Off-label use of drugs in neonatal and pediatric patients

The term off-label is used to refer to drugs lacking U.S. Food and Drug Administration (FDA)–approved dosing information for a specific age group or condition.⁵ Off-label prescribing is a commonly used and accepted medical practice. Although these drugs do have FDA approval, the approval is for a different use. Aspirin has been a common pain reliever for more than 100 years; in 1988, physicians began prescribing its use in preventing heart attacks. Use of aspirin for the prophylaxis of heart attack is considered an off-label use. It has been estimated that nearly half of all prescriptions today are written for off-label uses. Infants, children, and pregnant women are the most common groups in which off-label use medications are prescribed. More than 70% of the entire Physicians’ Desk Reference (PDR) entries have either no existing dosing information for pediatric patients or specific statements that the safety and efficacy in children have not been determined. It has been reported in the United Kingdom that when a “suitable alternative” did not exist, physicians prescribed unlicensed or off-label medicine in 90% of neonates in neonatal intensive care units, 70% of children in pediatric intensive care units, and two-thirds of children on general medical and surgical pediatric wards.

Even though the drug labeling often states that safety and efficacy in children have not been determined, many of the inhaled aerosol drugs reviewed in this text have clinical indications and uses in neonatal and pediatric patients. Virtually all inhaled β agonists and corticosteroid formulations have been approved by the FDA in patients older than 12 years.

Table 17-1 lists inhaled aerosol drugs and leukotriene modifiers that currently have an approved age labeling for pediatric use at the time of this edition. Drugs that are not listed in Table 17-1 do not have labeling for pediatric use. In March 2004, the U.S. Patent and Trademark Office (USPTO) issued a patent covering AccuNeb, the only FDA-approved (in 2001) lower concentration, unit-dose albuterol sulfate for the treatment of asthma in children 2 to 12 years old.

In 1994, the Center for Drug Evaluation and Research of the FDA issued guidelines encouraging pediatric testing of drugs.⁶ A subsequent FDA ruling mandated that drugs submitted for FDA approval after December 2000 be evaluated in children. Waivers can be given if the drug has no meaningful application in children or is likely to be unsafe or ineffective in pediatric patients.⁷ There is a substantial cost associated with additional studies to document safety and efficacy in pediatric patients. The creation of the “pediatric rule” has provided the pharmaceutical companies that carry out studies with pediatric patients an economic incentive by allowing extended time of marketing before generic formulations of the product are marketed.⁸ The FDA cannot, by law, regulate how a drug is used medically or “interfere with the practice of medicine.”⁵

Although it is legal for physicians to prescribe off-label use of drugs, drug dosing becomes more problematic when standardized dose guidelines have not been previously developed during drug clinical trials. Generally, drug dosing with inhaled aerosols for neonatal and pediatric patients is not based on body size and blood level but rather based on a target effect strategy with avoidance of toxicity. Aerosol doses to neonates or children are “self-limiting” because of differences between pediatric and adult airways.

Factors affecting neonatal and pediatric aerosol drug delivery

The same mechanisms of aerosol penetration and deposition in the lung that were outlined in Chapter 3 apply to aerosol therapy in neonatal and pediatric patients. The airway environment differs in neonatal and pediatric subjects compared with adults. Table 17-2 outlines functional and structural features of the infant lung that may affect aerosol delivery and deposition.

Although it may seem obvious that aerosol therapy in infants and young children is quite different from that of adults, much more research is required to confirm the differences in aerosol drug delivery. Some in vitro studies have suggested that the increasing upper airway geometry in adults may explain the higher amount of aerosol deposition reaching the lower airway compared with neonatal and pediatric patients.⁹ The nose may filter out 75% of the dose received by mouth breathing. A smaller fraction of the nominal dose of an aerosol reaches the lower airways with the child-size oropharynx compared with an adult-size oropharynx.¹⁰ The smaller diameter of neonatal and pediatric lower airways, added to the effects of bronchoconstriction, inflammation, secretions, and the possible presence of an endotracheal tube, dramatically decreases aerosolized drug deposition in the lungs.¹¹ Some of the variables associated with the reduction in lung dose in infants and young children are discussed subsequently.

Effect of age on aerosol lung dose

Systemic side effects rather than local side effects caused by treatment in the lung have been the basis for aerosol dose adjustment for age, which is usually based on body weight. However, the need for age adjustment of aerosol doses based on body weight has been clinically debated.¹² Available data suggest that the actual dose of an inhaled aerosol drug could be less than 1% in neonates and infants^13,14 and around 2.5% in young children¹⁵ compared with the traditional 10% to 15% cited for adults.^16,17 Although a smaller percentage of the aerosol deposits in the lungs, small patients may receive considerably higher drug per kilogram of body weight than adults. However, the lower deposition may provide a comparable safety and efficacy profile to that of adults.¹⁸

Anhoj and associates¹⁹ found that a pressurized metered dose inhaler (pMDI) of budesonide with a 250-ml steel NebuChamber (Astrazenica, London, UK) having less than 2 ml of dead space delivered the same approximate dose to a range of ages from 2 to 41 years. A face mask was used for children 2 to 3 years old, and a mouthpiece was used for older subjects. Although the resulting plasma concentration of drug was the same in children and adults (Figure 17-1), the inhaled dose and the dose reaching the lung were not the same. Because the holding chamber eliminated oropharyngeal and stomach loss and there is high first-pass metabolism of budesonide, plasma drug levels reflect dose in the lung. If the same dose went to the lungs in adults as in 2-year-olds, higher plasma levels would be observed in younger subjects who have smaller circulating blood volumes. This report suggests that inhaled dose need not be adjusted for age to reduce systemic levels and possible toxicity.¹⁹ When a fixed dose of 2.5 mg by nebulizer was compared with a dose of 0.1 mg/kg body weight in children 4 to 12 years old with acute asthma, there was no difference between the two dosing protocols in either clinical improvement measured by flows, oxygen saturations, and clinical score or cardiovascular and tremor side effects. The fixed dose of 2.5 mg by nebulizer was efficacious and safe.²⁰

Effect of small tidal volumes, short respiratory cycles, and low flow rates

Small pediatric patients have low tidal volume, low vital capacity, short respiratory cycle, and low inspiratory flow rates. Children inhale a smaller percentage of the emitted dose from either a small volume nebulizer (SVN) or a pMDI with a reservoir device (holding chamber or spacer). The aerosol deposition is reduced because of a short residence time in the airways. These factors can significantly alter the inhaled dose and the lung dose of patients younger than 6 months of age.

Effect on small volume nebulizer

If we assume a 6 L/min power gas, an adult with inspiratory flow of 500 mL/sec (30 L/min) and a tidal volume of 500 mL (500 mL/sec × 1 or 2 seconds) would completely inhale all of a nebulizer output. However, an infant with inspiratory flow of less than 100 mL/sec (less than 6 L/min) and a tidal volume less than 100 mL would not completely inhale all of the nebulizer output during the inspiratory phase (Figure 17-2).

Collis and associates²¹ studied the fraction of nebulizer output inspired by infants 1 to 12 months old, children 3 to 16 years old, and adults 20 to 23 years old. Infants were sedated with chloral hydrate, and tidal breathing was recorded by face mask and pneumotachygraph. The fraction of nebulizer output inspired was lower in infants younger than age 6 months, then reached a plateau and remained constant in subjects older than 6 months. Wildhaber and colleagues²² also found that inhaled aerosol dose from an SVN attached to a mask increased with weight in infants 4 to 12 months old and was lower in smaller infants.²³

Effect on reservoir dose

The same effect of low tidal volumes would theoretically reduce the amount of volume and drug mass inhaled from a reservoir chamber (Figure 17-3). The amount of reduction is proportional to the chamber volume for a given infant tidal volume. For a 50-mL tidal volume, approximately one-third of a 150-mL chamber and one-fifth (20%) of a 250-mL chamber would be inhaled. Even assuming no redistribution of aerosol in the chamber volume, gravitational settling would reduce available dose further within seconds of pMDI actuation into the chamber. The ideal volume for a spacer device is small enough to allow drug inhalation with few breaths for infants with low tidal volumes (less than 50 mL).

This theoretical prediction is supported by data from Everard and colleagues.²³ Delivery (not lung deposition) of pMDI cromolyn sodium by reservoir and face mask with tidal volumes of 25 mL, 50 mL, and 150 mL was measured in vitro using various sizes of chambers. Smaller tidal volumes were associated with decreased inhaled drug mass. Higher aerosol concentrations in a smaller chamber enhanced drug delivery with tidal volumes less than 150 mL. Introduction of dead space between the chamber outlet and the filter collecting inspired drug reduced the dose deposited by 50% or more.²⁴ The results are summarized in Table 17-3.

TABLE 17-3

Effect of Inspired Tidal Volumes on Mean (Range) Inhaled Aerosol Dose in Two Reservoir Devices

		TIDAL VOLUME (mL)
DEVICE	25	50	150
AeroChamber (150 mL)	0.33 mg (0.29-0.35 mg)	1.15 mg (1.08-1.24 mg)	1.41 mg (1.33-1.46 mg)
Nebuhaler (750 mL)	0.29 mg (0.26-0.32 mg)	0.93 mg (0.91-0.97 mg)	1.55 mg (1.48-1.61 mg)

Data from Everard ML, Clark AR, Milner AD: Drug delivery from holding chambers with attached facemask, Arch Dis Child 67:580, 1992.

In contrast, an in vivo study by Wildhaber and associates²² that showed decreasing inhaled dose from a nebulizer in infants 6 to 7 kg also found that there was no effect of size (weight) on inhaled dose for two chamber devices used with a pMDI. The two reservoir devices were the Babyhaler (GlaxoSmithKline UK, Middlesex, UK) (350-mL chamber, 40 mL dead volume) and the NebuChamber (250-mL chamber, no dead volume). The plastic reservoir device (Babyhaler, 350 mL) had the electrostatic charge removed before testing. Turpeinen and colleagues²⁴ compared the same reservoir devices and found that inhaled mass of budesonide did increase with increasing height, weight, and tidal volume with the Babyhaler but not with the NebuChamber. Such variation in study results indicates that testing conditions, type of drug, and choice of reservoir device can affect inhaled dose, although not necessarily the lung dose. Box 17-2 lists factors in reservoir devices that may affect the inhaled dose to neonates, infants, and small children.

BOX 17-2   Factors That May Affect Dose Inhaled from a Reservoir Chamber in Neonatal and Pediatric Patients

Mechanical and design factors

Chamber volume

Electrostatic charge on plastic devices

Shape of aerosol plume relative to chamber size

Design of inspiratory and expiratory valves, if present

Presence of inspiratory valve

Amount of dead volume in mouthpiece

Patient factors

Breathing pattern

Inspiratory flow rate

Tidal volume

Nebulized drug distribution

It might be obvious to the respiratory clinician that outcomes of aerosol therapy in young children are quite different from that in adults, and that much more research is required to confirm the differences in aerosol drug delivery. The most definitive data for answering the question of how much aerosol drug reaches the lungs of neonates and pediatric patients are actual measures of lung deposition. However, most radiolabeled substances used to estimate lung deposition may be harmful to children, limiting the scope of measurements.²⁵ Some available data indicate that the lung dose of an aerosol drug does in fact decrease with age. Anhoj and associates¹⁹ found that blood levels of drug, reflecting the dose reaching the lungs, were constant in younger and older subjects, despite the smaller circulating volume of younger patients.

It has been hypothesized that the greater the infant’s distress, the lower the lung deposition and the higher the upper respiratory tract and gastrointestinal tract deposition. Evaluation of distribution of nebulized bronchodilators in wheezy infants has shown an average of 10% to 12% adherence to the patient’s face, 7.8% ± 4.9% deposition in the upper respiratory and gastrointestinal tracts, and 1.5% ± 0.7% deposited in the lungs (Figure 17-4).^26,27

Figure 17-5 summarizes data on lung deposition with inhaled aerosols, compiled from four studies. All of the studies used a pMDI with a reservoir device and a face mask for delivery in subjects younger than 4 years. Values represent the percentage of total dose from the device. Fok and colleagues²⁸ found that 0.67% (standard error of the mean [SEM] 0.17) of the total dose of albuterol reached the lungs of infants with a mean age of 86 days (range 25 to 187 days).

Tal and associates²⁹ found 1.97% (standard deviation [SD] 1.4) as a lung dose of albuterol in patients with a mean age of 21 months (range 3 months to 5 years). Wildhaber and colleagues³⁰ found 5.4% (SD 2.1) and 9.6% (SD 3.9) of albuterol reached the lungs of 2- to 4-year-olds and 5- to 9-year-olds. Agertoft and coworkers,³¹ using indirect measures of plasma levels, found 6.1% of a budesonide dose reached the lungs of 3- to 6-year-olds. Similar data have been reported for aerosol delivery with nebulizers (see Table 3-4).

If the amount of aerosolized albuterol reaching the lungs of infants and children in the study by Tal and colleagues²⁹ is used, it can be shown that the self-limiting effect of younger ages on lung dose results in the same dose per amount of body weight in children as in adults (Table 17-4). The equivalence of dose per body weight illustrated in Table 17-4 and based on lung deposition data argues strongly against the need to adjust the nominal dose of an aerosol drug for age or body size with current aerosol delivery devices. Age and size have a self-limiting effect on lung dose, producing a natural titration of dose. This conclusion may need to be revised pending more efficient aerosol delivery devices.

Clinical response to aerosolized drugs in neonatal and pediatric patients

The lung deposition data reviewed in the previous section argue that aerosolized drugs reach the lungs of infants and do so in a self-regulating amount. The question of clinical response to aerosol drugs in infants and pediatric patients is not determined by lung deposition data. The most commonly studied drug class—and one of great interest in neonates and infants—is the adrenergic bronchodilator group. Compared with corticosteroids, the clinical response to bronchodilator occurs within minutes and is more feasible to study in young subjects.

Commonly cited studies from the late 1970s concluded that response to inhaled bronchodilators was lacking in infants and children younger than 18 months of age.^32,33 These studies found no change in respiratory resistance with phenylephrine, epinephrine, or salbutamol (albuterol) in infants and children 7 to 18 months of age using a forced oscillation technique. The authors of the studies speculated that there was either poor development of smooth muscle in children younger than 18 months of age or the bronchial obstruction was due to secretions and airway edema rather than bronchoconstriction.

A study by Turner and associates³⁴ in 1993 found that the level of response to a bronchodilator increases significantly with increasing age in young asthmatics 3 to 9 years old. However, studies of ventilated and nonventilated preterm infants have shown dose-related changes in respiratory mechanics, including airway resistance, and compliance with aerosolized bronchodilators.^35–43 Table 17-5 lists several studies and the outcomes measured that have documented clinical efficacy of aerosolized bronchodilators in infants.

Selection of delivery devices

The current methods to deliver therapeutic aerosols can be classified in three categories: nebulizers (jet or ultrasonic); pMDIs that can be used with a press-and-breathe technique, as a breath actuated device, or in combination with a valved-holding chamber (VHC) or spacer; and dry powder inhalers (DPIs). Table 17-6 gives the age guidelines for use of current aerosol delivery devices in infants and children, based on the 2007 National Asthma Education and Prevention Program (NAEPP) guidelines.⁴⁴ Either a jet nebulizer or an MDI can be used with suitable auxiliary devices attached. An evidence-based review by the American College of Chest Physicians determined that for most patients with asthma, SVNs, DPIs, and MDIs are equally effective in delivering short-acting β agonists.^45,46 Nebulizer systems and the pMDI plus spacer are the most suitable aerosol delivery systems for young children because they only require tidal breathing to inhale the aerosol. Even in acute asthma attacks, delivery of bronchodilators by pMDI plus spacer are equally effective as nebulizers.^4,47 Nebulizers could be considered as an alternative if the child appears very distressed during the administration of pMDI. Studies cited in Chapter 3 (see Table 3-4) showing equivalent clinical response between the MDI-reservoir systems, with or without a mask as needed by age, and jet nebulizers have been validated in young children.⁴⁸

Compliance and cooperation during aerosol therapy

The most important factor to consider in the administration of aerosol therapy in infants and young children is their compliance. Two practical issues are important when dealing with young children, particularly infants: face mask and crying. The interaction between crying and the face mask is complex. It is very likely that crying and distress, even with the best-designed face mask, explain the poor seal that seriously affects the efficiency of aerosol administration in young children.⁶⁵

Effects of crying on aerosol delivery

It is widely accepted that delivery devices that produce small particles are less flow dependent. This characteristic may be of critical importance for less cooperative children. Crying is associated with high inspiratory flows, high dose variability, and almost no lung deposition.66–69 A typical pediatric patient does not tolerate a mask applied to the face, and agitation and crying are frequently observed. The efficacy of aerosol therapy administered to a combative or crying toddler is known to be negligible because of the changes in respiratory patterns during nebulization. Amirav and associates²⁷ have shown that the more distress infants were in during the treatment, the more aerosol was deposited extrathoracically. This finding should alert clinicians to the potential for increased systemic absorption and greater risk for side effects.

Although theoretically the poor aerosol delivery associated with crying could make aerosol administration during sleep an attractive alternative, the positive results of in vitro studies⁷⁰ have not been found in vivo. Almost 70% of children wake up when aerosol is given during sleep and become distressed resulting in similar lung deposition found with crying. Because crying may be inevitable, the caregiver may have to find creative ways to prepare the child for the face mask at a time when the child does not need the treatment. This strategy would apply to maintenance therapy and not to the emergency setting or transport, where distracting and comforting the child may be the only available options to improve compliance. Dose variability seems to be independent of face mask design and more dependent on cooperation (Figure 17-6).⁷¹

Mask-fit-to-face and mask design

Because children must be about 3 years old before they fully understand how to use a mouthpiece, younger children must use a mask. Efficient aerosol therapy requires the mask to fit to the face tightly and still be comfortable. The absence of a tight seal between the mask and the patient’s face results in a decrease in the amount of medication available for inhalation.^59,62,72 Many parents are forced to hold the face mask near the face to avoid struggling with the child. This technique is well known as “blow-by.” However, it has been clearly documented in numerous studies that even a 0.5-cm gap between the mask and the face reduces the inhaled drug mass as a percentage of the nominal dose in a pediatric lung model of spontaneous breathing up to 50%.^73,74

Development of more efficient, more acceptable, and friendlier face mask interfaces has been evaluated as an option to improve the inhaled drug mass. More recent reports comparing the standard aerosol pediatric mask with other proprietary masks have shown that the newly designed masks significantly increase the inhaled drug mass (Figure 17-7).^75–77 It is recommended that children be switched from mask to mouthpiece as soon as they are old enough to inhale through the mouth voluntarily.¹⁵

Nebulizer hood

Because it is very difficult to hold a mask snugly fitted to the face, particularly with infants, other alternatives have been explored. The nebulizer hood was designed as an attempt to develop more acceptable and patient-friendly interfaces. Janssens and coworkers,⁶⁹ Amirav,⁷⁸ and Kesser and colleagues⁷⁹ all reported much greater aerosol delivery with a hood than the mask in vivo and in vitro. Hoods seem to reduce crying in infants significantly because nothing comes in contact with the infant’s face (Figure 17-8),

Aerosol administration in intubated neonatal and pediatric patients

Aerosol delivery seems to be less efficient in pediatric intubated patients than in spontaneously breathing patients.⁸⁰ It is important to consider changes associated with the use of jet nebulizers in-line on pediatric and particularly neonatal ventilated patients because unexpected changes in volume and pressure may have deleterious effects. An externally powered nebulizer increases volume and pressure during volume-targeted ventilation, creates a bias flow in the ventilator circuit that may interfere with patient-triggered modes of ventilation,⁸¹ may result in increased airway pressure and unexpected positive end-expiratory pressure (PEEP), and may result in variable fractional inspired oxygen (Fio₂) levels. Constant flow during expiration seriously limits the concentration of the inspired aerosol.¹⁰ Other nebulizer designs, such as vibrating mesh/membrane systems, do not require a gas source to operate and do not affect airway pressures during operation as usually seen with externally gas-powered nebulizers.^82,83 If rapid respiratory rates are used, the ventilator duty cycle may be inadequate for the aerosol cloud to develop in the circuit and may seriously decrease aerosol deposition.⁸⁴

The respiratory clinician should also be aware that aerosol delivery may be less effective with manual ventilation versus mechanical ventilation.⁵⁸ Placement of the aerosol delivery device in an intubated infant requires the clinician’s attention. Although most studies show a slightly higher lung deposition with the pMDI when inserted between the Y-piece and the endotracheal tube, with an SVN placed in the inspiratory limb away from the Y-piece, lung deposition also averages 1% of the nominal dose.³⁸ In pediatric patients, a pMDI and spacer with one-way valve is associated with a significantly larger amount of inhaled drug mass.⁸⁵ No difference has been found between in vitro and in vivo studies.⁸⁶ It has been suggested that the pMDI be actuated before inspiration to improve lung deposition.⁸⁷

Summary

Efficient aerosol therapy in young children is a challenge. Although the advantages with inhaled drugs to treat pulmonary problems in neonates and pediatric patients support their use, consensus is lacking in determining a suitable dose for this population. More recent research suggests that age has a dose-regulating effect on the amount of aerosol drug reaching the lungs, with less drug reaching the lungs of younger subjects. Safety profile, therapeutic efficacy, and efficiency of routinely aerosolized medications delivered to infants and children need to be rigorously studied. At less than 6 months of age, tidal volumes and inspiratory flow rates can reduce the amount of aerosol drug inhaled from nebulizers or pMDI and spacer devices. Even when the inhaled dose is the same for pediatric and adult patients, data indicate that the lung dose decreases for younger patients. Neonatal and pediatric patients should be assessed for adverse systemic effects with aerosol drug administration because of inefficient drug absorption from the lung and the presence of large extrathoracic deposition when masks are not tightly applied.

There is no difference in clinical effect for bronchodilators between pMDI and nebulizer administration. The pMDI dose may need to be adjusted upward for neonatal, pediatric, or adult use because the pMDI nominal dose is usually lower than the nebulizer dose. Neonates and very young pediatric patients show a clinical response to aerosolized bronchodilator administration. How to determine doses for aerosolized drugs delivered to neonatal and pediatric patients is not completely understood. Despite the differences in drug action between adults and children, the ability to control particle size by selecting the optimal aerosol delivery, placement of the aerosol device, and understanding patterns of aerosol generation are the key elements to improve efficiency of aerosol administration. Identifying the ability of the patient, rather than specific age, is also essential to selecting the most appropriate device in any population.⁸⁸

It needs to be remembered that optimal aerosol administration requires matching patient characteristics with the aerosol delivery system. Infants and young children are a special group of patients with different anatomic, physiologic, and behavioral characteristics that dramatically affect outcomes of pharmacotherapy. Physicians, respiratory therapists, and nurses need to know how to select the right aerosol delivery device appropriately for children of different ages. Lack of coordination, inadequate inspiratory flows, limited cooperation, and crying are factors in infants and young children that greatly affect the efficiency of aerosol therapy in this age group. Because of the seriousness of treatment and possible errors in the inhalation technique, it is recommended that caregivers be reassessed at each patient encounter and that instructions be written in a manner the caregivers can understand. The development of in vitro models that better replicate not only the anatomy but also realistic breathing patterns may allow a better prediction of in vivo lung deposition of aerosols in neonatal and pediatric patients.⁸⁹