Issues in the use of inhaled medications in children

October 2001

Giving medications by the orally inhaled route is common in infants and children. Various drugs can be administered by metered dose inhaler (MDI) or nebulization. Other agents can be given by dry powder inhaler (DPI), although these are usually reserved for older children, as inhalation requires more effort with these devices. The most commonly used drugs given by the inhaled route are probably corticosteroids and ß-agonists for asthma and other obstructive respiratory conditions. While nearly any liquid can potentially be given by nebulization, only one antibiotic is commercially available for nebulization. Tobramycin is approved for use in the treatment of pulmonary disease in patients with cystic fibrosis who have had Pseudomonas aeruginosa cultured from bronchial secretions. This month’s column will review several issues in the use of orally inhaled medications in children.

Drugs can be administered by inhalation to children through MDI, nebulization, or DPI. Several factors contribute to the efficacy of these formulations, such as patient preference, patient technique, efficiency of the delivery device, and attributes of the drug formulation. The most important are patient technique and the delivery device used. Medication administration by nebulization and MDI are the most commonly used methods. DPI, because they are activated by inspiration, are more suitable for older children. Use of nebulizers to administer medications can be greatly influenced by the quality and efficiency of the nebulizer.

Different types of nebulizers exist, with differing efficiencies, and it is quite possible that an older or poorly maintained nebulizer may be relatively inefficient at delivering an adequate dose of medication. Many clinicians view nebulizers as the most effective means to administer asthma and other medications to children. Patients may view nebulizers similarly, for they are commonly used in emergency departments and office settings. Nebulizers generally require less effort and less coordination than a MDI, although they can be noisy, expensive to purchase and operate in clinical settings (through respiratory therapy charges), require an external power source and require a child sit still for approximately 10 minutes.

Medications given by MDI require some degree of coordination, which can be minimized with use of a valved holding chamber, often referred to as a spacer. Use of a MDI and spacer is less cumbersome than use of nebulizer, less costly, and can be equally as effective as a nebulizer in many patients.

Several types of spacer devices are available, and they can vary in effectiveness with differing MDI products. Spacers serve several purposes. They reduce the amount of drug deposited in the oropharynx by reducing inhalation of larger particles of the actuated spray. Particles >5µm are too large for small airway deposition and deposit in the oropharynx, increasing systemic absorption by swallowing. Spacers also reduce the coordination necessary with MDI use, by temporally holding the actuated spray, thus allowing more time for the child to inhale. Spacer devices may be used with attached face masks in younger children, and have shown to be effective in children as young as 12 months. Spacer devices can be used effectively with ß-agonist MDI products and should be used with corticosteroid MDI products, for they reduce oropharynx deposition and concomitant systemic absorption.

Nebulizer vs. MDI

The literature includes numerous studies comparing the effectiveness of nebulized bronchodilators (ß-agonists) versus bronchodilators given by MDI (usually with a spacer device). Most of these studies have shown equivalence in efficacy in mild/moderate and even severe bronchoconstriction. Studies of children have included patients as young as 1 year. The Expert Panel Report 2 (Guidelines for the Diagnosis and Management of Asthma) published in 1997 by the National Institutes of Health states that studies have shown equivalent bronchodilation can be achieved in the treatment of an acute asthma exacerbation by high doses (6-12 puffs) of a ß-agonist/spacer as with nebulization.

Ploin recently conducted a randomized, double-blind trial in emergency departments with children 12-60 months of age comparing albuterol by MDI-spacer to albuterol by nebulization. Doses given were 1 puff/2 kg by MDI (maximum 10 puffs) or 0.15 mg/kg by nebulization, repeated for 3 doses at 20-minute intervals. A pulmonary clinical scoring system (pulmonary index) was used to assess lung function. Most patients entered the study with moderate wheezing and a mean pulse oximetry oxygen saturation of 95%. Results of this study showed equivalence in pulmonary index scores after treatment. Most parents considered the MDI-spacer easier to use and better accepted by their children.

Schuh also evaluated in a randomized, double-blind manner, administration of albuterol by MDI-spacer to albuterol by nebulization. Children between 5 and 17 years of age in an emergency department were given a single dose of albuterol by MDI-spacer (either high dose [6-10 puffs] or low dose [2 puffs]) or nebulizer (0.15 mg/kg) and were evaluated by peak flow, clinical scoring and oxygen saturation. Children entered had baseline FEV₁ values of 50%-79% of predicted. All treatment groups had similar responses to treatment, although children treated by nebulizer had significant increases in heart rate. As with the study by Ploin, most parents considered treatment by MDI spacer more convenient. Other studies, too numerous to describe here, have reached similar conclusions – that MDI spacers are clinically equivalent to nebulizers for bronchodilation in nearly all patients in a variety of settings.

Cost

Several studies have also evaluated cost issues when comparing MDI spacers with nebulizers. Bowton assessed the impact of routinely substituting albuterol MDI spacer devices for nebulization in a large tertiary-care hospital over a 7-month period (patient ages not specified). The policy resulted in >60% of all aerosol therapy given by MDI spacer. Time spent by respiratory therapists providing aerosol therapy fell by 37% while total costs for delivering aerosol therapy were decreased by 25%. It was estimated that patient charges were reduced by $300,000 per year. Leversha compared costs of albuterol by MDI spacer (6 puffs) with nebulization (2.5 mg) in children 1-4 years of age with moderate-severe acute asthma in an emergency department from a randomized, double-blind trial. Treatment with the MDI-spacer was equally effective as nebulization as judged by clinical score, respiratory rate and oxygen saturation. Significantly more children in the nebulizer group required hospital admission. Emergency department costs were reduced by 35%.

Adult studies

In a meta analysis, Turner reviewed the adult literature from 1966-1994, assessing studies comparing bronchodilator delivery by MDI or nebulization. Twelve studies totaling 507 patients (acute asthma or chronic obstructive pulmonary disease) were included. There was no difference in efficacy between administration by MDI or nebulization. Amirav evaluated the literature between 1980 and 1996 for studies comparing MDI spacers to nebulizers in children with acute asthma. Ten randomized trials were selected for review, although study selection criteria were not clearly explained. The selected trials differed markedly in MDI spacer devices used, drug used (bronchodilator), doses and dosing schedule.

Two studies concluded that MDI spacers were more effective, while the remainder found equal efficacy. Dose ratios (dose by MDI: dose by nebulizer) ranged from 1:1 to 1:6.9, indicating a relative inefficiency of nebulizers compared with MDI. A Cochrane Review similarly has been published which reviewed literature (Cochrane Controlled Trials Register) of randomized clinical trials comparing ß-agonists given by nebulizers to MDI spacers for acute asthma in children (>2 years) and adults. Sixteen trials totaling 686 children and 375 adults were evaluated, and it was concluded that MDI spacer delivery was equally effective as nebulization, and may offer advantages over nebulizers. Additionally, it was found that children’s length of stay in emergency departments was significantly shorter when MDI-spacer devices were used.

The literature also includes several editorials accompanying many of these published studies (Kercsmar, Newhouse). Many of the editorial authors express confusion as to why more patients are not treated with MDI spacer devices as compared with nebulizers. Their critiques of the literature conclude that MDI spacers are equivalent to nebulizers for bronchodilatory therapy, often with a more rapid effect, fewer adverse effects and at a lower cost. At least one author has stated the debate over equivalence between MDIs and nebulization has been solved. Other advantages of MDI spacer use in emergency departments, clinic offices, or hospitals, discussed includes opportunities for health professional staff to review patient technique, and a message sent to patients that MDIs are effective (when they are used in acute situations).

Appropriate technique of use

As mentioned above, technique of use with MDI spacer devices as well as nebulizers, is one of the most important determinants of efficacy when drugs are administrated by aerosol therapy. Although it is beyond the scope of this column to completely review correct use of all types of nebulizers or MDI spacer devices, a general review is warranted (see table). It is important for clinicians to review patient technique of use when given the opportunity (eg, office visits). It is also important to consider that not all MDI spacer devices or nebulizers are interchangeable. Clinicians should consult respiratory therapists or the literature (Lakamp) for more information on appropriate use of these devices. MDI spacer devices can be used in infants and small children when attached masks are used. Amirav recently evaluated the ability of parents to provide a good mask-face seal with three spacer masks. Significant variability among the masks was found. The AeroChamber mask was among the most efficient at providing a good seal. The importance of a good mask-face seal should be emphasized to parents.

For more information:

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children's Hospital, Des Moines, Iowa.

• Ploin D. High-dose albuterol by metered-dose inhaler plus a spacer device versus nebulization in preschool children with recurrent wheezing: a double-blind, randomized equivalence trial. Pediatrics. 2000;106:311-7.
• Schuh S. Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma. J Pediatr. 1999;135:22-7.
• Bowton DL. Substitution of metered-dose inhalers for hand-held nebulizers. Chest. 1992;101:305-8.
• Leversha AM. Costs and effectiveness of spacer versus nebulizer in young children with moderate and severe acute asthma. J Pediatr. 2000;136:497-502.
• Turner MO. Bronchodilator delivery in acute airflow obstruction. Arch Int Med. 1997;157:1736-44.
• Amirav I. Metered-dose inhaler accessory devices in acute asthma, efficacy and comparison with nebulizers: a literature review. Arch Pediatr Adol Med.1997;151:876-82.
• Cates C. Holding chambers versus nebulizers for beta-agonist treatment of acute asthma (Cochrane Review). In: The Cochrane Library 2001;3.
• Kercsmar CM. Aerosol treatment of acute asthma: and the winner is… J Pediatr. 2000;136:428-30.
• Newhouse MT. Asthma therapy with aerosols: are nebulizers obsolete? A continuing controversy. J Pediatr. 1999;135:5-7.
• Lakamp RE. Compatibility of spacers with metered-dose inhalers. American Journal of Health System Pharmacists 2001;58:585-90.
• Amirav I. Aerosol therapy with valved holding chambers in young children: importance of the facemask seal. Pediatrics. 2001;108:389-94.