10 minutes, followed by a

continuous infusion of 0.2 mcg/kg/minute. This dose can be increased by 0.1 mcg/kg q15

minutes, depending on the child’s response.

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The need to intubate a child with acute asthma is rare and usually involves an exhaustive,

somnolent and moribund looking patient. There is no absolute CO2 value above which

intubation is mandatory. Rather serial changes in CO2 levels and oxygen requirements must be

interpreted together with clinical changes after aggressive therapy. Ketamine is a useful sedating

agent for intubation, due its bronchodilator properties.

Considerations for Hospitalization

The decision to hospitalize children with asthma depends on the initial clinical assessment and

response to therapy. No single pre-treatment objective measure can reliably determine the need

for hospital admission. A recent study by Keogh et al found that the presence of three or more of

the following five parameters is associated with greater than 92% probability of the need for

hospitalization. The parameters are as follows: past ICU admission for asthma, baseline oxygen

saturation 92% or less, moderate to severe respiratory distress four hours following

corticosteroid therapy, oxygen saturation 92% or less four hours following corticosteroid

therapy, and inhaled albuterol more often than every hour four hours following corticosteroid

therapy [78]. A large multi-centre trial found that pre-treatment room air oxygen saturation on

its own is not a useful predictor for hospitalization; only children with saturation 88% or less

have 73% hospitalization rate, with a likelihood ratio for admission of 12 [4]. Non-medical

factors such as poor compliance with therapy or a long driving distance to hospital may also play

a role in the decision to hospitalize.

12

Discharge Planning

Virtually all children with acute asthma are discharged on inhaled 2 agonists. Since the

MDI/VHC route of delivery has not yet been shown to be effective in the acute phase therapy of

young asthmatic infants, most children under five to six months of age are discharged on

nebulization therapy (usually 0.15 mg/kg/dose q4h) for seven days, with gradually increasing

intervals between doses. Most children over six months of age can be discharged on salbutamol

via MDI/VHC. Those with severe disease benefit from 0.3 puffs/kg/dose q4h in the initial 24

hours [42], whereas lower doses of 2 puffs usually suffice for children with mild disease [79].

Detailed instructions regarding proper use of the VHC must be provided. Infants and pre-school

children take albuterol during tidal breathing, with five to six normal breaths between puffs,

while school-aged children follow deep inhalation technique with each puff. VHC with a

mouthpiece is recommended for children over six years of age. A course of oral prednisolone (1

mg/kg/dose q24 hours) for five days should be given to children with moderate to severe

exacerbations. Inhaled corticosteroids should be commenced for a four to eight week period to

prevent further exacerbations. At present, evidence for efficacy of inhaled corticosteroids alone

in the acute asthma therapy is not clear. In fact, a recent trial suggests that children with severe

disease do better on oral than inhaled corticosteroid therapy. Therefore at present time inhaled

corticosteroids should not be used alone in stabilization of children with acute asthma.

A follow-up by the primary care physician within 24 to 48 hours is advisable to provide the

opportunity for reassessment and further education. A recent study demonstrated efficacy of

home education programs by a nurse for children hospitalized for acute asthma [80].

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