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Pediatric Status Asthmaticus

Published:February 06, 2013DOI:https://doi.org/10.1016/j.ccc.2012.12.001

      Keywords

      Key points

      • Status asthmaticus is a frequent cause of admission to a pediatric intensive care unit. Prompt assessment and aggressive treatment are critical.
      • First-line or conventional treatment includes supplemental oxygen, aerosolized albuterol, and corticosteroids.
      • There are several second-line treatments available; however, few comparative studies have been performed and in the absence of good evidence-based treatments, the use of these therapies is highly variable and dependent on local practice and provider preference.

      Introduction

      Status asthmaticus is a major cause of acute illness in children and one of the top indications for admission to a pediatric intensive care unit (ICU).
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      Mortality is rare after a child arrives at medical attention, but morbidity can be high with some children requiring days or weeks of hospitalization and recovery. Additionally, even children with mild or intermittent baseline asthma can have severe exacerbations requiring ICU admission,
      • Carroll C.L.
      • Schramm C.M.
      • Zucker A.R.
      Severe exacerbations in children with mild asthma.
      so predicting who will progress to a more severe exacerbation is challenging. Several risk factors have been identified, but no combination can sufficiently predict the likelihood of a particular child developing a more severe exacerbation (Box 1).
      Risk factors for life-threatening deterioration during status asthmaticus
      • Prior history of life-threatening exacerbation
        • Previous ICU admission
        • Previous endotracheal intubation
      • Older age
      • Inability to recognize airflow obstruction
      • Poor asthma control

      Pathophysiology

      Bronchial smooth muscle spasm, airway inflammation, and increased mucous production are the key components of acute asthma.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      This pathophysiology results in increased pulmonary resistance, small airway collapse, and dynamic hyperinflation. Unlike during normal breathing, in status asthmaticus a child’s inspiratory muscle activity can persist through exhalation, significantly increasing respiratory muscle workload and fatigue.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      Additionally, because of heterogeneous areas of premature closure and obstruction, there can be significant ventilation-perfusion mismatching and hypoxemia.
      Cardiopulmonary interactions can also be an important factor during status asthmaticus. Dynamic hyperinflation and hypoxic pulmonary vasoconstriction contribute to a decrease in right ventricular preload and increase in biventricular afterload. These changes can be observed clinically in pulsus paradoxus, which is an exaggeration of the normal decrease in arterial pressure that occurs during inspiration.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      In addition, tachycardia caused by bronchodilators further reduces ventricular filling time and can have a net effect of reducing overall cardiac output. This can manifest clinically as a need for additional intravascular volume and low diastolic blood pressures, but does not typically require inotropic support in the absence of impaired end-organ perfusion and in children with appropriate urine output and mental status.
      Underlying components of the acute exacerbation are treated in different manners and at different times or phases of a child’s illness (Fig. 1). In the initial phase of an acute exacerbation, treatment of bronchospasm is paramount. Bronchodilator therapy has the potential to most rapidly improve clinical status. Corticosteroid therapy should also be initiated promptly, because although the peak action is later than bronchodilators, early administration of corticosteroids has been associated with improved outcomes.
      • Bhogal S.K.
      • McGillivray D.
      • Bourbeau J.
      • et al.
      Early administration of systemic corticosteroids reduces hospital admission rates for children with moderate and severe asthma exacerbation.
      After this acute bronchospastic phase begins to resolve, simple airway clearance techniques may be helpful in augmenting mucous clearance.
      Figure thumbnail gr1
      Fig. 1Pathophysiology and treatment of acute exacerbation.

      Evaluation

      Prompt assessment and rapid evaluation of clinical status are needed to determine the appropriate treatments and levels of monitoring in children with status asthmaticus.
      • U.S. Department of Health and Human Services
      National Heart, Lung and Blood Institute. National asthma education and prevention program expert panel report 3: guidelines for the diagnosis and management of asthma.
      Assessment of observed signs and symptoms can be helpful in determining degree of distress (Table 1). Whenever possible, this evaluation should be done without increasing patient anxiety, because crying increases turbulent airflow and work of breathing, and can make clinical assessment more challenging. To determine the appropriate types and levels of care, other testing and assessment may also be useful in certain situations.
      Table 1Signs and symptoms of severe disease
      SubjectiveObjective
      Shortness of breathRespiratory rate
      Work of breathing and accessory muscle useHeart rate
      Diminished or absent breath soundsPulse oximetry
      Degree and timing of wheezing
      Ability to speak in sentences or count to 10
      Level of alertness
      Anxiety or diaphoresis

      Quantifying Disease Severity

      Quantifying disease severity is an important tool in the clinical care of children with status asthmaticus. However, obtaining reliable and reproducible measures of pulmonary function or mechanics is difficult in sick children.
      • van der Windt D.A.
      • Nagelkerke A.F.
      • Bouter L.M.
      • et al.
      Clinical scores for acute asthma in pre-school children.
      • Keogh K.A.
      • Macarthur C.
      • Parkin P.C.
      • et al.
      Predictors of hospitalization in children with acute asthma.
      Often, because of age-related or developmental factors, sick children cannot perform the peak flow or spirometry that is routinely used in adults with acute asthma.
      • van der Windt D.A.
      • Nagelkerke A.F.
      • Bouter L.M.
      • et al.
      Clinical scores for acute asthma in pre-school children.
      • Keogh K.A.
      • Macarthur C.
      • Parkin P.C.
      • et al.
      Predictors of hospitalization in children with acute asthma.
      As a result, a variety of clinical asthma scores have been developed to quantify a child’s degree of respiratory distress.
      • van der Windt D.A.
      • Nagelkerke A.F.
      • Bouter L.M.
      • et al.
      Clinical scores for acute asthma in pre-school children.
      • Keogh K.A.
      • Macarthur C.
      • Parkin P.C.
      • et al.
      Predictors of hospitalization in children with acute asthma.
      These scores are used to communicate illness severity between providers, to determine types and levels of care, and to determine patient disposition. Clinical asthma scores use a combination of subjective and objective variables that are found in children with severe disease and then rank the degree of distress for each variable to determine a total numerical value. None of these clinical asthma scores have been shown to be superior to any other. However, when choosing a clinical asthma score, providers should use one that has a high degree of interobserver reliability and has been linked to clinical outcomes.

      Blood Gases

      Blood gases are frequently obtained on children with status asthmaticus and are used to predict impending respiratory failure in this population. However, blood gas findings should not be used to supersede a provider’s clinical judgment.
      • Werner H.A.
      Status asthmaticus in children.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      • Qureshi F.
      Management of children with acute asthma in the emergency department.
      Children with acute asthma most commonly have hypocarbia or normocarbia on their blood gases.
      • Werner H.A.
      Status asthmaticus in children.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      • Qureshi F.
      Management of children with acute asthma in the emergency department.
      A rising Pco2 may indicate impending respiratory failure, although modest degrees of hypercarbia can be well tolerated in nonintubated children with status asthmaticus.
      • U.S. Department of Health and Human Services
      National Heart, Lung and Blood Institute. National asthma education and prevention program expert panel report 3: guidelines for the diagnosis and management of asthma.
      Clinical decision-making in this population should be dependent on a combination of factors, and not primarily dictated by blood gas findings. Additionally, a provider should not be reassured by the absence of respiratory acidosis. Even in the absence of respiratory acidosis, a somnolent child struggling to breathe should be endotracheally intubated. Similarly, in an awake and alert child with tachypnea, increased work of breathing and respiratory acidosis does not typically require intubation. Importantly, if blood gases or other laboratory studies are ordered, they must not delay initiation of asthma treatment.
      • U.S. Department of Health and Human Services
      National Heart, Lung and Blood Institute. National asthma education and prevention program expert panel report 3: guidelines for the diagnosis and management of asthma.

      Chest Radiography

      Routine chest radiography is not indicated for all children with status asthmaticus. Generally, these radiographs do not add to the clinical care of this population and only rarely reveal findings that are useful in the treatment of children with status asthmaticus.
      • Brooks L.J.
      • Cloutier M.M.
      • Afshani D.
      Significance of reoentgenographic abnormalities in children hospitalized for asthma.
      • Hederos C.A.
      • Janson S.
      • Andersson H.
      • et al.
      Chest X-ray investigation in newly discovered asthma.
      However, there are certain clinical situations where radiography might be helpful. Specifically, a chest radiograph should be obtained when the cause of wheezing is unclear; when there are localizing findings on examination; or when there is suspected pneumonia or barotrauma (pneumothorax or pneumomediastinum).
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Brooks L.J.
      • Cloutier M.M.
      • Afshani D.
      Significance of reoentgenographic abnormalities in children hospitalized for asthma.
      • Hederos C.A.
      • Janson S.
      • Andersson H.
      • et al.
      Chest X-ray investigation in newly discovered asthma.

      First-line treatments

      General

      First-line or conventional treatment of status asthmaticus consists of supplemental oxygen for hypoxemia, aerosolized albuterol for bronchodilation, and corticosteroids for airway inflammation and edema (Table 2).
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      Typically, these are given in the emergency department setting. Therapies should be titrated according to clinical asthma score and using an asthma pathway or guidelines. The use of asthma guidelines and clinical asthma scoring systems to titrate these guidelines has been linked to improved outcomes including decreased length of stay and decreased hospital costs.
      • Norton S.P.
      • Pusic M.V.
      • Taha F.
      • et al.
      Effect of a clinical pathway on the hospitalisation rates of children with asthma: a prospective study.
      • Carroll C.L.
      • Schramm C.M.
      Protocol-based titration of intravenous terbutaline decreases length of stay in pediatric status asthmaticus.
      • Kelly C.S.
      • Andersen C.L.
      • Pestian J.P.
      • et al.
      Improved outcomes for hospitalized asthmatic children using a clinical pathway.
      • McDowell K.M.
      • Chatburn R.L.
      • Myers T.R.
      • et al.
      A cost-saving algorithm for children hospitalized for status asthmaticus.
      However, no specific guideline has been shown to be superior to any other. The mechanism behind these improved outcomes may be a more aggressive titration of therapy and a more efficient weaning process,
      • Carroll C.L.
      • Schramm C.M.
      Protocol-based titration of intravenous terbutaline decreases length of stay in pediatric status asthmaticus.
      rather than any specific drug effect per se.
      Table 2Ranking of status asthmaticus treatment
      Dosage/Type/Goal
      Conventional or first-line therapies
       Continuous albuterol nebulization10–25 mg/h
       Corticosteroids (prednisone or methylprednisolone)2–4 mg/kg/d divided q 6–12 h
       Supplemental oxygenTo maintain saturations >92%
      Early supplemental therapies
       Intravenous magnesium25–75 mg/kg (up to total of 2 g total) over 20 min
       Ipratropium nebulization0.25–0.5 mg every 20 min for 3 doses
      Second-line therapies
       Noninvasive positive pressureTitrated to comfort and tidal volume
       Intravenous terbutaline0.5–4 μg/kg/min
      Rescue therapies
       IntubationPressure-limited ventilation or pressure-regulated volume control modes
       Intravenous ketamineLoad of 2 mg/kg followed by infusion of 0.5–2 mg/kg/h
       Intravenous aminophyllineLoad of 6 mg/kg followed by infusion of 1 mg/kg/h with goal serum levels 10–20 μg/mL
       Inhaled anestheticsHalothane or isoflurane
       Helium-oxygen60%–80% helium/20%–40% oxygen
       Extracorporeal supportExtracorporeal life support or Extracorporeal carbon dioxide clearance

      Oxygen

      Children with status asthmaticus have a greater frequency of hypoxemia than adults. These children are at a higher risk of ventilation-perfusion mismatch because of age-related differences in pulmonary mechanics including lower functional residual capacity/total lung capacity ratio, increased chest wall compliance, and higher peripheral airways resistance.
      • Werner H.A.
      Status asthmaticus in children.
      This mismatch may be exacerbated initially by bronchodilators and can cause desaturation during the early stages of therapy. Pulse oximetry should be obtained and humidified oxygen should be delivered to relieve dyspnea.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      Decreased oxygen saturation on room air is associated with the need for hospitalization in this population.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      In children with chronic lung disease, supplemental oxygen may be associated with hypoventilation because of suppression of hypoxemic respiratory drive; however, this consideration is not a factor in an otherwise healthy child with asthma.
      • Werner H.A.
      Status asthmaticus in children.

      Albuterol

      β-Adrenergic agonists, such as albuterol, are the most effective and commonly used bronchodilators in the United States and form the foundation of treatment of acute asthma. These medications bind to β2-adrenergic receptors in the airway smooth muscle to produce bronchodilation by smooth muscle relaxation. Albuterol is initially delivered by intermittent nebulization, and changed to continuous nebulization in children with inadequate response. Continuously administered albuterol has been shown to improve outcomes and to be more cost effective than continued intermittent therapy.
      • Papo M.C.
      • Frank J.
      • Thompson A.E.
      A prospective, randomized study of continuous versus intermittent nebulized albuterol for severe status asthmaticus in children.
      High doses (as much as 20–30 mg/hour) are generally well tolerated and have been used for days in this population.
      • Werner H.A.
      Status asthmaticus in children.
      • Bhogal S.K.
      • McGillivray D.
      • Bourbeau J.
      • et al.
      Early administration of systemic corticosteroids reduces hospital admission rates for children with moderate and severe asthma exacerbation.
      • Carroll C.L.
      • Schramm C.M.
      • Zucker A.R.
      Slow responders to IV β2-adrenergic receptor agonist therapy: defining a novel phenotype in pediatric asthma.
      Differences in tidal volume, airflow turbulence, and nebulizer gas flow all significantly impact the amount of drug delivered; therefore, weight adjusting of albuterol aerosol dosages is not necessary.
      • Werner H.A.
      Status asthmaticus in children.
      These agents can also cause tachycardia and hypertension through binding of other systemic β-adrenergic receptors, although when delivered by aerosol, these systemic effects are reduced. Orally administered β-adrenergic agents are not indicated for status asthmaticus.
      Titrating albuterol aerosol therapy using a clinical asthma score may be helpful in reducing length of stay and duration of therapy in children with status asthmaticus. As a child improves, this continuously administered aerosol can be weaned in dosage, then changed to intermittent dosing, which can also be weaned in frequency as clinical status improves. No specific guideline has been shown to be superior to any other.
      Levalbuterol, which contains only the single active (R)-enantiomer of typically delivered racemic albuterol, is a potentially attractive selective bronchodilator in the treatment of status asthmaticus, because previous authors have suggested that repeated doses of the racemic albuterol mixture may be related to more severe bronchospasm.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      However, a recent negative randomized controlled trial of racemic albuterol versus levalbuterol in children with status asthmaticus adds to the literature that levalbuterol does not convey additional benefit and does not lead to reduced side effects.
      • Andrews T.
      • McGintee E.
      • Mittal M.K.
      • et al.
      High-dose continuous nebulized levalbuterol for pediatric status asthmaticus: a randomized trial.
      Considering the increased cost and the lack of improvement in outcomes, the routine use of this medication cannot be recommended in this population.

      Corticosteroids

      Corticosteroids are used to treat airway inflammation and edema in children with acute asthma.
      • Bhogal S.K.
      • McGillivray D.
      • Bourbeau J.
      • et al.
      Early administration of systemic corticosteroids reduces hospital admission rates for children with moderate and severe asthma exacerbation.
      • Smith M.
      • Iqbal S.
      • Rowe B.H.
      • et al.
      Corticosteroids for hospitalized children with acute asthma.
      • Warner J.O.
      • Naspitz C.K.
      Third international pediatric consensus statement on the management of childhood asthma: international pediatric asthma consensus group.
      These medications have been shown to improve outcomes by reducing inflammatory cellular mediators and proinflammatory cytokines and by decreasing mucous production. Short-term usage is usually not associated with significant side effects. However, hyperglycemia, hypertension, and behavioral changes have been reported, and neuromyopathies can occur in children treated with corticosteroids and neuromuscular blocking agents.
      • Newth C.J.
      • Meert K.L.
      • Clark A.E.
      • et al.
      Fatal and near-fatal asthma in children: the critical care perspective.
      There is little published evidence regarding the duration and dosage of corticosteroids for the treatment of status asthmaticus in children. Duration of therapy is typically driven by the severity of the exacerbation and the rapidity of response to therapy.
      • Werner H.A.
      Status asthmaticus in children.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      • U.S. Department of Health and Human Services
      National Heart, Lung and Blood Institute. National asthma education and prevention program expert panel report 3: guidelines for the diagnosis and management of asthma.
      If corticosteroid treatment is longer than 7 days, a slow dosage taper is recommended.
      • Warner J.O.
      • Naspitz C.K.
      Third international pediatric consensus statement on the management of childhood asthma: international pediatric asthma consensus group.
      Currently, National Heart, Lung and Blood Institute guidelines recommend administration of corticosteroids systemically rather than by an inhaled route.
      • U.S. Department of Health and Human Services
      National Heart, Lung and Blood Institute. National asthma education and prevention program expert panel report 3: guidelines for the diagnosis and management of asthma.
      Orally administered medications may be used if a child can tolerate oral medication, but if not, intravenous (IV) medication is preferred. Children receiving high-dose β-adrenergic agonist therapy may develop impaired gastric absorption and vomiting, so in these children IV administration may be preferable. Early administration of systemic corticosteroids is key and has been shown to improve outcomes. In one study, children treated within 75 minutes of triage had significantly reduced hospitalization rates and lengths of treatment.
      • Bhogal S.K.
      • McGillivray D.
      • Bourbeau J.
      • et al.
      Early administration of systemic corticosteroids reduces hospital admission rates for children with moderate and severe asthma exacerbation.
      The National Heart, Lung and Blood Institute guidelines suggest that 2 mg/kg/d of systemic prednisone or methylprednisolone be used for acute asthma, but offer no recommendations for children in impending respiratory failure.
      • U.S. Department of Health and Human Services
      National Heart, Lung and Blood Institute. National asthma education and prevention program expert panel report 3: guidelines for the diagnosis and management of asthma.
      In this population of children with more severe disease, some authors have suggested using dosages as high as 4 mg/kg/d. There is no evidence that this increased dosage is superior; however, the practice of using this higher dosage seems to be widespread. In a recent national survey of pediatric intensivists, almost a third reported using a starting dosage of 4 mg/kg/d and most cited clinical experience as their rationale for this dosage.
      • Giuliano J.S.
      • Faustino E.V.
      • Li S.
      • et al.
      Corticosteroid therapy in critically ill pediatric asthmatic patients.
      Research is needed to determine the appropriate dosage and duration of therapy in this population.

      Hydration Status

      The need for IV fluid boluses should not be overlooked in children with status asthmaticus.
      • Werner H.A.
      Status asthmaticus in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      Several pathophysiologic mechanisms contribute to the need for robust intravascular volume in these children. Specifically, an increased intrathoracic pressure from air-trapping can lead to decreased venous return, which coupled with bronchodilator-induced tachycardia can reduce filling time and also potentially decrease cardiac output. Additionally, children with acute disease frequently present somewhat dehydrated because of decreased oral intake and elevated respiratory rate. This dehydration can also be exacerbated by the nausea and vomiting associated with β-adrenergic agonist therapy. All of these factors contribute to the need to restore euvolemia in this population. However, previous authors have identified a syndrome of inappropriate antidiuretic hormone in children with status asthmaticus, so fluid balance should be monitored carefully.
      • Baker J.W.
      • Yerger S.
      • Segar W.E.
      Elevated plasma antidiuretic hormone levels in status asthmaticus.

      Second-line treatments

      Any child who does not sufficiently respond to first-line treatment of status asthmaticus should be strongly considered for admission to an ICU setting. These children require close monitoring of their clinical status including continuous cardiorespiratory monitoring. Second-line therapies should be considered, but these should be additive and not replace the first-line therapies. There are several second-line treatments available; however, few comparative studies have been performed, and none have been shown to be superior to any of the others.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.
      In the absence of good evidence-based treatments, the use of these therapies is highly variable and dependent on local practice and provider preference.
      • Bratton S.L.
      • Odetola F.O.
      • McCollegan J.
      • et al.
      Regional variation in ICU care for pediatric patients with asthma.
      • Roberts J.S.
      • Bratton S.L.
      • Brogan T.V.
      Acute severe asthma: differences in therapies and outcomes among pediatric intensive care units.
      • Bratton S.L.
      • Newth C.J.
      • Zuppa A.F.
      • et al.
      Critical care for pediatric asthma: wide care variability and challenges for study.
      Nonetheless, it is possible to determine a broad-based ranking of therapies in this population when examining the literature (see Table 2). For example, magnesium and ipratropium therapy have been shown to be effective early in the course of a child’s disease and not in the later stages of illness, whereas such therapies as terbutaline and noninvasive positive pressure have been shown to be effective during the whole course of a child’s illness. Other therapies with a weaker evidence basis, however, such as ketamine, inhaled anesthesia, and helium-oxygen mixtures, should be used solely as rescue therapies.

      Magnesium

      Magnesium causes bronchodilation by inhibiting smooth muscle contraction, and by decreasing cholinergic stimulation and histamine release.
      • Markovitz B.
      Does magnesium sulphate have a role in the management of paediatric status asthmaticus?.
      • Cheuk D.K.
      • Chau T.C.
      • Lee S.L.
      A meta-analysis on intravenous magnesium sulphate for treating acute asthma.
      Studies conflict on the use of magnesium therapy, but IV magnesium has been shown to reduce hospitalization when added to conventional therapy in children with status asthmaticus.
      • Markovitz B.
      Does magnesium sulphate have a role in the management of paediatric status asthmaticus?.
      • Cheuk D.K.
      • Chau T.C.
      • Lee S.L.
      A meta-analysis on intravenous magnesium sulphate for treating acute asthma.
      Toxicity, which includes weakness, respiratory depression, and cardiac arrhythmias, is rare in children with asthma.
      • Werner H.A.
      Status asthmaticus in children.

      Anticholinergics

      Anticholinergic medications, such as ipratropium, cause bronchodilation through bronchial smooth muscle relaxation mediated by the parasympathetic nervous system. Additionally, the cardiovascular side effects of ipratropium, which is not absorbed into the bloodstream when delivered by inhalation, are minimal. In children with status asthmaticus, the addition of ipratropium nebulizations to albuterol therapy has been shown to significantly reduce hospitalizations.
      • Crave D.
      • Kercsmar C.M.
      • Myers T.R.
      • et al.
      Ipratropium bromide plus nebulized albuterol for the treatment of hospitalized children with acute asthma.
      • Schuh S.
      • Johnson D.W.
      • Callahan S.
      • et al.
      Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.
      • Qureshi F.
      • Pestian J.
      • Davis P.
      • et al.
      Effect of nebulized ipratropium on the hospitalization rates of children with asthma.
      This therapy was most effective in moderate to severely ill children.
      • Schuh S.
      • Johnson D.W.
      • Callahan S.
      • et al.
      Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.
      • Qureshi F.
      • Pestian J.
      • Davis P.
      • et al.
      Effect of nebulized ipratropium on the hospitalization rates of children with asthma.
      However, the continuation of anticholinergic medications after this initial period is not routinely recommended.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.

      Terbutaline

      The use of IV β-adrenergic agonist therapy, such as terbutaline, is frequently considered as a second-line treatment of acute asthma.
      • Werner H.A.
      Status asthmaticus in children.
      • Norton S.P.
      • Pusic M.V.
      • Taha F.
      • et al.
      Effect of a clinical pathway on the hospitalisation rates of children with asthma: a prospective study.
      • Bogie A.L.
      • Towne D.
      • Luckett P.M.
      • et al.
      Comparison of intravenous terbutaline versus normal saline in pediatric patients on continuous high-dose nebulized albuterol for status asthmaticus.
      • Stephanopoulos D.E.
      • Monge R.
      • Schell K.H.
      • et al.
      Continuous intravenous terbutaline for pediatric status asthmaticus.
      Some children, including those with severe obstruction and small effective tidal volumes, may have ineffective delivery of nebulized medications, such as albuterol. In these children, IV β-adrenergic receptor agonists may be used despite the risk of systemic side effects. IV terbutaline has been shown to acutely improve pulmonary function and gas exchange, and to shorten hospital and ICU length of stay when delivered according to a nurse-driven protocol in children with status asthmaticus.
      • Carroll C.L.
      • Schramm C.M.
      Protocol-based titration of intravenous terbutaline decreases length of stay in pediatric status asthmaticus.
      • Stephanopoulos D.E.
      • Monge R.
      • Schell K.H.
      • et al.
      Continuous intravenous terbutaline for pediatric status asthmaticus.
      The one randomized placebo-controlled trial of IV terbutaline versus placebo showed no statistically significant improvement when terbutaline was added to standard therapy. However, there was a trend toward decreased ICU length of stay and improved clinical asthma score in the first 24 hours.
      • Bogie A.L.
      • Towne D.
      • Luckett P.M.
      • et al.
      Comparison of intravenous terbutaline versus normal saline in pediatric patients on continuous high-dose nebulized albuterol for status asthmaticus.
      There is some evidence that certain children are better responders to β-adrenergic agonist therapy than others.
      • Carroll C.L.
      • Schramm C.M.
      • Zucker A.R.
      Slow responders to IV β2-adrenergic receptor agonist therapy: defining a novel phenotype in pediatric asthma.
      Previous investigators have linked obesity and ethnicity to a slower response to therapy during severe asthma exacerbations. Some of this decreased response may be caused by genetics; however, these studies are preliminary and require replication.
      • Carroll C.L.
      • Sala K.
      • Zucker A.R.
      • et al.
      Beta-adrenergic receptor polymorphisms and response to therapy in pediatric status asthmaticus: a prospective cohort study.
      • Carroll C.L.
      • Stoltz P.
      • Schramm C.M.
      • et al.
      β2-adrenergic receptor polymorphisms affect response to treatment in near fatal asthma exacerbations in children.
      When receiving IV β-adrenergic agonist therapy, a child requires close monitoring for systemic side effects. Although tachyarrhythmias are rare, children receiving IV terbutaline should have continuous cardiac monitoring. Several authors have found a low and transient incidence of cardiotoxicity, as measured by elevated serum troponins, in children treated with IV terbutaline.
      • Chiang V.W.
      • Burns J.P.
      • Rifai N.
      • et al.
      Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: a prospective assessment.
      • Carroll C.L.
      • Coro M.
      • Cowl A.
      • et al.
      Occult cardiotoxicity in children receiving continuous beta-agonist therapy.
      However, tachyarrythmias, such as supraventricular tachycardia, have also been reported. Other common side effects include hypertension, electrolyte disturbances, nausea and vomiting, and agitation.

      Noninvasive Positive Pressure Ventilation

      Noninvasive positive pressure ventilation (NPPV) is used increasingly in the care of children with status asthmaticus. Early intervention has been shown to improve outcomes and potentially avoid endotracheal intubation in this population.
      • Carroll C.L.
      • Schramm C.M.
      Non-invasive ventilation for the treatment of status asthmaticus in children.
      • Meduri G.U.
      • Cook T.R.
      • Turner R.E.
      • et al.
      Noninvasive positive pressure ventilation in status asthmaticus.
      • Hill N.S.
      Noninvasive positive pressure ventilation for non chronic obstructive pulmonary disease causes of acute respiratory failure.
      • Pollack C.V.
      • Fleisch K.B.
      • Dowsey K.
      Treatment of acute bronchospasm with ß-adrenergic agonist aerosols delivered by a nasal bilevel positive airway circuit.
      • Soroksky A.
      • Stav D.
      • Shpirer I.
      A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack.
      • Basnet S.
      • Mander G.
      • Andoh J.
      • et al.
      Safety, efficacy and tolerability of early initiation of noninvasive positive pressure ventilation in pediatric patients admitted with status asthmaticus: a pilot study.
      NPPV improves the condition of children with asthma by preventing airway collapse during exhalation and thereby unloading fatigued respiratory muscles. During an acute asthma exacerbation, inflammation of small airways leads to increased airways resistance and expiratory time constants.
      • Meduri G.U.
      • Cook T.R.
      • Turner R.E.
      • et al.
      Noninvasive positive pressure ventilation in status asthmaticus.
      This results in premature airway closure during exhalation and dynamic hyperinflation.
      • Meduri G.U.
      • Cook T.R.
      • Turner R.E.
      • et al.
      Noninvasive positive pressure ventilation in status asthmaticus.
      Positive pressure can maintain small airway patency and reduce the change in alveolar pressure needed to initiate inspiration by providing a continuous expiratory pressure.
      • Meduri G.U.
      • Cook T.R.
      • Turner R.E.
      • et al.
      Noninvasive positive pressure ventilation in status asthmaticus.
      Adding inspiratory pressure further improves dyspnea and gas exchange by augmenting spontaneous tidal volumes. NPPV has the additional benefit of preserving the child’s natural airway and thereby potentially avoiding some of the complications of the more invasive endotracheal intubation.
      • Meduri G.U.
      • Cook T.R.
      • Turner R.E.
      • et al.
      Noninvasive positive pressure ventilation in status asthmaticus.
      • Hill N.S.
      Noninvasive positive pressure ventilation for non chronic obstructive pulmonary disease causes of acute respiratory failure.
      • Pollack C.V.
      • Fleisch K.B.
      • Dowsey K.
      Treatment of acute bronchospasm with ß-adrenergic agonist aerosols delivered by a nasal bilevel positive airway circuit.
      However, the use of NPPV requires close monitoring by trained providers. One of the primary predictors of success with the use of NPPV is the involvement of providers who are trained and comfortable with the care of children receiving NPPV.
      • Carroll C.L.
      • Schramm C.M.
      Non-invasive ventilation for the treatment of status asthmaticus in children.
      The initiation of this therapy must be performed gradually, with attention paid to avoiding any increase in anxiety in the child from either the mask itself or the airflow. Finding an appropriate sized mask can be challenging because of the great variation in size and shape of children’s faces. Sedation should be used sparingly and cautiously, because sedation can potentially reduce a child’s already taxed respiratory drive. Providers should also observe children closely for potential complications of therapy including skin breakdown, gastric distention, and the development of barotrauma.
      • Carroll C.L.
      • Schramm C.M.
      Non-invasive ventilation for the treatment of status asthmaticus in children.
      • Meduri G.U.
      • Cook T.R.
      • Turner R.E.
      • et al.
      Noninvasive positive pressure ventilation in status asthmaticus.
      • Hill N.S.
      Noninvasive positive pressure ventilation for non chronic obstructive pulmonary disease causes of acute respiratory failure.
      • Pollack C.V.
      • Fleisch K.B.
      • Dowsey K.
      Treatment of acute bronchospasm with ß-adrenergic agonist aerosols delivered by a nasal bilevel positive airway circuit.
      • Soroksky A.
      • Stav D.
      • Shpirer I.
      A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack.
      • Basnet S.
      • Mander G.
      • Andoh J.
      • et al.
      Safety, efficacy and tolerability of early initiation of noninvasive positive pressure ventilation in pediatric patients admitted with status asthmaticus: a pilot study.

      Rescue therapies

      Intubation

      Intubation should be a last resort therapy for children with status asthmaticus. The presence of a tracheal foreign body can aggravate bronchospasm, children can require significant amounts of sedation to facilitate this therapy, and gas exchange immediately after intubation is frequently worse than before intubation. Clearly, however, there are children who require intubation for impending respiratory failure, but weighing the risks and benefits can be challenging a priori. After the decision to intubate has been made, this procedure should be performed by an experienced clinician because these children are frequently unstable.
      Several authors have found that children intubated outside the ICU setting are intubated for shorter durations than children intubated in the ICU setting.
      • Newth C.J.
      • Meert K.L.
      • Clark A.E.
      • et al.
      Fatal and near-fatal asthma in children: the critical care perspective.
      • Carroll C.L.
      • Smith S.R.
      • Collins M.
      • et al.
      Endotracheal intubation and pediatric status asthmaticus: site of original care affects treatment.
      Some have suggested that these children may represent an acute asphyxia asthma phenotype of children that progress to respiratory failure rapidly and then resolve quickly.
      • Maffei F.A.
      • van der Jagt E.W.
      • Powers K.S.
      • et al.
      Duration of mechanical ventilation in life-threatening pediatric asthma: description of an acute asphyxial subgroup.
      However, there is mounting evidence that nonclinical factors, such as provider practice and local geography, may play a larger role than patient characteristics in the decision to intubate a child with status asthmaticus.
      • Newth C.J.
      • Meert K.L.
      • Clark A.E.
      • et al.
      Fatal and near-fatal asthma in children: the critical care perspective.
      Once intubated, the management of children with status asthmaticus is challenging and requires close monitoring of gas exchange and hemodynamic parameters. Permissive hypercapnea and lung protective strategies should be used while allowing for sufficient exhalation to minimize the amount of dynamic hyperinflation. A ventilator mode with a decelerating flow pattern, such as pressure-limited ventilation or pressure-regulated volume control, results in a lower peak airway pressure and a higher mean airway pressure than a volume control mode, and theoretically provides better ventilation in children with status asthmaticus.
      • Sarnaik A.P.
      • Daphtary K.M.
      • Meert K.L.
      • et al.
      Pressure-controlled ventilation in children with severe status asthmaticus.
      • Sabato K.
      • Hanson J.H.
      Mechanical ventilation for children with status asthmaticus.
      Sufficient positive end-expiratory pressure should be provided to surpass the lower inflection point of alveolar collapse duration exhalation.
      • Werner H.A.
      Status asthmaticus in children.
      Sedation and sometimes muscle relaxation are needed to facilitate mechanical ventilation in children, although the duration and depth of muscle relaxation should be limited when possible to reduce the risk of myopathies.

      Ketamine

      Ketamine is a dissociative anesthetic with sympathomimetic and bronchodilator properties.
      • Petrillo T.M.
      • Fortenberry J.D.
      • Linzer J.F.
      • et al.
      Emergency department use of ketamine in pediatric status asthmaticus.
      Unfortunately, the usefulness of ketamine is somewhat mitigated by its potential to increase bronchial secretions and its dissociate properties including a frightening emergence phenomenon in older children. However, ketamine is a potentially attractive agent in children intubated and mechanically ventilated for status asthmaticus.
      • Werner H.A.
      Status asthmaticus in children.
      • Chipps B.E.
      • Murphy K.R.
      Assessment and treatment of acute asthma in children.
      • Mannix R.
      • Bachur R.
      Status asthmaticus in children.
      • Kercsmar C.M.
      Acute inpatient care of status asthmaticus.
      • Smith S.R.
      • Strunk R.C.
      Acute asthma in the pediatric emergency department.

      Methylxanthines

      Once the primary treatment of status asthmaticus, methylxanthines, such as theophylline and aminophylline, have recently fallen out of favor. This is caused in part by decreased bronchodilator effectiveness compared with β-adrenergic agonists and the small therapeutic window and their unfavorable side effect profile. However, they still may have a role in select patients with refractory status asthmaticus.
      • Ream R.S.
      • Loftis L.L.
      • Albers G.M.
      • et al.
      Efficacy of IV theophylline in children with severe status asthmaticus.
      • Self T.H.
      • Redmond A.M.
      • Nguyen W.T.
      Reassessment of theophylline use for severe asthma exacerbation.

      Inhaled Anesthetics

      Inhalational anesthetics, such as halothane and isoflurane, can cause bronchodilation through smooth muscle relaxation and have been used anecdotally to treat status asthmaticus in children refractory to conventional therapies.
      • Shankar V.
      • Churchwell K.B.
      • Deshpande J.K.
      Isoflurane therapy for severe refractory status asthmaticus in children.
      • Restrepo R.D.
      • Pettignano R.
      • DeMeuse P.
      Halothane, an effective infrequently used drug, in the treatment of pediatric status asthmaticus: a case report.
      • Tobias J.D.
      Therapeutic applications and uses of inhalational anesthesia in the pediatric intensive care unit.
      Unfortunately, the use of these medications requires intubation and mechanical ventilation and a scavenging system typically found only in the operating room of many institutions, thereby limiting the usefulness of this therapy. Additionally, there is also sometimes a reduced ability to provide effective mechanical ventilation in these children, because the ventilatory equipment needed to provide the medication may not be as sophisticated as the ventilators in the ICU.

      Helium-oxygen

      The use of a helium-oxygen gas mixture is another potentially attractive therapy for the treatment of status asthmaticus in children. Because of its lower density and higher viscosity, a mixture of helium and oxygen flows through small and obstructed airways with less turbulence and resistance than the nitrogen and oxygen mixture of gases found in atmospheric air. Theoretically, the use of helium-oxygen–driven aerosolized therapy might also be expected to increase drug delivery by improving gas exchange to the distal airways. Unfortunately, the literature regarding the effectiveness of this therapy in children with acute asthma has been mixed.
      • Rivera M.L.
      • Kim T.Y.
      • Stewart G.M.
      • et al.
      Albuterol nebulized in heliox in the initial ED treatment of pediatric asthma: a blinded, randomized controlled trial.
      • Kudukis T.M.
      • Manthous C.A.
      • Schmidt G.A.
      • et al.
      Inhaled helium-oxygen revisited: effect of inhaled helium-oxygen during the treatment of status asthmaticus in children.
      • Kim I.K.
      • Phrampus E.
      • Venkataraman S.
      • et al.
      Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial.
      • Bigham M.T.
      • Jacobs B.R.
      • Monaco M.A.
      • et al.
      Helium/oxygen-driven albuterol nebulization in the management of children with status asthmaticus: a randomized, placebo-controlled trial.
      Randomized controlled studies of helium-oxygen therapy in this population have been contradictory and have not demonstrated efficacy in terms of shortening durations of exacerbation or improving outcomes.
      • Rivera M.L.
      • Kim T.Y.
      • Stewart G.M.
      • et al.
      Albuterol nebulized in heliox in the initial ED treatment of pediatric asthma: a blinded, randomized controlled trial.
      • Kudukis T.M.
      • Manthous C.A.
      • Schmidt G.A.
      • et al.
      Inhaled helium-oxygen revisited: effect of inhaled helium-oxygen during the treatment of status asthmaticus in children.
      • Kim I.K.
      • Phrampus E.
      • Venkataraman S.
      • et al.
      Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial.
      • Bigham M.T.
      • Jacobs B.R.
      • Monaco M.A.
      • et al.
      Helium/oxygen-driven albuterol nebulization in the management of children with status asthmaticus: a randomized, placebo-controlled trial.
      Furthermore, to significantly reduce airways resistance, 60% to 80% helium is needed in the gas mixture. This limits the use of helium-oxygen mixtures in hypoxemic children with status asthmaticus. In the literature, most of the benefit of a helium-oxygen mixture has been found early in the acute phase of illness,
      • Kudukis T.M.
      • Manthous C.A.
      • Schmidt G.A.
      • et al.
      Inhaled helium-oxygen revisited: effect of inhaled helium-oxygen during the treatment of status asthmaticus in children.
      • Kim I.K.
      • Phrampus E.
      • Venkataraman S.
      • et al.
      Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial.
      but it may also be useful as a rescue therapy in certain children with lower oxygen requirements and refractory status asthmaticus.

      Extracorporeal Support

      Extracorporeal life support and extracorporeal carbon dioxide clearance have been advocated in extreme cases of status asthmaticus.
      • Zabrocki L.A.
      • Brogan T.V.
      • Statler K.D.
      • et al.
      Extracorporeal membrane oxygenation for pediatric respiratory failure: survival and predictors of mortality.
      • Hebbar K.B.
      • Petrillo-Albarano T.
      • Coto-Puckett W.
      • et al.
      Experience with the use of extracorporeal life support for severe refractory status asthmaticus in children.
      • Elliot S.C.
      • Paramasivam K.
      • Oram J.
      • et al.
      Pumpless extracorporeal carbon dioxide removal for life-threatening asthma.
      A recent review of the extracorporeal life support registry found that 71 children with status asthmaticus were treated with extracorporeal life support and survival in this population was 83%.
      • Zabrocki L.A.
      • Brogan T.V.
      • Statler K.D.
      • et al.
      Extracorporeal membrane oxygenation for pediatric respiratory failure: survival and predictors of mortality.
      Clearly, however, this therapy is associated with a significant risk of adverse events, and should only be undertaken as a rescue technique. The use of extracorporeal carbon dioxide clearance is experimental at this time.
      • Elliot S.C.
      • Paramasivam K.
      • Oram J.
      • et al.
      Pumpless extracorporeal carbon dioxide removal for life-threatening asthma.

      Airway clearance techniques

      Theoretically, airway clearance techniques can be helpful in improving the speed of resolution of status asthmaticus.
      • Echeverria Zudaire L.
      • Tomico Del Rio M.
      • Bracamonte Bermejo T.
      • et al.
      Status asthmaticus: is respiratory physiotherapy necessary?.
      • De Boeck K.
      • Vermeulen F.
      • Vreys M.
      • et al.
      Airway clearance techniques to treat acute respiratory disorders in previously healthy children: where is the evidence?.
      • Malmstrom K.
      • Kaila M.
      • Korhonen K.
      • et al.
      Mechanical ventilation in children with severe asthma.
      Mucous production is increased during acute asthma, and several mechanisms, such as respiratory muscle fatigue and bedrest, may contribute to ineffective airway clearance by children during acute exacerbations. Aggressive airway clearance techniques, such as chest percussion, vibration, and postural drainage, have been found to improve airway clearance in children with other types of chronic lung disease.
      • Echeverria Zudaire L.
      • Tomico Del Rio M.
      • Bracamonte Bermejo T.
      • et al.
      Status asthmaticus: is respiratory physiotherapy necessary?.
      In children with asthma, reducing mucous plugging could, in theory, improve gas exchange through improvement in ventilation-perfusion mismatch, and potentially also shorten the duration of illness.
      However, despite the use of these therapies clinically, there is little evidence in the literature supporting the effectiveness of these techniques.
      • De Boeck K.
      • Vermeulen F.
      • Vreys M.
      • et al.
      Airway clearance techniques to treat acute respiratory disorders in previously healthy children: where is the evidence?.
      Additionally, these techniques are often bundled into the term “chest physiotherapy,” which obscures the potentially significant variation in the types and performance of these techniques by a variety of practitioners.
      • De Boeck K.
      • Vermeulen F.
      • Vreys M.
      • et al.
      Airway clearance techniques to treat acute respiratory disorders in previously healthy children: where is the evidence?.
      A more specific description of the type and method of each technique and how they are performed in children with asthma might aid in investigating whether these techniques improve outcomes.
      Frequently in pediatrics, augmenting mucous clearance can be accomplished by getting a child upright, out of bed, and ambulating. Often, a child needs little encouragement to perform these simple techniques. Anecdotally, these techniques can sometimes dramatically improve mucous plugging and speed recovery, but importantly should only be performed as bronchospasm starts to improve. However, until there is more literature exploring the use of more aggressive airway clearance techniques in children with status asthmaticus, the routine use of these more vigorous techniques is not recommended, and providers need to balance the risks and benefits in specific children.

      Summary

      Despite a plateau in the incidence of asthma and a decreasing incidence of hospital admissions for asthma, status asthmaticus is a frequent cause of admission to the ICU. Prompt assessment and aggressive treatment are crucial steps toward improving outcomes in this population. Fortunately, most children with status asthmaticus improve rapidly, but there is a cohort of difficult-to-treat children who are challenging to study and who have significant variations in terms of response to treatment. As a result, therapies are used in a trial-and-error format, without a clear evidence-based rationale to therapy. A broad-based ranking of therapies is possible to develop when examining the literature, but more research is needed into the small but significant population of children with status asthmaticus.

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