Status Asthmaticus

Although unusual anatomic conditions of the lower airways can occur in pediatric patients (Table 72-1), status asthmaticus and bronchiolitis are probably the most common causes of lower-airway disease encountered in the pediatric ICU. Asthma is common in the industrialized world, and the overall mortality rate attributable to asthma in the United States is estimated at 2.6 deaths per million children per year.¹ Recurrent hospitalizations, previous ICU admissions, and the need for mechanical ventilatory support have been identified as risk factors for death from asthma.² Status asthmaticus is characterized by acute, severe airway obstruction due to bronchoconstriction that is refractory to initial management with supplemental oxygen, inhaled bronchodilators, and corticosteroids. The pathophysiology of this condition begins with a precipitant that triggers contraction of hyperresponsive bronchial smooth muscle, mucus secretion, and mucosal edema, all of which lead to the obstruction of large and small airways (Figure 72-1). Hyperinflation from airflow limitation and premature closure of lower airways in expiration leads to increased end-expiratory lung volume³ and an increased respiratory workload, which ultimately set the stage for alveolar hypoventilation and hypoxemia. An abrupt and profound acidosis can develop when respiratory compensation for accumulated inorganic acids ceases to occur.³ On physical examination, the child with status asthmaticus can appear anxious or lethargic, will often demonstrate accessory muscle use, and depending on the quality of air entry, can demonstrate either cough with profound inspiratory and/or expiratory wheezing and prolongation of audible expiration, or a silent chest. An exaggerated pulsus paradoxus can often be demonstrated, a finding that reflects the profoundly negative intrapleural pressures generated by these patients during spontaneous respiration.

TABLE 72-1 Anatomic Causes of Lower-Airway Dysfunction

Figure 72-1 Pathophysiology of status asthmaticus.

(Modified from Helfaer M, Nichols D, Rogers M. Lower airway disease: bronchiolitis and asthma. In: Rogers M, editor. Textbook of Pediatric Intensive Care. 3rd ed. Baltimore: Williams and Wilkins; 1996, p. 141.)

Bronchiolitis

Bronchiolitis is a clinical term implying an invasion of the large and small airway respiratory epithelium by inflammatory cells in the setting of acute respiratory illness. The primary cause of bronchiolitis is respiratory syncytial virus (RSV), which is responsible for 45% to 75% of cases, although parainfluenza viruses, rhinoviruses, adenoviruses, influenza viruses, enteroviruses, and Mycoplasma pneumoniae can produce the syndrome as well. RSV dependably produces yearly epidemics occurring during the winter and spring months. Infection with RSV is nearly universal among infants and children by 2 years of age. Although hospitalization rates vary seasonally and regionally, a recent study cited an average hospitalization rate between 3 per 1000 among children younger than 5 years of age, and 17 per 1000 among children younger than 6 months.²¹ Among all hospitalized children, the percentage requiring intensive care has been reported as 7% to 9% among patients without comorbidity and as high as 20% to 37% in those with preceding cardiac disease, chronic lung disease, prematurity, immunocompromise, and age younger than 6 weeks.²² Patients with these coexisting conditions are also at increased risk of mortality from RSV²³ and have been identified as candidates to receive monthly prophylaxis with an RSV antigen–specific monoclonal antibody (Palivizumab [MedImmune Inc., Gaithersburg, Maryland]) during RSV season. However, recent epidemiologic data indicate that most RSV-infected children have no significant comorbidities, suggesting that prevention strategies targeting only medically complex patients may have minimal impact on the overall disease burden.²¹

RSV transmission can occur either by direct contact with contagious secretions or by exposure to aerosolized particles from the respiratory mucosa.²⁴ The incubation period varies from 2 to 8 days,²⁴ symptoms tend to escalate over 3 to 5 days, and convalescence can be prolonged up to several weeks in the most vulnerable small infants. On histologic examination, reappearance of ciliated respiratory epithelium commonly takes more than 2 weeks.²⁴ Viral shedding from the respiratory tract typically occurs over 3 to 8 days but may also continue for up to 4 to 6 weeks in small infants. Symptoms typically begin with signs of upper respiratory illness, including fever, coryza, and possibly otitis media. Small infants commonly present with lethargy and central apnea²⁵ early in the course of illness. Cough and tachypnea soon develop as the illness progresses to the lower airways, usually 1 to 3 days following incubation.²⁴ Wheezing produced by flow limitation in peripheral airways is a nearly universal finding and may be due in large part to intermittent obstruction of large and small airways with necrotic epithelial debris, edema, and mucus²⁴ rather than to the bronchospasm more commonly seen in asthma. Radiographic findings are often nonspecific but commonly include hyperinflation, peribronchial thickening, subsegmental consolidation, and multiple areas of atelectasis or infiltration involving most frequently the right middle and right upper lobes. A large prospective study of RSV-infected hospitalized children found that secondary bacterial infection occurred in only 1.2% of the study cohort, establishing that risk of bacterial disease is low in RSV bronchiolitis, despite potentially suggestive radiographic findings and the widespread empirical use of broad-spectrum antimicrobial agents in these patients.²⁶

Mechanical Ventilation

The need for mechanical ventilation in the patient with lower airways disease commonly arises from failure of ventilation and resulting hypercapnia. Hypoxemia and recurrent apnea, which are common in young infants with bronchiolitis, also frequently precipitate the institution of ventilatory support. Assuming adequate airway protection, oxygenation, and respiratory drive, it is probably best to avoid intubation in the patient with lower airways disease unless the overall clinical status of the child warrants the risk of augmenting airway hyperreactivity through airway instrumentation.³⁹ To this end, there are several adjunct therapies that may obviate the need for intubation when added to aggressively applied conventional therapies. An inspired mixture of helium and oxygen (heliox) has been used to alleviate airflow limitation in pediatric patients. Owing to its low density and reduced Reynolds number, helium is able to convert turbulent gas flow to laminar flow in airways, and its clinical effect is generally immediate. Because it is an inert gas, it can potentially lower airway resistance without toxicity. When given as 60% to 80% of the total inspired gas mixture, helium can produce more efficient delivery of oxygen as well as nebulized drugs.⁴⁰

The use of heliox in patients with lower-airway disease has generally produced inconsistent results. A small randomized controlled trial in spontaneously breathing children with status asthmaticus demonstrated that administration of heliox improves respiratory mechanics by lowering the pulsus paradoxus, increasing peak flow, and decreasing the dyspnea index, which may decrease the need for mechanical ventilation.⁴¹ In another small series, a 60 : 40 heliox mixture administered to 7 intubated patients resulted in a 15% to 50% reduction in peak inspiratory pressure and a 30% to 60% reduction in PaCO₂.⁴² A recent literature review on the use of heliox in patients of all ages with acute asthma concluded that it may be useful in the short-term management of these patients, but any clinical advantage attributable to its use seems to diminish over time.⁴³ There is little evidence available on the use of heliox in critically ill patients with bronchiolitis. This issue was prospectively investigated in a nonrandomized study of 38 nonintubated infants with RSV bronchiolitis admitted to an ICU.⁴⁴ The investigators were able to demonstrate favorable changes in respiratory status through the first 4 hours of heliox administration and a significant decrease in ICU length of stay among infants who received heliox therapy.⁴⁴ In a small randomized crossover study of RSV-positive, nonintubated patients, clinical indicators of respiratory status improved during heliox administration, particularly among children with more severe disease.⁴⁵ However, many of the patients required another form of respiratory support, and the study was not designed to evaluate longer-term outcomes such as ICU length of stay.⁴⁵

The application of noninvasive forms of mechanical support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) using either a nasal interface or full face mask has potential advantage in the patient with adequate respiratory drive. Careful titration of applied CPAP (or positive end-expiratory pressure [PEEP]) noninvasively may prevent premature airway closure during expiration and decrease gas trapping (see later discussion). The patient who develops high levels of intrinsic PEEP due to hyperinflation manifests an increased work of breathing and, ultimately, respiratory muscle fatigue, which may precipitate dramatic and rapid clinical deterioration. Noninvasive respiratory support may allow unloading of the muscles of respiration without adding to airway reactivity and has been used with success in managing asthma as well as bronchiolitis.^46–48

In the patient with respiratory failure for whom noninvasive mechanical support is not feasible, intubation and mechanical ventilation is warranted. As tracheal intubation is performed in the patient with airways disease, the clinician should be watchful for complications arising from the transition to positive-pressure ventilation. In the spontaneously breathing child with severe airway obstruction, profoundly negative intrathoracic pressures develop in order to generate lung inflation. These conditions produce maximal venous return as right atrial pressure remains subatmospheric.⁴⁹ The transition to positive-pressure ventilation in this setting increases juxtacardiac pressures and right ventricular afterload, resulting in decreased venous return, decreased left ventricular compliance, and decreased left ventricular end diastolic volume,⁴⁹ with risk of hypotension and cardiac arrest.³

In intubated patients with status asthmaticus or bronchiolitis, low elastic recoil and increased airway resistance due to bronchoconstriction, airway edema, and mucus plugging contribute to regional gas trapping and dynamic hyperinflation (Figure 72-2, A). Gas trapping can also be exacerbated by the patient’s forced expiratory efforts, during which increased abdominal pressure is transmitted to the pleural space, potentiating premature airway closure and the development of excess or intrinsic PEEP (“auto-PEEP”). The magnitude of the auto-PEEP reflects the degree of dynamic hyperinflation in patients with severe asthma.⁵⁰ Dynamic hyperinflation and auto-PEEP have an adaptive purpose in increasing the elastic recoil pressure of the lung to a level that would eventually allow complete evacuation of inhaled volume.⁵⁰ However, this increase in lung volume takes place at the expense of an unfavorable change in pulmonary compliance. Other potential consequences of dynamic hyperinflation and auto-PEEP include air leak, hemodynamic compromise from sustained elevations in pulmonary vascular resistance, and increased inspiratory workload from the patient’s attempts to drop the ventilator circuit pressure below the total PEEP level (applied or set PEEP plus auto-PEEP) to trigger a breath (see Figure 72-2, B). The development of gas trapping and auto-PEEP can be inferred if the flow-versus-time waveform on the ventilator console shows initiation of inspiratory flow before the expiratory flow from the preceding breath reaches zero. Alternatively, the ventilator can quantify auto-PEEP by allowing the alveolar pressure to equilibrate with pressure at the airway opening during an end-expiratory hold maneuver. The accuracy and reliability of each of these techniques rest on the premise that all lung units communicate with the airway opening, which may not be true if bronchial obstruction is severe.⁵¹

Figure 72-2 A, Dynamic hyperinflation.

Expiratory flow limitation in the asthmatic lung (upper tracing) causes incomplete evacuation of lung volume at end exhalation. Repetitive cycles of gas trapping lead to excess pressure accumulation at end exhalation (“auto-PEEP”), with a progressive shift toward ventilation on the less compliant (upper and outer) portion of the pressure-volume curve (see also Figure 35-3).

(Adapted from Stather DR, Stewart TE. Clinical review: mechanical ventilation in severe asthma. Crit Care 2005;9:581-7.)

B, Effect of auto-PEEP on inspiratory threshold load.

Ventilator circuit pressure, alveolar pressure, and trigger sensitivity setting are indicated. The difference between peak inspiratory circuit pressure and peak inspiratory alveolar pressure reflects increased airway resistance. Difference between end-expiratory circuit pressure and end-expiratory alveolar pressure reflects expiratory flow limitation and auto-PEEP. Pressure drop required to generate inspiratory flow (“trigger threshold”) is the difference between end-expiratory pressure and sensitivity setting. Auto-PEEP will require the patient to generate a larger inspiratory pressure drop to generate inspiratory flow.

Excessive gas trapping and auto-PEEP are managed though adherence to the basic principles of mechanical ventilatory support of patients with lower airways disease: (1) limitation of tidal volume, plateau pressure, and respiratory rate; (2) reducing inspiratory time, and (3) judiciously titrating applied PEEP. In the spontaneously breathing mechanically ventilated patient, increases in applied PEEP can reduce auto-PEEP by reducing the tendency to premature airway closure during exhalation and restoring a pressure gradient between the alveoli and airway opening that favors a return toward normal end-expiratory lung volume. Reduction of auto-PEEP through this kind of maneuver can facilitate the triggering of ventilator breaths and decrease the inspiratory workload. However sound this concept may appear in theory, it can be difficult to optimize in practice. If increases in applied PEEP fail to improve respiratory mechanics or worsen gas trapping, the clinician may consider a trial of neuromuscular blockade in an effort to facilitate enforcement of permissive hypercapnia and further reductions in minute ventilation.

In summary, initial ventilator settings in patients with lower-airway disease should be guided by observation, auscultation, careful ventilator waveform analysis, and attention to inspiratory plateau pressure. Ultimately, the choice of ventilator mode is not as important as a thorough understanding of how any mode might be strategically manipulated to alleviate the pathophysiology of gas trapping and auto-PEEP. It is generally preferable to allow the patient to breathe in a spontaneous ventilator mode, using a strategy of permissive hypercapnia. In spontaneously breathing mechanically ventilated patients, applied PEEP can be titrated cautiously upward as needed to improve respiratory mechanics to a level not exceeding 80% of the auto-PEEP, or until the plateau pressure begins to exceed a tolerable limit, which is usually around 30 cm H₂O.^51,52 If controlled ventilation is necessary, it is preferable to apply the lowest minute ventilation that provides adequate gas exchange.⁵³ The use of neuromuscular blocking agents should be limited to the shortest feasible course because of their potentially detrimental effect on the relationship between ventilation and perfusion, and because of the risk of myopathy when these agents are administered together with corticosteroids.⁵⁴ High-frequency oscillatory ventilation (see later discussion) has been used to rescue a limited number of pediatric patients with asthma and bronchiolitis who demonstrate respiratory failure refractory to management with conventional ventilation.⁵⁵ One recent report recommends the use of high distending pressures to decrease airway resistance, as well as low frequencies, longer expiratory times, and muscle relaxation to minimize gas trapping.⁵⁶

Sedation is an important component of managing intubated patients with lower-airway disease. Besides alleviating distress and promoting synchrony with the ventilator, sedative agents can be helpful adjuncts in limiting carbon dioxide production and reducing mechanical ventilatory requirements.⁵¹ Ketamine, a dissociative anesthetic with sympathomimetic and bronchodilatory properties, is often used for sedation in the intubated asthmatic child.⁵⁷ Because of its favorable effects on airway reactivity, the inhalational anesthetic, isoflurane, may be a useful adjunct to managing severe status asthmaticus in the intubated child who is difficult to sedate or unresponsive to other therapies. The mechanism underlying its bronchodilatory properties is not well understood.⁵⁸ Although isoflurane has a better safety profile than halothane when used for this purpose, periodic monitoring of renal function may be advisable in the child who requires prolonged therapy with this agent.⁵⁸

Viral Pneumonia

Defined as acute respiratory symptoms accompanied by parenchymal infiltrates on chest x-ray, pneumonia is a common syndrome in children and is most commonly caused by viral or bacterial pathogens.⁵⁹ Important viral pathogens responsible for pneumonia in infants and children include RSV, influenza, parainfluenza, and adenovirus. As previously discussed, each of these is agents is also capable of producing the clinical syndrome of bronchiolitis in infants and children. The precise infectious etiology for pediatric viral pneumonias may be suggested by the physical examination, the age of the patient, and seasonal incidence patterns. Confirmatory testing through microbiologic analysis is generally sought to facilitate therapeutic decision making and cohorting of similarly affected patients. RSV is the most common viral cause of lower respiratory infection in infancy⁶⁰ and primarily infects the small airways. Influenza is another very important cause of pediatric pneumonia. Infection rates in healthy children are estimated at 10% to 40% each year, and approximately 1% of these children require hospitalization.⁶⁰ The course of up to 25% of infected children is complicated by lower respiratory tract disease.⁶⁰ Neonates and children up to 5 years of age, especially those with underlying lung disease, congenital heart disease, immunocompromise, and other chronic conditions, seem to be at special risk for influenza pneumonia.⁶⁰ Neonates are at risk for especially severe influenza syndromes which may also include apnea and sepsis.⁶⁰ Infants and children older than 6 months of age, especially those in high-risk categories, are candidates for annual vaccination against influenza.⁶¹ Antiviral therapy for A and B strains of influenza are now available and can be considered for patients of appropriate age who are at high risk of complicated or severe disease.⁶⁰ When administered within 48 hours of disease onset, amantadine, which is approved for use in children older than 1 year of age, may decrease the severity of influenza A disease, but data in young patients are limited.⁶⁰ Oseltamivir, a neuraminidase inhibitor active against both A and B strains of influenza, has been demonstrated to decrease symptom duration when administered early in disease. When originally licensed for pediatric administration, oseltamivir was not approved for use in infants younger than 1 year.⁶² However, increased experience using oseltamivir in smaller infants during the 2009 H1N1 influenza pandemic produced some consensus on appropriate dosing guidelines in this age group.⁶³ Unlike RSV, influenza is commonly associated with secondary bacterial pneumonia that is typically caused by Streptococcus pneumoniae or Staphylococcus aureus, making it especially important to consider appropriate empirical antimicrobial therapy when clinically appropriate.^64,65 Parainfluenza viruses are also responsible for causing pneumonia in children, and seasonal epidemics commonly occur in autumn.⁶⁰ Primary infection tends to occur in young children 2 to 6 years of age, and recurrent infection is generally less severe, except perhaps in the immunocompromised host.⁶⁰ Finally, adenoviruses have been reported to cause up to 20% of pneumonias in children younger than 5 years of age, and the mortality rate attributable to the disease in this population has been reported as high as 20%.⁶⁶ In neonates, adenovirus can produce an especially severe syndrome of disseminated disease and sepsis, which can present in the first 10 days of life.⁶⁶ The incubation period is generally 2 to 14 days,⁶⁰ and the virus can produce a profound and destructive lower-respiratory process. Necrotizing bronchitis, purulent exudative alveolitis, and hyaline membrane formation have been identified on autopsy specimens of affected patients.⁶⁶ Survivors of severe adenoviral infections commonly demonstrate chronic sequelae such as recurrent wheezing and bronchiolitis obliterans.⁶⁶

Bacterial Pneumonia

Most commonly, bacterial presence is established in the lower respiratory tract as a result of oropharyngeal overgrowth of environmentally acquired pathogens and subsequent introduction of these secretions into the lower airways. Children with aspiration syndromes, immunodeficiencies, and malformations of the respiratory tract are at increased risk of bacterial lower respiratory infection.⁶⁷ Bacterial pathogens remain an important cause of potentially lethal pediatric pneumonias in the developing world, and they are the most important cause of severe pneumonia in Europe and North America, especially when complicated by parenchymal necrosis and/or parapneumonic effusion.⁵⁹ It is challenging to establish a causal role for specific bacteria when these agents are normally found in the upper airway secretions, the specimen most commonly sampled for microbiologic diagnosis in children. The best data regarding the etiology of community acquired pneumonia come from lung-puncture studies revealing that S. pneumoniae, Hemophilus influenzae, and S. aureus are among the most important causes.⁵⁹ Since the introduction of a conjugate vaccine against H. influenzae type B (Hib) in 1988, the incidence of invasive disease in infants and young children attributable to this organism has declined by 99%.⁶⁰ Other serotypes of the organism, including nonencapsulated strains, may also cause pneumonia in children.⁶⁰

A comprehensive review of necrotizing pneumonia cases occurring in predominantly immunocompetent children admitted to Children’s Hospital Boston between 1990 and 2005 indicates that parenchymal necrosis appears to be an increasingly common complication of pediatric bacterial pneumonia.⁶⁸ In this series, S. pneumoniae was the predominant inciting organism, accounting for 22% of cases. Since 2002, many more organisms, including methicillin-sensitive S. aureus, methicillin-resistant S. aureus, Fusobacterium species, Pseudomonas species, and other Streptococcus species, have emerged as important causes of necrotizing pneumonia as well. Despite the short-term morbidity in these children, conservative management (consisting mainly of antibiotics and chest drainage) appeared sufficient to produce resolution of clinical symptoms within 2 months of hospital discharge, and marked improvement of imaging findings within 6 months.

Recent studies on the epidemiology of pediatric pneumonia complicated by parapneumonic effusion indicate that the incidence of empyema appears to have risen during the 1990s.^69–71 During that period, S. pneumoniae was isolated most commonly from patients with empyema, followed by Streptococcus pyogenes and S. aureus.^70,71 As in the case of necrotizing pneumonia, temporal trends in the epidemiology of pediatric empyema in the United States show a shift in causative organisms after the year 2000, when the heptavalent pneumococcal conjugate vaccine (PCV) was licensed for widespread use. A large case series reported from Texas Children’s Hospital indicates that since 2000, S. aureus has overtaken S. pneumoniae as the most common bacterial pathogen isolated from children with empyema, and the majority of S. aureus isolates in this cohort were methicillin resistant.⁶⁹ In addition, nonvaccine serotypes (particularly serotypes 1, 3, and 19A) predominate among causes of pneumococcal empyema in the post-PCV era.^70,72 The overall impact of widespread vaccination with PCV on the incidence of pediatric empyema across the United States is less clear. In Utah, where pneumococcal serotype 1 has always been prevalent, the incidence of pediatric empyema is still rising, while data from Texas Children’s Hospital show a decrease in the incidence of empyema since the vaccine became available.^69,70

In neonates and young infants up to about 3 months of age, group B Streptococcus