Croup- Pharmacologic and Supportive Interventions

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Charles R Woods, MD, MSSection Editor

Sheldon L Kaplan, MDDeputy Editor

Carrie Armsby, MD, MPH

Croup: Pharmacologic and supportive interventions

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Oct 2015. | This topic last updated: Jan 30, 2014.

INTRODUCTION — Croup (laryngotracheitis) is a respiratory illness characterized by inspiratory stridor,barking cough, and hoarseness. It typically occurs in children six months to three years of age and is causedby parainfluenza virus. (See "Croup: Clinical features, evaluation, and diagnosis".)

The treatment of croup has changed significantly since the 1980s. Glucocorticoids and nebulizedepinephrine have become the cornerstones of therapy. Substantial clinical evidence supports the efficacy ofthese interventions [15]. The impact also is evident in the decrease in annual hospital admissions for croupin children in the United States between 1979 to 1982 and 1994 to 1997 (from 2.8 to 2.1 per 1000 forchildren <1 year and from 1.8 to 1.2 per 1000 children for children 1 to 4 years) [6].

Treatment of croup may involve a variety of pharmacologic and nonpharmacologic interventions. It mayoccur entirely at home, or in the office, emergency department (ED), or hospital setting. Supportive andpharmacologic interventions will be discussed below. The clinical features and evaluation of croup and theapproach to management are discussed separately. (See "Croup: Clinical features, evaluation, anddiagnosis" and "Croup: Approach to management".)

GLUCOCORTICOIDS — Glucocorticoids provide longlasting and effective treatment of mild, moderate, andsevere croup [3,79]. The antiinflammatory actions of glucocorticoids are thought to decrease edema in thelaryngeal mucosa of children with croup. Improvement is usually evident within six hours of administrationbut seldom is dramatic [7,10].

Treatment with glucocorticoids at various doses and by various routes has been shown to improve croupscores and to decrease unscheduled medical visits, length of stay in the emergency department or hospital,and the use of epinephrine [7]. Among the available glucocorticoids, dexamethasone has been used mostfrequently, 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 glucocorticoidshave been shown to be effective in croup of all levels of severity [7,8]. Dexamethasone (oral or IM) andbudesonide (inhaled) were the agents used in the majority of studies. A systematic review included 24 trials(with collective enrollment of 2878 children) that objectively measured the effectiveness of glucocorticoidtreatment for croup compared with placebo [7]. Fourteen other trials compared different glucocorticoidagents or different routes or dosages of the same agent [7]. Compared with treatment with placebo,treatment with glucocorticoid was associated with:

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Improvement in the croup score at six hours with a weighted mean difference of 1.2 (95% CI 1.6 to0.8) 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 2.70.2)

Fewer return visits and/or (re)admissions (relative risk 0.50, 95% CI 0.30.7)

Decreased length of time spent in emergency department or hospital (weighted mean difference 12hours, 95% CI 519 hours)

Decreased use of epinephrine (risk difference 10 percent; 95% CI 120 percent)

There were no significant differences in clinical efficacy between the routes or agents, and thecombination of oral or IM dexamethasone with inhaled budesonide was not superior to either agent



Another systematic review of eight randomized controlled trials compared the administration of nebulizedglucocorticoids with placebo. Children treated with nebulized glucocorticoids were significantly more likely toshow improvement in croup score at five hours (combined relative risk (RR) 1.48, 95% CI 1.271.74) andsignificantly less likely to need hospital admission (combined RR 0.56, 95% CI 0.420.75) [13].

Adverse effects — Few serious adverse effects have been reported in the studies evaluating the efficacy ofa single dose of glucocorticoids in croup [14]. However, most of these studies were too small to sufficientlyevaluate rare (<1 percent) adverse effects [15,16].

The primary concern is potential risk of progressive viral infection or secondary bacterial infection, whichhave been reported in patients who received glucocorticoid treatment over several days [16], or receivednebulized dexamethasone and had neutropenia [17]. These complications have not been described inchildren who have received single doses of oral, intramuscular, or intravenous glucocorticoids for croup.

Glucocorticoid use may exacerbate active varicella and tuberculosis and should be avoided in children withthese infections and in those recently exposed to, and possibly incubating, varicella [18,19]. (See "Clinicalfeatures of varicellazoster virus infection: Chickenpox".)

Administration of glucocorticoids may mask the presentation of steroidresponsive upper airway lesions,such as hemangiomas, which also can present with stridor, particularly during a viral upper respiratory tractinfection [20]. (See "Epidemiology, pathogenesis, clinical features, and complications of infantilehemangiomas".)

Agents

Dexamethasone — Dexamethasone may be administered IM, IV, or orally. To date, no clinicallysignificant difference in croup outcomes between IM or orally administered dexamethasone has beendemonstrated [7]. When dexamethasone is administered IM or IV, a single dose of 0.6 mg/kg (maximumdose of 10 mg) is used most frequently. Smaller doses appear to be equally effective for mild croup whenadministered orally, as illustrated below:

The second study described above [22] included a small number of children with relatively mild croup andconsequently may have been underpowered (unable) to detect a clinically important difference, particularlyin children with more severe symptoms [14].

Children with mild croup who can tolerate oral medications can be given either dexamethasone 0.15 mg/kgor dexamethasone 0.6 mg/kg orally, to a maximum total dose of 10 mg. Although the lower 0.15 mg/kg doseappears to be efficacious [21], we continue to suggest the higher dose [23,24].

The oral preparation of dexamethasone (1 mg per mL) has a foul taste. The intravenous preparation is moreconcentrated (4 mg per mL) and can be given orally mixed with syrup [11,25,26].

Studies of nebulized dexamethasone in children with croup have mixed results. One study found nebulizeddexamethasone to be less effective than oral dexamethasone in preventing the need for subsequenttreatment with glucocorticoid or epinephrine in children with mild croup [27]. Another study found thattreatment with nebulized dexamethasone in children with moderate croup improved croup scores at fourhours but did not affect the rate of hospitalization [17]. In addition, two patients with neutropenia who were

alone [11,12].

In one study, 100 children with mild croup were randomly assigned to receive oral dexamethasone(0.15 mg/kg) or placebo in the emergency department [21]. Eight children in the placebo group, andnone 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 oraldose of dexamethasone (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg) or placebo [22]. There was no difference induration of hospitalization, reduction in croup score, or epinephrine use among the three groupsreceiving dexamethasone.



treated with dexamethasone developed bacterial tracheitis.

Budesonide — Nebulized budesonide has been shown to be more effective than placebo 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, a single dose of budesonide may be mixed with epinephrine and administered

simultaneously. (See "Croup: Approach to management", section on 'Moderate to severe croup'.)

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

prednisolone (2 mg/kg per day for three days) is an alternative to oral dexamethasone [29]. The use of

prednisolone in the treatment of croup has been evaluated in a limited number of studies.

A 2011 metaanalysis of two trials [30,31] that compared a single dose of oral dexamethasone (0.6 mg/kg or

0.15 mg/kg) with a single dose of oral prednisolone (1 mg/kg) showed no difference in croup scores, but

children randomized to receive dexamethasone had fewer return visits and/or subsequent admissions (9.6

versus 29.7 percent, RR 0.3, 95% CI 0.20.6) [7].

A subsequent randomized trial compared oral dexamethasone (0.6 mg/kg on the first day followed by

placebo on the next two days) with oral prednisolone (2 mg/kg per day for three days) in 87 children with

mild or moderate croup who were treated as outpatients [29]. There were no differences between groups in

additional health care visits (2 versus 7 percent [not significant]), duration of symptoms (2.8 versus 2.2

days), duration of nonbarky cough (6.1 versus 5.9 days), nights with disturbed parental sleep (0.7 versus

1.2), or days with stress (1.6 versus 1.4).

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).

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

trials. However, it has equivalent potency to prednisolone and, in theory, should have similar effects. Despite

its lack of proven benefit, prednisone is widely used in the outpatient management of croup [32].

If prednisone is to be used, it is important to administer a dose that is equivalent in strength to the doses of

glucocorticoids that have been better studied. Dexamethasone has 6.67 times the glucocorticoid 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 (six months to six years) with mild

to moderate croup who were treated in the emergency department [33]. 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 glucocorticoids in 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

glucocorticoids for croup occurred with repeated dosing over several days [34], or in neutropenic patients

[17]. (See 'Adverse effects' above.)



Moderate to severe symptoms that persist for more than a few days should prompt investigation for other

causes of airway obstruction. (See "Croup: Clinical features, evaluation, and diagnosis", section on

'Differential diagnosis'.)

NEBULIZED EPINEPHRINE — The administration of nebulized epinephrine to patients with moderate to

severe croup often results in rapid improvement of 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 and a metaanalysis have demonstrated the benefit

of racemic epinephrine compared with placebo in reducing the croup scores 30 minutes after treatment in

children in the emergency department, hospital, and intensive care unit [1,3537]. The magnitude of

reduction in mean croup score from baseline ranged from 2.2 to 3.6 at 20 to 30 minutes (compared with

approximately 1 in the placebo group). However, by 120 minutes, croup scores returned to baseline or near

baseline [1,36]. In one trial, treatment with IM dexamethasone and nebulized epinephrine was associated

with decreased duration of hospitalization compared with IM dexamethasone and placebo (32 hours, 95%

CI 59.1 to 4.9) [38,39].

Administration of epinephrine does not alter the natural history of croup in the short (>2 hours) or longer term

(24 to 36 hours) [1,36,39].

In the studies described above, racemic epinephrine was administered either by nebulization alone or by

nebulization combined with intermittent positive pressure breaths [1,35,36]. Another study compared these

two methods of administration and found them to be similarly effective [2].

Racemic versus Lepinephrine — Racemic epinephrine, which is a 1:1 mixture of the D and Lisomers,

was initially thought to produce fewer systemic side effects, such as tachycardia and hypertension [18].

However, a randomized doubleblind study comparing racemic epinephrine and Lepinephrine in children

with croup found no difference between the two preparations in 30minute croup score, heart rate, blood

pressure, respiratory rate, fraction of inspired oxygen, or oxygen saturation [40]. 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

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 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 more than 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 received three doses of racemic epinephrine within 60 minutes has been

reported [41]. 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

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.

Lepinephrine is administered as 0.5 mL/kg per dose (maximum of 5 mL) of a 1:1000 dilution [40]. It is

given via nebulizer over 15 minutes.



potential systemic impact of nebulized epinephrine). Continuous electrocardiographic monitoring (orequivalent 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 are hypoxemic (oxygen saturation of <92 percent in room air)and/or in moderate to severe respiratory distress [14,24]. Supplemental oxygen should be humidified todecrease drying effects on the airways, since drying may impede the physiologic removal of airwaysecretions via mucociliary and cough mechanisms. (See "Continuous oxygen delivery systems for infants,children, and adults".)

Heliox — Helium is inert, nontoxic, and of very low density. Heliox is a mixture of helium (70 to 80 percent)and oxygen (20 to 30 percent). It can flow through airways with less turbulence and resistance than pureoxygen. (See "Physiology and clinical use of heliox".)

Heliox decreases the work of respiration in children with croup and theoretically could be used as atemporizing measure, to prevent the need for intubation while waiting for glucocorticoids to decrease airwayedema [42]. However, in clinical trials, heliox has not definitively been shown to be more effective thanhumidified oxygen or racemic epinephrine in reducing croup scores [4345]. A 2013 systematic review foundonly three methodologically limited trials (91 patients) evaluating heliox in children with croup and concludedthat a larger trial is needed before recommendations regarding the use of heliox in children with croup canbe made [45].

MIST THERAPY — Humidified air is frequently used in the treatment of croup, although there have been nostudies supporting its efficacy in reducing symptoms [46]. Two randomized trials (one comparing mist versusno mist and the other comparing no mist, low humidity, and 100 percent humidity) among children brought toan emergency department for croup demonstrated no significant change in croup scores from baselinebetween the groups [47,48].

Although humidified air does not reduce subglottic edema, it may provide other benefits. Inhalation of moistair, relative to dry air, may decrease drying of inflamed mucosal surfaces and reduce inspissation ofsecretions [49]. In addition, a mist source may provide a sense of comfort and reassurance to both the childand family [5052]. In medical settings, mist therapy may be provided by blowby or saline nebulizationtreatments. Croup tents should be avoided, since they can aggravate a child's anxiety and make vital signsand other visual assessments of the child more difficult. Some guidelines recommend against the use of misttherapy for children who are hospitalized with croup [24]. Certainly if the child is agitated by the provision ofmist, mist therapy should be discontinued.

OTHER THERAPIES

Antibiotics — Antibiotics have no role in the routine management of uncomplicated croup, since mostcases 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 respiratorytract infections). Codeine, which is a more potent cough suppressant, can alter the child's sensorium,making it difficult to follow the clinical course.

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

Sedatives — The routine use of sedative agents in effort to improve airway obstruction by relieving anxietyand apprehension is not recommended. Sedatives may treat the symptom of agitation while masking theunderlying causes of air hunger and hypoxia. They also may decrease respiratory effort (and therefore croupscores), without improving ventilation [14,53].

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REFERENCES

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Treatment with glucocorticoids (oral, intramuscular, or nebulized) has been shown to decrease croupscores, unscheduled medical visits, length of stay in the emergency department or hospital, and theuse of epinephrine. A single dose of oral or intramuscular dexamethasone is appropriate and adequatefor most children. (See 'Glucocorticoids' above and "Croup: Approach to management", section on'Initial treatment'.)

Treatment with nebulized epinephrine results in rapid improvement of upper airway obstruction, but theduration of effect is less than two hours. Racemic epinephrine and Lepinephrine appear to be equallyeffective. (See 'Nebulized epinephrine' above.)

Humidified air is frequently used as a supportive treatment for croup; however, there have been nostudies 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 severerespiratory distress. (See 'Oxygen' above.)

Heliox has not definitively been shown to be more effective than humidified oxygen or racemicepinephrine in reducing croup scores. (See 'Heliox' above.)

Antibiotics should be used only to treat specific bacterial complications of croup. (See 'Antibiotics'above and "Croup: Approach to management", section on 'Complications'.)

Antitussives and decongestants are of unproven benefit in the management of croup. Sedatives maydecrease the work of breathing and improve agitation without actually improving ventilation oraddressing the underlying cause of agitation (hypoxemia). (See 'Other therapies' above.)



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Disclosures: Charles R Woods, MD, MS Other Financial Interest: Cerexa [Epiglottitis (Data Safety Monitoring Board for pediatric

trials of the antibiotic agent ceftaroline)]. Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [vaccine (PCV13)];

Forest Lab [antibiotic (Ceftaroline)]; Optimer [antibiotic (fidaxomicin)]. Consultant/Advisory Boards: Pfizer [vaccine (PCV13)]. Carrie

Armsby, MD, MPH Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting

through a multilevel review process, and through requirements for references to be provided to support the content. Appropriately

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