Pediatric Bronchospasm

Etiology

Many disease processes induce bronchospasm in the pediatric population, and several will be described in detail in this review: acute asthma exacerbation, acute viral bronchiolitis, and anaphylaxis. A more brief discussion will occur on the topics of foreign body aspiration and vascular ring.

Asthma is a pulmonary disease characterized by airway inflammation, smooth muscle constriction, edema, and mucus production, leading to obstruction and air trapping. Asthma is exacerbated by environmental triggers, resulting in excessive bronchoconstriction out of proportion to a normal airway’s reaction known as airway hyperresponsiveness. Frequent triggers of asthma-related bronchospasm include viral respiratory infections, tobacco exposure, weather fluctuations, potent odors, air pollution, and other irritants.

Bronchiolitis, a viral lower respiratory tract infection affecting children two years and younger, is known to cause bronchospasm, resulting from the inflammation, edema, and necrosis of the cells lining the bronchioles. Additionally, bronchiolitis causes increased production of mucus in these small airways, prompting further obstruction. Finally, bronchospasm presents in patients suffering from anaphylaxis, an acute systemic allergic reaction that is typically mediated by immunoglobulin E.

Epidemiology

Asthma prevalence varies significantly based on community development, region, and climate. According to the 2017 asthma data from the Centers for Disease Control and Prevention, 6.2 million children (0 to 17 years) have asthma in the United States. Children aged 0 to 17 years have a higher prevalence of asthma and higher visit rates to primary care physicians and emergency departments than adults, yet lower mortality.[1] Racial disparities exist in pediatric asthma with the highest prevalence, nonadherence, emergency department and hospitalization rates, and death rates in African American children.[2]

Bronchiolitis most frequently presents in the winter season due to the plethora of viral pathogens--the most common of which is Respiratory syncytial virus. Bronchiolitis is more common in males, non-breastfed infants, and children who have crowded living conditions. On average, over 130000 children less than two years of age are hospitalized each year for bronchiolitis in the United States, with estimated annual healthcare costs of $1.73 billion.[3] This disease process accounts for approximately 16% of the total hospitalizations in this age group.[3] Factors that put children at higher risk for severe disease include age less than 12 weeks, history of premature birth, congenital or underlying cardiopulmonary disease, and immunodeficiency.[4]

In developed countries, estimates are that there is a lifetime prevalence of anaphylaxis of 0.5 to 2%.[5] In the United States, the lifetime prevalence is estimated to be more than 1.6%.[6] The diagnosis of anaphylaxis is on the rise in the United States, doubling from 5.7 to 11.7 patients per 10000 visits to emergency departments between 2009 and 2013.[7] 

History and Physical

Bronchospasm clinically presents itself as wheezing on physical exam. However, some additional indirect signs and symptoms may prompt a healthcare provider to suspect bronchospasm. The child may complain of chest tightness, shortness of breath, or cough. Parents will sometimes describe “noisy breathing.” On exam, accessory respiratory muscle use, nasal flaring, tachypnea, and prolonged expiratory phase are clues. Children with a past medical history of other atopic diseases (such as allergic rhinitis or atopic dermatitis) are more likely to have asthma. In bronchiolitis, the child additionally will have signs and symptoms of a viral prodrome such as rhinorrhea, nasal congestion, and sometimes fever. Anaphylaxis causes multi-system signs and symptoms, including wheezing secondary to bronchospasm (with symptomology similar to asthma), throat “tightness”, stridor, urticaria, flushing, edema and/or pruritus of the lips and tongue, nausea, vomiting, abdominal pain, dizziness, syncope, tachycardia, hypotension, anxiety, and periorbital edema. In the history, there is an acute onset of symptoms typically within seconds to minutes after exposure to a potential trigger.

Other unique presentations of medical conditions associated with bronchospasm and/or wheezing include foreign body aspiration and vascular ring. Foreign body aspiration typically occurs in late infancy or toddlerhood; the time when children can explore the world with their gained mobility but still enjoy frequently putting items in their mouths. There is an acute onset of respiratory distress with symptoms based on the location of the foreign body. Children present with stridor, unilateral wheezes, coughing, and choking. Alternatively, if a patient presents with long-standing symptoms of dysphagia and “noisy breathing” (such as stridor, wheezing, and high-pitched cough) without associated viral symptomatology, one may suspect a vascular ring compressing the trachea and/or esophagus.

Evaluation

To evaluate bronchospasm, a healthcare provider will work-up the suspected etiology.

Pediatric asthma is often diagnosed clinically based on the presentation of symptoms consistent with airway constriction and inflammation in response to an environmental trigger. By six years of age, children typically have the cognitive and physical ability to participate in spirometry, a test to measure airflow obstruction and aid in the diagnosis of asthma. It is helpful to perform this testing in a healthy state in order to solidify a baseline. Annual follow-up spirometry may be performed to assess if one’s asthma is controlled and if treatment regimens need adjustment. During an acute exacerbation of asthma, the patient is assessed clinically and a treatment plan is generated based on the history and physical. If a child with status asthmaticus, the most severe form of an asthma exacerbation, is deteriorating from a respiratory perspective or has altered mental status, one may consider performing an arterial blood gas to evaluate the patient’s gas exchange. A chest radiograph may be to evaluate for pneumothorax, atelectasis, and pneumonia.

Acute viral bronchiolitis is a clinical diagnosis based on a child’s history and physical exam findings. Laboratory and imaging studies are not routinely required. However, if there is not a consistent history of a viral prodrome, it is outside the typical season (winter), the patient’s clinical exam is not entirely consistent with bronchiolitis, and/or the child has increased risk factors for severe disease, laboratory studies as well as chest radiographs may need to be considered in the work-up.[4]

Anaphylaxis recognition can be challenging due to the various organ systems that can be involved. It is a clinical diagnosis based on diagnostic criteria that have been developed. Anaphylaxis is highly likely if one of the following criteria are fulfilled: 1) acute onset of skin/mucous membrane involvement, plus either respiratory compromise or shock; 2) after an exposure to a likely allergen, two or more of these symptoms: skin/mucous membrane involvement, respiratory compromise, hypotension, or gastrointestinal dysfunction; and 3) hypotension after exposure to a known allergen for that patient.[8] Although it is not needed for diagnosis, elevated levels of serum total tryptase can support the clinical findings consistent with the diagnosis of anaphylaxis.

If foreign body aspiration is suspected in older children, inspiration and expiration anteroposterior chest radiographs can be performed. On the expiration film, the laterality of the airway obstruction from the foreign body is determined by the exhibition of unilateral air trapping. Infants and toddlers are unable to follow directions for such imaging. In this population, lateral decubitus films are performed bilaterally. The side with the foreign body is determined by the lung that will not deflate due to its obstruction when it is put in the dependent position.[9] If this imaging does not provide the expected result yet the clinical suspicion is high, more extensive imaging (such as computed tomography of the chest) or a more invasive diagnostic test (such as rigid bronchoscopy) can be performed, the latter of which can also serve as treatment.

Treatment / Management

Asthma

Treatment of an acute asthma exacerbation targets the main components of the underlying pathophysiology: airway inflammation, smooth muscle constriction, edema, and mucus production. The standard initial therapy includes oxygen, intermittent dosing of a short-acting beta-2 agonist (i.e., albuterol), an inhaled anticholinergic (i.e., ipratropium bromide), and corticosteroids. Mucus plugging and atelectasis provoke ventilation-perfusion mismatch, leading to hypoxemia. Patients may paradoxically have a worsening of hypoxemia with the use of beta-2 agonists, as they eliminate the body’s compensatory mechanism of hypoxic pulmonary vasoconstriction. With the increased insensible losses from the respiratory tract, intravenous fluids will be necessary. If the acute exacerbation is worsening, a bolus dose of magnesium sulfate can be given as a rescue. Magnesium sulfate causes smooth muscle relaxation by inhibiting calcium uptake, thereby causing bronchodilation. Additionally, it inhibits mast cells degranulation and histamine release, reducing inflammation and edema.[10]

Children with status asthmaticus (a severe asthma exacerbation that is refractory to standard treatment and potentially fatal) require admission to the pediatric intensive care unit. Continuous albuterol nebulization is initiated and enacts on the beta-2 adrenergic receptors in the lungs, resulting in bronchiole smooth muscle relaxation and dilation. Meanwhile, the patient requires monitoring for albuterol’s side effects: restlessness, tachycardia (due to the inadvertent effect of the drug on beta-1 receptors), arrhythmias, nausea, hypokalemia (from potassium shifting intracellularly), hyperglycemia, and tremors. If the patient is not improving with continuous albuterol, it may be due to the drug not reaching its targeted small airways, as the severity of bronchospasm is limiting gas flow and tidal volume. In this setting, an intravenous beta-2 agonist, terbutaline, can be used. An initial loading dose of terbutaline is given subcutaneously or intravenously, followed by a continuous intravenous infusion. This beta-agonist is preferred over epinephrine, as it has a more favorable side effect profile that is similar to albuterol. Rarely, myocardial ischemia can occur; this should be monitored with daily electrocardiograms. Repeated boluses or a continuous infusion of magnesium sulfate can also be added to the child’s regimen. Ketamine is an anesthetic, sedative, and analgesic working as an antagonist to the N-methyl-D-aspartate receptor and has bronchodilatory effects. A bolus dose of ketamine followed by an infusion intravenously can serve as both a bronchodilator and sedative while on non-invasive positive pressure ventilation (NPPV) or invasive mechanical ventilatory support.[10]

Intubation and invasive mechanical ventilatory support are reserved for the most severe cases of status asthmaticus, in which maximal medical therapy has been exhausted, and an indication of persistent hypoxia, severe acidosis, or altered mental status exists. It is avoided if possible, as manipulation of the airway in the setting of bronchial hyperresponsiveness can worsen the obstruction and hypercapnia. It is also difficult to ventilate this patient population due to airway obstruction and impeded exhalation, putting them at risk for barotrauma. If invasive mechanical ventilation is necessary, use a lung-protective strategy. Permissive hypercapnia should be tolerated. Using a ventilator mode with a decelerating flow pattern, such as pressure-regulated volume control, can be helpful in mechanically ventilated patients in status asthmaticus.[11],[12][11] Compared to a volume control mode, it allows for higher mean airway pressures, yet lower peak inspiratory pressures.[11],[12] Avoiding the use of neuromuscular blockade permits the use a spontaneous breathing mode--ideally one that allows the patient to regulate their own inspiratory and expiratory times. Additionally, it reduces the risk of myopathy of critical illness that occurs in the setting of combined use of corticosteroids and neuromuscular blocking agents.  (B2)

Methylxanthines, such as theophylline, have historically been used in the treatment of status asthmaticus due to their bronchodilatory effects. Additionally, they have anti-inflammatory and immune modulation properties.[10] However, they are falling out of favor for use in children due to the narrow therapeutic window, toxic effects (arrhythmias, seizures, cerebral vasoconstriction), and availability of safer alternative therapies. Other inhaled gases can be mixed with or added to oxygen to 1) reduce turbulent flow (helium-oxygen mixture referred to as heliox via a mask or high flow nasal cannula), or 2) administer a potent bronchodilator (inhaled volatile anesthetics via the ventilator). The former may have limited use in the presence of hypoxemia, as the fraction of inspired oxygen in the gas mixture is restricted to 0.21 to 0.4 for the helium proportion to be significant enough to have the desired effect.[10] Utilization of inhaled volatile anesthetics is generally the final medication in the treatment arsenal or used as a bridge to get a child on extracorporeal life support for status asthmaticus. However, its use may be hampered by its need for specialized equipment, the risk of developing malignant hyperthermia, and its adverse effects (myocardial depression, arrhythmias, and cerebral vasodilation).[13]

Bronchiolitis

The mainstay of treatment of bronchiolitis is supportive care with supplemental oxygen, hydration, and clearing the airways of secretions. Some children’s respiratory support requires escalation to invasive mechanical ventilation. Alpha and/or beta-adrenergic agents with bronchodilatory effects, such as albuterol and epinephrine, are not recommended in the treatment of wheezing in bronchiolitis.[4] This restriction includes all forms of epinephrine: nebulized racemic and parenteral. A Cochrane review of 30 randomized controlled trials demonstrated no statistically significant improvement in oxygen saturation, rate of hospitalization, duration of hospitalization, or time to resolution of illness with the use of bronchodilators in the setting of bronchiolitis.[14] Clinical score improvement with bronchodilators was statistically significant in the outpatient setting; however, the clinical significance came into question due to the small degree of change observed.[14] In contrast, the inpatient population showed no improvement in the mean clinical score.[14] In a small study of 22 mechanically ventilated infants with respiratory syncytial virus bronchiolitis, bronchodilators caused a small but statistically significant fall in peak inspiratory pressures.[15] The authors noted the effects were minute and unlikely to be clinically significant, while the statistically significant tachycardia (from the bronchodilators) had greater potential to be clinically significant.[15](A1)

Nebulized hypertonic saline is not recommended for use in infants with bronchiolitis in the emergency department setting. Due to inconsistent outcomes in randomized controlled trials, a nebulized hypertonic saline is an option in hospitalized infants and children with bronchiolitis; however, note that this therapy has not been studied in critically ill children. Bronchospasm is a potential adverse effect of nebulized hypertonic saline, so it is typically co-administered with an inhaled bronchodilator. Corticosteroids are not a recommended intervention in the treatment of bronchiolitis.[4](A1)

Anaphylaxis

Early recognition of anaphylaxis is paramount. Prompt treatment with epinephrine is necessary to prevent the progression of anaphylaxis to a state of life-threatening respiratory and/or hemodynamic compromise. If anaphylaxis is suspected, treatment should not be delayed, as anaphylaxis severity and rate of progression is unpredictable. 

First assess the airway, breathing, and circulation of the patient. Place the child on a cardiorespiratory monitor, provide supplemental oxygen, and acquire intravenous or intraosseous access for aggressive volume resuscitation. Epinephrine is the most important treatment. As readily as possible, administer intramuscular epinephrine to the anterolateral surface of the child’s mid-thigh.[16] Intramuscular epinephrine is preferred over intravenous because it is typically faster to administer, has fewer cardiovascular complications (arrhythmias, myocardial ischemia, hypertension), and has less dosing errors.[17] Avoid subcutaneous epinephrine administration, as it is slower to absorb than intramuscular, has inconsistent pharmacodynamics, and the response is unreliable.[16] Epinephrine dosing is repeatable every five to 15 minutes. If the patient is hemodynamically unstable and not responding to repeated doses of intramuscular epinephrine and fluid resuscitation, then an intravenous epinephrine infusion can be initiated. If stridor, other signs of airway involvement, or severe respiratory compromise are present, the child should undergo immediate intubation. If the healthcare provider is unable to secure an airway, an emergent cricothyroidotomy or tracheostomy should be performed. Additional therapies used in conjunction with epinephrine are H1 antihistamines (i.e., diphenhydramine), H2 antihistamines (i.e., ranitidine), bronchodilators, and glucocorticoids. If bronchospasm is present and unresponsive to epinephrine, inhaled bronchodilators use is necessary.(A1)

Differential Diagnosis

Acute asthma exacerbation, bronchiolitis, and anaphylaxis are a few of the most common causes of bronchospasm in the pediatric population. There are a wide variety of other disease processes that can cause bronchospasm and present with wheezing on physical exam. It is also imperative that one be mindful of the conditions that may mimic the symptomatology of bronchospasm. The differential diagnosis in these cases should include, but not be limited to, the following: 

• Foreign body aspiration 
• Vascular ring
• Tracheobronchomalacia
• Reactive airway disease
• Gastroesophageal reflux disease
• Oropharyngeal dysphagia with aspiration
• Bronchopulmonary dysplasia
• Exercise-induced bronchospasm
• Cystic fibrosis
• Vocal cord dysfunction
• Disorders of cilia motility
• Tracheoesophageal fistula
• Cardiac disease with pulmonary over circulation or pulmonary venous congestion
• Mediastinal mass
• Primary immunodeficiencies
• Bronchiectasis
• Bronchiolitis obliterans

Prognosis

Wheezing is a common presenting symptom in the preschool age group. However, the majority of these children do not develop a chronic, persistent form of asthma. The odds of developing early childhood asthma are two to three times higher in infants with one or more episodes of bronchiolitis.[18] Infants requiring hospitalization for bronchiolitis have higher early childhood asthma morbidity.[18] Epidemiologic studies have aided in the development of an Asthma Predictive Index to improve the accuracy of diagnosing children younger than three years old with asthma. The Asthma Predictive Index is considered positive if a child has had at least three episodes of wheezing per year, plus meets either one major criterion (parental asthma, atopic dermatitis, or sensitization to air allergens) or two minor criteria (food allergies, wheezing unrelated to “colds”, or eosinophilia greater than or equal to 4%). A positive Asthma Predictive Index means the child is at a significantly higher risk of having asthma later in life. As high as 76% of toddlers with a positive Asthma Predictive Index will have active asthma symptoms when they are school age.[19][20] In regards to the prognosis in anaphylaxis, early identification and treatment with epinephrine are critical to stopping the progression of anaphylaxis to respiratory or cardiac arrest and death.

Complications

In the setting of air trapping from the obstruction caused by bronchospasm, patients are at higher risk for pneumothoraces and/or pneumomediastinum. In severe cases of bronchospasm causing acute respiratory failure with hypoxia and/or hypercapnia, extracorporeal life support may be required.