Abstract
Introduction
Croup is characterised by the abrupt onset, most commonly at night, of a barking cough, inspiratory stridor, hoarseness, and respiratory distress due to upper airway obstruction. It leads to signs of upper airway obstruction, and must be differentiated from acute epiglottitis, bacterial tracheitis, or an inhaled foreign body. Croup affects about 3% of children a year, usually between the ages of 6 months and 3 years, and 75% of infections are caused by parainfluenza virus. Symptoms usually resolve within 48 hours, but severe infection can, rarely, lead to pneumonia, and to respiratory failure and arrest.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in children with: mild croup; moderate to severe croup; and impending respiratory failure because of severe croup? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, corticosteroids, dexamethasone (intramuscular, oral, single-dose oral, route of administration), heliox, humidification, intermittent positive pressure breathing, L-adrenaline, nebulised adrenaline (epinephrine), nebulised budesonide, nebulised short-acting beta2 agonists, oral decongestants, oral prednisolone, oxygen, and sedatives.
Key Points
Croup leads to signs of upper airway obstruction, and must be differentiated from acute epiglottitis, bacterial tracheitis, or an inhaled foreign body.
Croup affects about 3% of children a year, usually between the ages of 6 months and 3 years, and 75% of infections are caused by parainfluenza virus.
Symptoms usually resolve within 48 hours, but severe infection can, rarely, lead to respiratory failure and arrest.
A single oral dose of dexamethasone improves symptoms in children with mild croup, compared with placebo.
Although humidification and oral decongestants are often used in children with mild to moderate croup, there is no evidence to support their use in clinical practice.
There is consensus that antibiotics do not improve symptoms in croup of any severity, as croup is usually viral in origin.
In children with moderate to severe croup, intramuscular or oral dexamethasone, nebulised adrenaline (epinephrine), and nebulised budesonide reduce symptoms compared with placebo.
Oxygen is standard treatment in children with respiratory distress. Oral dexamethasone is as effective as nebulised budesonide at reducing symptoms, and is less distressing for the child.
A dexamethasone dose of 0.15 mg/kg may be as effective as a dose of 0.6 mg/kg. Adding nebulised budesonide to oral dexamethasone does not seem to improve efficacy compared with either drug alone.
Nebulised adrenaline (epinephrine) has a short-term effect on symptoms of croup, but we don't know whether adding intermittent positive-pressure breathing to nebulised adrenaline further improves symptoms.
We don't know whether heliox (helium–oxygen mixture), humidification, short-acting nebulised beta2 agonists, or oral decongestants are beneficial in children with moderate to severe croup, or with impending respiratory failure.
In children with impending respiratory failure caused by severe croup, nebulised adrenaline (epinephrine) is considered likely to be beneficial. Oxygen is standard treatment.
Nasogastric prednisolone reduces the need for, or duration of, intubation, but sedatives and antibiotics are unlikely to be beneficial.
About this condition
Definition
Croup is characterised by the abrupt onset, most commonly at night, of a barking cough, inspiratory stridor, hoarseness, and respiratory distress due to upper airway obstruction. Croup symptoms are often preceded by symptoms like those of upper respiratory tract infection. The most important diagnoses to differentiate from croup include bacterial tracheitis, epiglottitis, and the inhalation of a foreign body. Some investigators distinguish subtypes of croup. Those most commonly distinguished are acute laryngotracheitis and spasmodic croup. Children with acute laryngotracheitis have an antecedent upper respiratory tract infection, are usually febrile, and are thought to have more persistent symptoms. Children with spasmodic croup do not have an antecedent upper respiratory tract infection, are afebrile, have recurrent croup, and are thought to have more transient symptoms. However, there is little empirical evidence that spasmodic croup responds differently from acute laryngotracheitis. Population: In this review, we have included children up to the age of 12 years with croup; no attempt has been made to exclude spasmodic croup. We could not find definitions of clinical severity that are either widely accepted or rigorously derived. For this review, we have elected to use definitions derived by a committee consisting of a range of specialists and sub-specialists during the development of a clinical practice guideline from Alberta Medical Association (Canada). The definitions of severity have been correlated with the Westley croup score (see table 1 ), as it is the most widely used clinical score, and its validity and reliability have been well demonstrated. However, RCTs included in the review use a variety of croup scores. Mild croup: occasional barking cough; no stridor at rest; and no to mild suprasternal, intercostal indrawing (retractions of the skin of the chest wall), or both corresponding to a Westley croup score of 0–2. Moderate croup: frequent barking cough, easily audible stridor at rest, and suprasternal and sternal wall retraction at rest, but no or little distress or agitation, corresponding to a Westley croup score of 3–5. Severe croup: frequent barking cough, prominent inspiratory and — occasionally — expiratory stridor, marked sternal wall retractions, decreased air entry on auscultation, and significant distress and agitation, corresponding to a Westley croup score of 6–11. Impending respiratory failure: barking cough (often not prominent), audible stridor at rest (can occasionally be hard to hear), sternal wall retractions (may not be marked), usually lethargic or decreased level of consciousness, and often dusky complexion without supplemental oxygen, corresponding to a Westley croup score of greater than 11. During severe respiratory distress, a young child's compliant chest wall "caves in" during inspiration, causing unsynchronised chest and abdominal wall expansion (paradoxical breathing). By this classification scheme, about 85% of children attending general emergency departments with croup symptoms have mild croup, and less than 1% have severe croup (unpublished prospective data obtained from 21 Alberta general emergency departments).
Table 1.
Clinical scores for assessing severity of croup.
| Croup scoring systems |
| Downes and Raphaely croup score |
| Total score ranging from 0–10 points. Five component items make up the score: |
| • Inspiratory breath sounds (0 = normal, 1 = harsh with rhonchi, 2 = delayed) |
| • Stridor (0 = normal, 1 = inspiratory, 2 = inspiratory and expiratory) |
| • Cough (0 = none, 1 = hoarse cry, 2 = bark) |
| • Retractions/nasal flaring (0 = normal, 1 = suprasternal/present, 2 = suprasternal and intercostal/present) |
| • Cyanosis (0 = none, 1 = in room air, 2 = in FIO2 0.4) |
| Taussig croup score |
| Total score ranging from 0–14 points. Five component items make up the score: |
| • Colour (0 = normal, 1 = dusky, 2 = cyanotic in air, 3 = cyanotic in 30–40% oxygen) |
| • Air entry (0 = normal, 1 = mildly diminished, 2 = moderately diminished, 3 = substantially diminished) |
| • Retractions (0 = none, 1 = mild, 2 = moderate, 3 = severe) |
| • Level of consciousness (0 = normal, 1 = restlessness, 2 = lethargy [depression]) |
| • Stridor (0 = none, 1 = mild, 2 = moderate, 3 = severe [or no stridor in the presence of other signs of severe obstruction]) |
| Westley croup score |
| Total score ranging from 0–17 points. Five component items make up the score: |
| • Stridor (0 = none, 1 = with agitation only, 2 = at rest) |
| • Retractions (0 = none, 1 = mild, 2 = moderate, 3 = severe) |
| • Cyanosis (0 = none, 4 = cyanosis with agitation, 5 = cyanosis at rest) |
| • Level of consciousness (0 = normal [including asleep], 5 = disorientated) |
| • Air entry (0 = normal, 1 = decreased, , 2 = markedly decreased) |
Incidence/ Prevalence
Croup has an average annual incidence of 3%, and accounts for 5% of emergency admissions to hospital in children aged under 6 years in North America (unpublished population-based data from Calgary Health Region, Alberta, Canada, 1996–2000). One retrospective Belgian study found that 16% of children aged 5–8 years had suffered from croup at least once, and 5% had experienced recurrent croup (at least 3 episodes). We are not aware of epidemiological studies establishing the incidence of croup in other parts of the world.
Aetiology/ Risk factors
One long-term prospective cohort study suggested that croup occurred most commonly in children aged between 6 months and 3 years, but can also occur in children as young as 3 months and as old as 12–15 years. Case-report data suggest that it is extremely rare in adults. Infections occur predominantly in late autumn, but can occur during any season. Croup is caused by a variety of viral agents and, occasionally, by Mycoplasma pneumoniae. Parainfluenza accounts for 75% of all cases, with the most common type being parainfluenza type 1. Prospective cohort studies suggest that the remaining cases are mainly respiratory syncytial virus, metapneumovirus, influenza A and B, adenovirus, coronavirus, and mycoplasma. Viral invasion of the laryngeal mucosa leads to inflammation, hyperaemia, and oedema. This leads to narrowing of the subglottic region. Children compensate for this narrowing by breathing more quickly and deeply. In children with more severe illness, as the narrowing progresses, their increased effort at breathing becomes counter-productive, airflow through the upper airway becomes turbulent (stridor), their compliant chest wall begins to cave in during inspiration, resulting in paradoxical breathing, and consequently the child becomes fatigued. With these events — if untreated — the child becomes hypoxic and hypercapnoeic, which eventually results in respiratory failure and arrest.
Prognosis
Croup symptoms resolve in most children within 48 hours. However, a small percentage of children with croup have symptoms that persist for up to a week. Rates of hospital admission vary significantly between communities but, on average, less than 5% of all children with croup are admitted to hospital. Of those admitted to hospital, only 1%–3% are intubated. Mortality is low; in one 10-year study, less than 0.5% of intubated children died. Uncommon complications of croup include pneumonia, pulmonary oedema, and bacterial tracheitis.
Aims of intervention
To minimise the duration and severity of disease episodes, with minimal adverse effects.
Outcomes
Symptom severity: change in clinical severity over time (as measured by a range of clinical scores — e.g., the Westley croup score [see table 1 ]); change in upper airway obstruction (as measured by several pathophysiological measurement tools). Need for additional medical attention / admission to hospital: rate of return to healthcare practitioner after an episode; rate and duration of hospital admission. Adverse effects of treatment. For the question concerning children with impending respiratory failure because of severe croup: rate and duration of airway intubation; symptom severity; adverse effects of treatment.
Methods
Clinical Evidence search and appraisal June 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2008, Embase 1980 to June 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2 (1966 to date of issue). An additional search was carried out of the NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs, RCTs, and observational studies (cohort studies, case studies, and case reports) in any language. There was no minimum length of follow-up required to include studies. We did not exclude studies on the basis of loss to follow-up. We did not exclude RCTs described as "open", "open label", or not blinded. Studies on corticosteroids were required to have at least 20 participants, but for all other interventions we included studies of any size. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Croup.
| Important outcomes | Need for additional medical attention / admission to hospital, Need for intubation, Symptom severity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments in children with mild croup? | |||||||||
| 1 (720) | Symptom severity | Oral dexamethasone versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (820) | Need for additional medical attention / admission to hospital | Oral dexamethasone versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of treatments in children with moderate to severe croup? | |||||||||
| 6 (287) | Symptom severity | Nebulised budesonide versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of children with mild croup |
| 4 (228) | Need for additional medical attention / admission to hospital | Nebulised budesonide versus placebo | 4 | 0 | 0 | –2 | +1 | Moderate | Directness points deducted for inclusion of children with mild croup and composite outcome (visits and admissions). Effect size point added for RR <0.5 |
| 5 (215) | Symptom severity | Intramuscular or oral dexamethasone versus placebo | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results at different end points |
| 2 (154) | Symptom severity | Intramuscular dexamethasone versus nebulised budesonide | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and for flaws with blinding |
| 1 (95) | Need for additional medical attention / admission to hospital | Intramuscular dexamethasone versus nebulised budesonide | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and for flaws with blinding |
| 1 (198) | Symptom severity | Oral dexamethasone versus nebulised budesonide | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (278) | Need for additional medical attention / admission to hospital | Oral dexamethasone versus nebulised budesonide | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (232) | Need for additional medical attention / admission to hospital | Oral dexamethasone versus oral prednisolone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results (including not carrying out a between-group assessment in one RCT). Consistency point deducted for conflicting results |
| 2 (372) | Need for additional medical attention / admission to hospital | Intramuscular versus oral dexamethasone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for flaws with blinding. Directness point deducted for inclusion of children with mild croup |
| 1 (120) | Symptom severity | Higher-dose dexamethasone versus lower-dose dexamethasone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (168) | Need for additional medical attention / admission to hospital | Higher-dose dexamethasone versus lower-dose dexamethasone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for composite outcome (return visit or hospital admission) |
| 1 (198) | Symptom severity | Oral dexamethasone plus nebulised budesonide versus nebulised budesonide alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (198) | Need for additional medical attention / admission to hospital | Oral dexamethasone plus nebulised budesonide versus nebulised budesonide alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for small number of events (1 event in total) |
| 1 (198) | Symptom severity | Oral dexamethasone plus nebulised budesonide versus oral dexamethasone alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (270) | Need for additional medical attention / admission to hospital | Oral dexamethasone plus nebulised budesonide versus oral dexamethasone alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for small number of events (1 event in total in 1 RCT) |
| 3 (87) | Symptom severity | Nebulised adrenaline (epinephrine) versus placebo or no treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (29) | Symptom severity | Adrenaline, nebulised versus heliox (helium–oxygen mixture) | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results at different time points |
| 1 (31) | Symptom severity | L-adrenaline versus racemic adrenaline (epinephrine) | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (14) | Symptom severity | Nebulisation alone versus nebulisation plus intermittent positive pressure breathing (IPPB) | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (15) | Symptom severity | Heliox (helium–oxygen mixture) versus oxygen alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and short follow-up |
| 4 (275) | Symptom severity | Humidified air versus non-humidified or low humidified air | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| What are the effects of treatments in children with impending respiratory failure because of severe croup? | |||||||||
| 10 (1196) | Need for intubation | Corticosteroids versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of different doses and routes of corticosteroids |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Intermittent positive pressure breathing
A type of physiotherapy which involves assisted breathing with a pressure cycled ventilator triggered into inspiration by the user and allowing passive expiration. The user begins to inhale through the machine, which senses the breath and augments it by delivering gas to the user. When a preset pressure is reached, the machine stops delivering gas and allows the user to breathe out. In most devices, the inspiratory sensitivity, flow rate, and pressure can be varied to suit the user's needs, but some devices adjust the sensitivity and flow automatically. The aim is to increase lung volume, which is thought to cause a reduction in airways resistance and an improvement in ventilation.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Paradoxical breathing (thoracoabdominal asynchrony)
A form of breathing that occurs in young children with severe respiratory distress. Typically, in well people the abdomen and chest expand and contract in a synchronised fashion with respiration. Children compensate for narrowing of their upper airway by increasing their work of breathing, which increases intrapleural pressure and the rate of airflow through the upper airway. With greater increases in pleural pressure, during inspiration, a young child's compliant chest wall begins to collapse as the abdomen protrudes, owing to diaphragmatic contraction. This thoracoabdominal asynchrony is commonly referred to as paradoxical breathing. The severity of paradoxical breathing can be measured using a respiratory inductance plethysmograph, which measures the phase angle. A decrease in phase angle equates to a reduction in the severity of paradoxical breathing.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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