Pharmacologic and Supportive Interventions for Croup

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Pharmacologic and supportive interventions for croup

Author

Charles R Woods, MD, MS Section Editor

Ralph D Feigin, MD

Ellen M Friedman, MD Deputy Editors

Mary M Torchia, MD

Last literature review version 16.1: January 2008 | This Topic Last Updated:

August 31, 2006 (More)

INTRODUCTION Croup (laryngotracheitis) is a respiratory illness

characterized by inspiratory stridor, barking cough, and hoarseness. It typically

occurs in children 3 months to 3 years of age and is caused by parainfluenza

virus. (See "Clinical features, evaluation, and diagnosis of croup").

The treatment of croup has changed significantly since the 1980s.

Corticosteroids and nebulized epinephrine have become the cornerstones of

therapy. Substantial clinical evidence supports the efficacy of these

interventions [1-5] . The impact also is evident in the decrease in annual

hospital admissions for croup in children in the United States between 1979 to1982 and 1994 to 1997 (from 2.8 to 2.1 per 1000 for children


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emergency department (ED), or hospital setting. Supportive and pharmacologic

interventions will be discussed below. The clinical features and evaluation of

croup and the approach to management are discussed separately. (See

"Clinical features, evaluation, and diagnosis of croup" and see "Approach to the

management of croup").

CORTICOSTEROIDS Corticosteroids provide long-lasting and effective

treatment of mild, moderate, and severe croup [3,7-9] . The anti-inflammatory

actions of corticosteroids are thought to decrease edema in the laryngeal

mucosa of children with croup. Improvement is usually evident within six hours

of administration, but seldom is dramatic [7,10] .

Treatment with corticosteroids at various doses and by various routes has been

shown to improve croup scores and to decrease unscheduled medical visits,length of stay in the emergency department or hospital, and the use of

epinephrine [7] . Among the available corticosteroids, dexamethasone has

been used most frequently, is the least expensive, has the longest duration of

action, and is the easiest to administer.

Efficacy Intramuscular (IM), intravenous (IV), oral, and inhaled routes of

administration of corticosteroids have been shown to be effective in croup of all

levels of severity [7,8] . Dexamethasone (oral or IM) and budesonide (inhaled)

were the agents used in the majority of studies. A systematic review included31 trials that objectively measured the effectiveness of corticosteroid

treatment for croup compared to placebo or other active treatment [7] .

Compared to treatment with placebo, treatment with glucocorticoid was

associated with: Improvement in the croup score at six hours with a weighted

mean difference of -1.2 (95% Cl -1.6 to -0.8) and at 12 hours -1.9 (95% CI -2.4

to -1.3); at 24 hours this improvement was no longer significant (-1.3, 95% CI

-2.7 to 0.2). Fewer return visits and/or (re)admissions (relative risk 0.50, 95% CI

0.36-0.70). Decreased length of time spent in emergency department or

hospital (weighted mean difference 12 hours, 95% CI 5 to 19 hours). Decreased

use of epinephrine (risk difference 10 percent; 95% CI 1 to 20 percent). Therewere no significant differences in clinical efficacy between the routes or agents,

and the combination of oral or IM dexamethasone with inhaled budesonide was

not superior to either agent alone [11,12] .


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Another systematic review of eight randomized controlled trials compared the

administration of nebulized corticosteroids with placebo. Children treated with

nebulized corticosteroids were significantly more likely to show improvement in

croup score at five hours (combined relative risk (RR) 1.48, 95% CI 1.27-1.74)

and significantly less likely to need hospital admission (combined RR 0.56, 95%

CI 0.42-0.75) [13] .

Adverse effects Few serious adverse effects have been reported in the

studies evaluating the efficacy of a single dose of corticosteroids in croup [14] .

However, most of these studies were too small to sufficiently evaluate rare (


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(maximum dose of 10 mg) is used most frequently. Smaller doses appear to be

equally effective for mild croup when administered orally, as illustrated below:

- In one study, 100 children with mild croup were randomly assigned to

receive oral dexamethasone (0.15 mg/kg) or placebo in the emergencydepartment [21] . Eight children in the placebo group, and none in the

dexamethasone group, returned for medical care (a statistically significant

difference).

- In another study, 120 hospitalized children with croup were randomly

assigned to receive a single oral dose of dexamethasone (0.15 mg/kg, 0.3

mg/kg, 0.6 mg/kg) or placebo [22] . There was no difference in duration of

hospitalization, reduction in croup score, or epinephrine use among the three

groups receiving dexamethasone.

The second study described above [22] included a small number of children

with relatively mild croup and consequently may have been underpowered

(unable) to detect a clinically important difference, particularly in children with

more severe symptoms [14] .

Children with mild croup who can tolerate oral medications can be given either

dexamethasone 0.15 mg/kg or dexamethasone 0.6 mg/kg orally to a maximum

total dose of 10 mg. Although the lower 0.15 mg/kg dose appears to be

efficacious [21] , we continue to suggest the higher dose [23,24] . The higher

dose can be given all at once or divided into four doses over 24 hours if desired

[23] .

The oral preparation of dexamethasone (1 mg per mL) has a foul taste. The

intravenous preparation is more concentrated (4 mg per mL) and can be given

orally mixed with syrup [11,24-26] .

Studies of nebulized dexamethasone in children with croup have mixed results.

One study found nebulized dexamethasone to be less effective than oral

dexamethasone in preventing the need for subsequent treatment with

corticosteroid or epinephrine in children with mild croup [27] . Another study

found that treatment with nebulized dexamethasone in children with moderate


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croup improved croup scores at four hours, but did not affect the rate of

hospitalization [17] . In addition, two patients with neutropenia who were

treated with dexamethasone developed bacterial tracheitis.

Budesonide Nebulized budesonide has been shown to be more effective thanplacebo, and as effective as IM or oral dexamethasone for the treatment of

croup [7,28] . However, nebulized budesonide is more expensive and more

difficult to administer than IM or oral dexamethasone and is not routinely

indicated in the treatment of croup. However, nebulized budesonide may

provide an alternative to IM or IV dexamethasone for children with vomiting or

severe respiratory distress [24] . In children with severe respiratory distress,

budesonide may be mixed with epinephrine and administered simultaneously

[24] . (See "Approach to the management of croup" section on Moderate to

severe croup).

Prednisolone The use of prednisolone in the treatment of croup has been

evaluated in a limited number of studies, described below. One study

compared a single oral dose of prednisolone (1 mg/kg) to a single oral dose of

dexamethasone (0.15 mg/kg) in 133 children with mild to moderate croup

[29] . Compared to those who received dexamethasone, those who received

prednisolone were more likely to present for unscheduled medical care in the

following 7 to 10 days (29 versus 7 percent). There were no significant

differences in secondary outcome measures: croup score, epinephrine usage,

time spent in the emergency department, duration of croup and viralsymptoms. Another study of 70 children compared prednisolone (1 mg/kg

every 12 hours) with placebo in children with croup who were already

intubated [8] . Children who received prednisolone had a shorter median

duration of intubation than those in the placebo group (98 versus 138 hours).

In addition, fewer children in the prednisolone group required reintubation (5

versus 34 percent).

Some authorities suggest that for children who are treated as outpatients, oral

prednisolone (2 mg/kg per day in two divided doses for two days) is analternative to oral dexamethasone [23] . However, these two regimens have

not been compared in clinical trials.

Prednisone The use of prednisone in the management of croup has not been

evaluated in clinical trials. However, it has equivalent potency to prednisolone


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and in theory, should have similar effects. Despite its lack of proven benefit,

prednisone is widely used in the outpatient management of croup [30] .

If prednisone is to be used, it is important to administer a dose that is

equivalent in strength to the doses of corticosteroids that have been betterstudied. Dexamethasone has 6.67 times the corticosteroid potency of

prednisone (4 mg/kg of prednisone = 0.6 mg/kg of dexamethasone; 2 mg/kg of

prednisone = 0.3 mg/kg of dexamethasone; and 1 mg/kg of prednisone = 0.15

mg/kg of dexamethasone). If choosing to use the higher dose (ie, 4 mg/kg of

prednisone), the volume required may be prohibitive given that the

concentration of the oral solution of prednisone is 1 mg/1 mL.

Betamethasone A pilot study compared the effectiveness of a single oral

dose of betamethasone (0.4 mg/kg) with a single dose of IM dexamethasone(0.6 mg/kg) in 52 children (6 months to 6 years) with mild to moderate croup

who were treated in the emergency department [31] . Despite randomization,

mean baseline croup scores were higher in the dexamethasone group (3.6

versus 2). Croup scores declined significantly in both groups and there were no

differences between groups in mean croup scores four hours after treatment,

rate of hospitalization, time to resolution of symptoms, need for additional

treatment, or number of return visits to the emergency department.

Repeated dosing The majority of clinical trials of oral and IM corticosteroidsin croup have used a single dose. Repeat doses are not necessary on a routine

basis. Although repeat doses may be reasonable in the occasional child who

has persistent symptoms, they should be used with caution. The anecdotal

cases of progression of viral illness and secondary bacterial infection that have

been reported with use of corticosteroids for croup occurred with repeated

dosing over several days [15] , or in neutropenic patients [17] . (See "Adverse

effects" above).

Moderate to severe symptoms that persist for more than a few days shouldprompt investigation for other causes of airway obstruction. (See "Clinical

features, evaluation, and diagnosis of croup", section on Differential diagnosis).

NEBULIZED EPINEPHRINE The administration of nebulized epinephrine to

patients with moderate to severe croup often results in rapid improvement of


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upper airway obstruction. Epinephrine constricts precapillary arterioles in the

upper airway mucosa and decreases capillary hydrostatic pressure, leading to

fluid resorption and improvement in airway edema [18] . Even a modest

increase in airway diameter can lead to significant clinical improvement.

Benefits Several small randomized controlled trials have demonstrated the

benefit of racemic epinephrine compared to placebo in reducing the croup

scores of children with croup in children in the emergency department,

hospital, and intensive care unit [1,32,33] . The magnitude of reduction in

mean croup score from baseline ranged from 2.2 to 3.6 at 20 to 30 minutes

(compared to approximately 1 in the placebo group). However, by 120

minutes, croup scores returned to baseline or near baseline [1,33] .

Administration of epinephrine does not alter the natural history of croup in the

short (>2 hours) or longer term (24 to 36 hours) [1,33] .

In the studies described above, racemic epinephrine was administered either

by nebulization alone or by nebulization combined with intermittent positive

pressure breaths [1,32,33] . Another study compared these two methods of

administration and found them to be similarly effective [2] . Racemic versus L-

epinephrine Racemic epinephrine, which is a 1:1 mixture of the D- and L-

isomers, was initially thought to produce fewer systemic side effects, such as

tachycardia and hypertension [18] . However, a prospective randomized

double-blind study comparing racemic epinephrine and L-epinephrine in

children with croup found no difference between the two preparations in croupscore, heart rate, blood pressure, respiratory rate, fraction of inspired oxygen,

or oxygen saturation [34] . This finding is particularly important outside of the

United States where racemic epinephrine is not readily available. Either form of

epinephrine is acceptable to use in the United States.

Dose Racemic epinephrine is administered as 0.05 mL/kg per dose (maximum

of 0.5 mL) of a 2.25 percent solution diluted to 3 mL total volume with normal

saline. It is given via nebulizer over 15 minutes. L-epinephrine is administered

as 0.5 mL/kg per dose (maximum of 5 mL) of a 1:1000 dilution [35] . It is givenvia nebulizer over 15 minutes.

Nebulized epinephrine treatments may be repeated every 15 to 20 minutes if

warranted by the clinical course. Children who require repeated frequent

dosing (eg, three or more doses within two to three hours) to achieve


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stabilization of their respiratory function, generally should be admitted to an

intensive care unit or intermediate care setting (depending on the severity of

persisting signs).

Precautions The clinical effects of nebulized epinephrine last for no morethan two hours. After the effects have worn off, symptoms may return to

baseline (an apparent worsening, sometimes referred to as the "rebound

phenomenon"). Children who receive even a single dose of nebulized

epinephrine should be observed in the emergency department or hospital

setting for at least three to four hours after administration to ensure that

symptoms do not return to baseline.

Serious adverse effects from nebulized epinephrine are exceedingly rare.

However, a case of myocardial infarction in a child with croup who receivedthree doses of racemic epinephrine within 60 minutes has been reported [36] .

Thus, it seems prudent to place children who require ongoing epinephrine

treatments more frequently than every one to two hours on cardiac monitors

(both because of the severity of illness and the potential systemic impact of

nebulized epinephrine). Continuous electrocardiographic monitoring (or

equivalent cardiac monitoring) also should be considered in these cases.

OXYGEN Oxygen is not known to have any direct impact on the subglottic

edema or airway narrowing, but should be administered to children who arehypoxemic (oxygen saturation of


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Heliox decreases the work of respiration in children with croup and

theoretically could be used as a temporizing measure, to prevent the need for

intubation [37] , while waiting for corticosteroids to decrease airway edema.

However, in clinical trials, heliox has not been shown to be more effective than

humidified oxygen [38] , or racemic epinephrine [39] in reducing croup scores.

MIST THERAPY Humidified air is frequently used in the treatment of croup,

although there have been no studies supporting its efficacy in reducing

symptoms [40] . Two randomized trials (one comparing mist versus no mist

and the other comparing no mist, low humidity, and 100 percent humidity)

among children brought to an emergency department for croup demonstrated

no significant change in croup scores from baseline between the groups

[41,42] .

Although humidified air does not reduce subglottic edema, it may provide other

benefits. Inhalation of moist air, relative to dry air, may decrease drying of

inflamed mucosal surfaces and reduce inspissation of secretions [43] . In

addition, a mist source may provide a sense of comfort and reassurance to

both the child and family [44-47] . In medical settings, mist therapy may be

provided by blow-by or saline nebulization treatments. Croup tents should be

avoided, since they can aggravate a child's anxiety and make vital signs and

other visual assessments of the child more difficult. Some guidelines

recommend against the use of mist therapy for children who are hospitalized

with croup [24] . Certainly if the child is agitated by the provision of mist, misttherapy should be discontinued.

OTHER THERAPIES

Antibiotics Antibiotics have no role in the routine management of

uncomplicated croup since most cases are caused by viruses [14] . Antibiotics

should be used only to treat specific bacterial complications such as tracheitis.

Antitussives Nonprescription antitussive agents are of unproven benefit for

croup (or other respiratory tract infections). Codeine, which is a more potent

cough suppressant, can alter the child's sensorium, making it difficult to follow

the clinical course.


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Decongestants Decongestants also are of unproven benefit for croup [14,24]

Sedatives Sedative agents may improve airway obstruction by relievinganxiety and apprehension. However, their routine use is not recommended [24]

. Sedatives may treat the symptom of agitation while masking the underlying

causes of air hunger and hypoxia. They also may decrease respiratory effort

(and therefore croup scores), without improving ventilation [14,48] . Judicious

use of sedatives in an intensive care setting (with close monitoring of

respiratory function) in an effort to avoid intubation may be reasonable,

although evidence demonstrating the benefit of this strategy is lacking.

INFORMATION FOR PATIENTS Educational materials on this topic areavailable for patients. (See "Patient information: Croup in infants and

children"). We encourage you to print or e-mail this topic review, or to refer

parents to our public web site, www.uptodate.com/patients, which includes this

and other topics.

SUMMARY Treatment with corticosteroids (oral, intramuscular, or nebulized)

has been shown to decrease croup scores, unscheduled medical visits, length

of stay in the emergency department or hospital, and the use of epinephrine.

(See "Corticosteroids" above). Treatment with nebulized epinephrine results inrapid improvement of upper airway obstruction, but the duration of effect is

less than two hours. Racemic epinephrine and L-epinephrine appear to be

equally effective. (See "Nebulized epinephrine" above). Humidified air is

frequently used as a supportive treatment for croup; however there have been

no studies supporting its efficacy in reducing symptoms. (See "Mist therapy"

above). Humidified oxygen should be administered to children who are

hypoxemic and/or in moderate to severe respiratory distress. (See "Oxygen"

above). Heliox has not been shown to be more effective than humidified

oxygen or racemic epinephrine in reducing croup scores. (See "Heliox" above).

Antibiotics should be used only to treat specific bacterial complications of

croup. (See "Antibiotics" above and see "Approach to the management of

croup" section on Complications). Antitussives and decongestants are of

unproven benefit in the management of croup. Sedatives may decrease the

work of breathing and improve agitation without actually improving ventilation

or addressing the underlying cause of agitation (hypoxemia). (See "Other

therapies" above).


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Pharmacologic and Supportive Interventions for Croup