Which drug is most appropriate for a patient experiencing an acute asthma attack?

Approach Considerations

After confirming the diagnosis and assessing the severity of an asthma attack, direct treatment toward controlling bronchoconstriction and inflammation. Beta-agonists, corticosteroids, and theophylline are mainstays in the treatment of status asthmaticus. Sevoflurane, a potent inhalation agent, was successful in a single case report in which it was used when conventional treatment failed in a woman aged 26 years. [15]

Fluid replacement

Hydration, with intravenous normal saline at a reasonable rate, is essential. Special attention to the patient's electrolyte status is important.

Hypokalemia may result from either corticosteroid use or beta-agonist use. Correcting hypokalemia may help to wean an intubated patient with asthma from mechanical ventilation. Hypophosphatemia may result from poor oral intake and is also an important consideration when weaning such patients.

Antibiotics

The routine administration of antibiotics is discouraged. Patients are administered antibiotics only when they show evidence of infection (eg, pneumonia, sinusitis). In some situations, sinus imaging using computed tomography (CT) scanning or plain radiography [16, 17] may be essential to rule out chronic sinusitis. [18]

Oxygen monitoring and therapy

Monitoring the patient's oxygen saturation is essential during the initial treatment of status asthmaticus. Arterial blood gas (ABG) values are usually used to assess hypercapnia during the patient's initial assessment. Oxygen saturation is then monitored via pulse oximetry throughout the treatment protocol. Oxygen saturation may increase following the use of bronchodilators secondary to an increase in V/Q mismatch.

Oxygen therapy is essential, with hypoxia being the leading cause of death in children with asthma. Oxygen therapy can be administered via a nasal canula or mask, although patients with dyspnea often do not like masks. With the advent of pulse oximetry, oxygen therapy can be easily titrated to maintain the patient's oxygen saturation above 92% (>95% in pregnant patients or those with cardiac disease).

In the event of significant hypoxemia, non-rebreathing masks may be used to deliver as much as 98% oxygen. Tracheal intubation and mechanical ventilation are indicated for respiratory failure.

Chest tube placement

Chest tube placement may be necessary in the management of pneumothorax.

Nitrate oxide

Nitrate oxide has been employed in a child with refractory asthma. The future role of this therapy remains to be determined.

Leukotriene modifiers

Leukotriene modifiers are useful for treating chronic asthma but not acute asthma. This treatment may be beneficial if used via a nebulizer, but it remains experimental. Most studies have examined intravenous use. [19, 20]  Montelukast can be used as an add-on treatment for asthma in general. It is mostly used for improving the quality of life as an add-on therapy to inhaled corticosteroids and not necessarily just for status asthmaticus. There has been one study that showed minimal to no effect of using montelukast in the emergency department setting for patients with status asthmaticus. [21, 22] In general, it did not show any significant benefit. It is not used specifically for status asthmaticus prevention.

ICU admission criteria

Indications for ICU admission include the following:

• Altered sensorium

• Use of continuous inhaled beta-agonist therapy

• Exhaustion

• Markedly decreased air entry

• Rising PCO2 despite treatment

• Presence of high-risk factors for a severe attack

• Failure to improve despite adequate therapy

Surgery

Status asthmaticus is generally managed by means of medical therapy, with some exceptions. For example, thoracostomy is indicated in pneumothoraces.

Some children may have asthma that is primarily exacerbated by gastroesophageal reflux disease. Some patients can be treated with a combination of antireflux (eg, proton pump inhibitors) and histamine 2 (H2)–receptor antagonist agents. However, surgery, such as Nissen fundoplication, is occasionally required.

Anesthesia support is needed if inhaled anesthetic agents are considered for refractory severe intubated status asthmaticus.

If all other support modalities fail and extracorporeal membrane oxygenation (ECMO) is required, surgical support for cannula placement should take place at an established pediatric ECMO center.

Diet

Some children with asthma may have episodes triggered by food allergies. Consultation with a nutritionist may be necessary to provide appropriate dietary management.

Beta2-Agonists

The first line of therapy is bronchodilator treatment with a beta2-agonist, typically albuterol. Handheld nebulizer treatments may be administered either continuously (10-15 mg/h) or by frequent timing (eg, q5-20min), depending on the severity of the bronchospasm.

The dose of albuterol for intermittent dosing is 0.3-0.5 mL of a 0.5% formulation mixed with 2.5 mL of normal saline. Many of these preparations are available in a premixed form with a concentration of 0.083%.

Studies have also demonstrated an excellent response to the well-supervised use of albuterol via an MDI with a chamber. The dose is 4 puffs, repeated at 15- to 30-minute intervals as needed. Most patients respond within 1 hour of treatment.

The US Food and Drug Administration (FDA) approved the use of the R isomer of albuterol, known as levalbuterol, for treating patients with acute asthma. This isomer has fewer effects on the heart rhythm (ie, tachyarrhythmia) and is associated with fewer occurrences of tremors, while having the same or greater clinical bronchodilator effects as racemic albuterol. The decreased prevalence of adverse effects with this single isomer medication may allow physicians to use nebulizer therapy in patients with acute asthma more frequently, with less concern over the adverse effects that occur with other bronchodilators (eg, albuterol, metaproterenol). The dose of levalbuterol is either a 0.63-mg vial for children or a 1.26-mg vial for adults. A study in 2009 documented that although a slight decrease may have occurred in the duration of continuous nebulizer treatment with levalbuterol compared with albuterol, the difference was not statistically significant. [23]

The above drugs, especially albuterol, are safe to use during pregnancy. Beta2-agonists act via stimulation of cyclic adenosine monophosphate (AMP)–mediated bronchodilation. The airway is rich in beta receptors; the stimulation of these receptors relaxes airway smooth muscles, increases mucociliary clearance, and decreases mucous production.

The nebulized, inhaled route of administration is generally the most effective route of delivery for beta2-agonists. Inhaled beta-agonists can be administered intermittently or as continuous, nebulized aerosol in a monitored setting. Some patients with severe, refractory status asthmaticus may benefit from the addition of beta-agonists delivered intravenously.

Beta-agonists are generally most effective in the early asthma reaction phase. However, patients who present with status asthmaticus despite frequent use of beta-agonists at home may have tachyphylaxis and may exhibit resistance to these agents. Similar issues may be seen in patients using long-term inhaled long-acting beta-agonists. Therefore, these patients may not respond as well when these agents are given in the hospital setting.

Endotracheal adrenaline in patients who are intubated has been associated with variable success in different studies. However, based on the current literature, no specific advantage can be gained at this point by using endotracheal adrenaline. [24]

Continuous inhaled albuterol and intravenous methylprednisolone are considered important in the management of status asthmaticus. In a report by Beach et al, [25] a 40-year-old patient with status asthmaticus acquired an accelerated idioventricular rhythm while on this treatment. The rhythm resolved after the condition was controlled and the treatment was discontinued. Three months’ follow-up showed no sequelae. Therefore, this type of rhythm appears to be benign and should not pose a significant alarm.

High-dose albuterol has been started in a limited fashion in children with status asthmaticus. The high dose was defined as 150 mg/h and the lower dose was 75 mg/h. The higher dose resulted in low rate of subsequent mechanical ventilation and a short pediatric intensive care unit length of stay. There was no evidence of toxicity.

Nonselective beta2-agonists

Patients whose bronchoconstriction is resistant to continuous, handheld nebulizer treatments with traditional beta2-agonists may be candidates for nonselective beta2-agonists (eg, epinephrine [0.3-0.5 mg] or terbutaline [0.25 mg]) administered subcutaneously. [26] However, systemic therapy has no proven advantage over aerosol therapy with selective beta2 agents.

Exercise caution in patients with other complicating factors (eg, congestive heart failure (CHF), history of cardiac arrhythmia). Intravenous isoproterenol is not recommended for the treatment of asthma, because of the risk of myocardial toxicity. [27]

Some practitioners advocate monitoring cardiac enzyme levels in patients who receive prolonged, significant infusions of intravenous beta-agonists. Small studies in children have documented that enzymes such as troponin I may be elevated during terbutaline infusion, although these levels normalize as terbutaline is discontinued. The clinical significance of such enzyme elevation remains unclear. [28, 29]

Anticholinergics

Anticholinergic agents are believed to work centrally by suppressing conduction in vestibular cerebellar pathways. They may have an inhibitory effect on parasympathetic nervous system. They may also decrease mucus production and improve mucociliary clearance

Ipratropium bromide

Ipratropium bromide (Atrovent), a quaternary amine that does not cross the blood-brain barrier, is the recommended anticholenergic parasympatholytic agent of choice. This synthetic ammonium compound is very similar structurally to atropine. It comes in premixed vials at 0.2%, is administered every 4-6 hours, and can be synergistic with albuterol or other beta2-agonists when treating severe acute asthma exacerbations.

Ipratropium may also be used as an alternative bronchodilator in patients who are unable to tolerate inhaled beta2-agonists. Because children appear to have more cholinergic receptors, they are more responsive to parasympathetic stimulation than adults.

Atropine, a tertiary amine, may also be used and nebulized. However, the drug may cause CNS effects because it may cross the blood brain barrier.

Glucocorticosteroids

Glucocorticosteroids are the most important treatment for status asthmaticus. [30] These agents can decrease mucus production, improve oxygenation, reduce beta-agonist or theophylline requirements, and activate properties that may prevent late bronchoconstrictive responses to allergies and provocation.

In addition, corticosteroids can decrease bronchial hypersensitivity, reduce the recovery of eosinophils and mast cells in bronchioalveolar lavage fluid, decrease the number of activated lymphocytes, and help to regenerate the bronchial epithelial cells.

Corticosteroids may be administered intravenously or orally. Although most practitioners administer corticosteroids intravenously during status asthmaticus, some studies indicate that early administration of oral corticosteroids may be just as effective.

Corticosteroid action usually requires at least 4-6 hours to occur following corticosteroid administration because protein synthesis is required before the initiation of a corticosteroid’s anti-inflammatory effects. Because of this, patients with status asthmaticus must depend on other supportive measures (eg, beta2-agonists, oxygen, adequate ventilation) in their initial treatment while awaiting the action of corticosteroids. The usual dose is oral prednisone at 1-2 mg/kg daily.

Methylprednisolone is used to treat inflammatory and allergic reactions. By reversing increased capillary permeability and suppressing polymorphonuclear (PMN) cell activity, it may decrease inflammation. Other corticosteroids may be used in equivalent dosages. In some authors' experience, methylprednisolone provides excellent efficacy in pediatric patients when given intravenously at 1 mg/kg/dose every 6 hours. [31, 32]

Corticosteroid treatment for acute asthma is necessary but has potential adverse effects. The serum glucose value must be monitored. Insulin can be administered on a sliding scale if needed. Monitoring a patient's electrolyte levels, especially potassium, is essential. Hypokalemia can cause muscle weakness, which may worsen respiratory distress and cause cardiac arrhythmias.

Adverse effects of pulse therapy, in some authors' experience, are minimal and are comparable to those of the traditional doses of intravenous corticosteroids. The adverse effects may include hyperglycemia, which is usually reversible once steroid therapy is stopped, increased blood pressure, weight gain, increased striae formation, and hypokalemia. Long-term adverse effects depend on the duration of steroid therapy after the patient leaves the hospital.

Nebulized steroids

The use of nebulized corticosteroids for treating status asthmaticus is controversial. Data comparing nebulized budesonide with prednisone in children suggest that the latter therapy is more effective for treating status asthmaticus.

No good scientific evidence supports using nebulized dexamethasone or triamcinolone via a handheld nebulizer. In fact, in some authors' experience, more adverse effects, including a cushingoid appearance and irritative bronchospasms, have occurred with these nebulizers.

Other Bronchodilators

Methylxanthines

The role of methylxanthines, such as theophylline or aminophylline, in the treatment of severe acute asthma has been diminished since the advent of potent selective beta-agonists and their use at higher doses. [33] At therapeutic doses, methylxanthines are weaker bronchodilators than beta-agonists and have many undesirable adverse effects, such as frequent induction of nausea and vomiting. Furthermore, most studies have failed to show additional benefit when methylxanthines are administered to patients who are already receiving frequent beta-agonists and corticosteroids.

Nevertheless, several prospective, randomized, controlled studies in children with refractory status asthmaticus have reexamined the role of the methylxanthines theophylline and aminophylline and have demonstrated improvement in the clinical asthma scores when compared with placebo control.

One study compared intravenous theophylline with intravenous terbutaline in critically ill children with refractory asthma and demonstrated equal therapeutic efficacy but significantly lower costs associated with theophylline use. [34]

Theophylline

Among the effects of theophylline that are important in managing asthma are bronchodilatation, increased diaphragmatic function, and central stimulation of breathing.

Usually, theophylline is given parenterally, but it can also be given orally, depending on the severity of the asthma attack and the patient's ability to take medications. This class of drugs can induce tachycardia and decrease the seizure threshold (especially in children); therefore, therapeutic monitoring is mandatory.

In the past the typical theophylline therapeutic levels ranged from 10-20 mcg/mL. However, adverse effects can occur even with therapeutic levels. A lower therapeutic range of 8-15 mcg/mL has therefore been adopted by many institutions. Seizures have occurred even with levels below 10 mcg/mL.

Theophylline also has significant drug interactions with medications such as ciprofloxacin, digoxin, and warfarin. These interactions may decrease the rate of theophylline clearance by interfering with P-450 site metabolism. On the other hand, phenytoin and cigarette smoking can increase the rate of metabolism of theophylline and, therefore, can decrease the therapeutic level of the drug.

Manage the theophylline dose in persons who quit smoking fewer than 6 months previously as if they are still smoking. Patients who smoke or those on phenytoin require higher loading and maintenance doses of theophylline. Other adverse effects can include nausea, vomiting, and palpitations.

The usual loading dose of theophylline is 6mg/kg, followed by maintenance doses of 1mg/kg/h in the emergent setting. In patients who smoke, the maintenance dose may be higher and the loading dose may be slightly higher. Patients on phenytoin should also receive increased maintenance doses of theophylline. Patients with liver disease or elderly patients may require a maintenance dose as low as 0.25mg/kg/h.

Aminophylline

Conflicting reports on the efficacy of aminophylline therapy have made it controversial. Starting intravenous aminophylline may be reasonable in patients who do not respond to medical treatment with bronchodilators, oxygen, corticosteroids, and intravenous fluids within 24 hours. [35]

Data suggest that aminophylline may have an anti-inflammatory effect in addition to its bronchodilator properties. The loading dose is usually 5-6 mg/kg, followed by a continuous infusion of 0.5-0.9 mg/kg/h.

Magnesium sulfate

Intravenous magnesium sulfate infusion has been advocated in the past for the treatment of acute asthma. Magnesium can relax smooth muscle and hence may cause bronchodilation by competing with calcium at calcium-mediated smooth muscle ̶ binding sites. Usually 1 gram or a maximum of 2.5 grams during the initiation of therapy may be considered.

One double-blind, placebo-controlled study reported a significant increase in PEF, FEV1, and forced vital capacity in children who had asthma and were treated with a single 40-mg/kg dose of magnesium sulfate infused over 20 minutes, along with steroids and inhaled bronchodilators, compared with control subjects who received saline placebo. [36] In addition, patients who received intravenous magnesium (8 of 16 patients) were significantly more likely to be discharged home from the presenting emergency department than were control subjects (0 of 14 patients).

No data regarding duration of effect or efficacy with repeated doses are available, and no guidelines describe the monitoring of serum magnesium levels if more than an initial magnesium dose is administered. In one small study of four children who received 40-50 mg/kg of magnesium sulfate, serum magnesium levels were all less than 4 mg/dL, whereas electrocardiographic changes are generally not seen until levels exceed 4-7 mg/dL. Adverse effects may include facial warmth, flushing, tingling, nausea, and hypotension.

This therapy can be tried, especially in pregnant women, as an adjunct to beta2 bronchodilator therapy. However, more studies have not confirmed the effectiveness of this treatment, [37, 38] and its use is still controversial.

Inhaled magnesium sulfate has generated some interest with regard to the treatment of status asthmaticus, when combined with beta-agonist use. [39]

In a retrospective study by Vaiyani and Irazuzla, [40] magnesium sulfate infusion for status asthmaticus in children was evaluated. Two groups of patients were identified. Nineteen of the first group received high-dose prolonged magnesium infusions consisting of 75 mcg/kg if the weight was less than 30 kg. If the weight was more than 30 kg, the dose was 50 mg/kg. In both situations, the infusion of magnesium sulfate was continuous over 4 hours given at 40 mg/kg/h. In the second group, no loading dose was given. The dose was 50 mg/kg/h over 5 hours. There was no difference in the magnesium concentration in the serum in both of these groups, and the amount of bronchodilation was similar. Based these and other data, magnesium sulfate remains an important regimen in the treatment of status asthmaticus, with excellent tolerability. [41]

Sedatives

Patients may benefit from sedatives in very small doses and under controlled, monitored settings. Sedatives should be used judiciously, if at all. For example, lorazepam (0.5 or 1 mg intravenously) could be used for patients who are very anxious and are undergoing appropriate and aggressive bronchodilator therapy. More powerful agents (eg, oxybutynin) can be administered to intubated patients to achieve sedative, amnestic, and anxiolytic effects.

In the past several years, new therapies have been developed in patients with severe and resistant status asthmaticus despite mechanical ventilation.

Anesthetics

Ketamine

Ketamine is a short-acting pentachlorophenol derivative that exerts bronchodilatory effects because it leads to an increase in endogenous catecholamine levels, which may bind to beta receptors and cause smooth muscle relaxation and bronchodilation.

Ketamine was used in the management of status asthmaticus in a prospective trial in patients with respiratory failure who did not respond adequately to mechanical ventilation. [42] This agent improved airway resistance, particularly the lower airways, as well as improve lung compliance. Significant improvement in oxygenation and hypercarbia has been reported, even 15 minutes after the administration of ketamine.

Case reports have also described the use of ketamine as a sedative to reduce anxiety and agitation that can exacerbate tachypnea and work of breathing and potentially obviate further respiratory failure in small children with status asthmaticus.

Ketamine as a continuous infusion may induce relaxation of the airways with limited anesthesia. However, its role is still limited in status asthmaticus. Central nervous system sedation, which may require intubation, is a limitation in its use. It is also noted that its use has been limited to the pediatric population and at a very low dosage. [43, 44, 45]

Inhaled anesthetic agents

Inhaled anesthetic agents, such as halothane, isoflurane, and enflurane, have been used with varying degrees of success in refractory, intubated patients with severe asthma. The mechanism of action is unclear but they may have direct relaxant effects on airway smooth muscle. [46, 47]

Other inhaled anesthetics that have been studied include propofol and sevoflurane. Prolonged propofol administration, however, may be complicated by generalized seizure, increased carbon dioxide production, and hypertriglyceridemia.

Sevoflurane has been employed more commonly than halothane and isoflurane. Care must be used with this medication, even though it is relatively safe, because of the risk of hepatotoxicity and renal tubular injury. In children, sevoflurane has been shown in some studies to be safe and effective. In adults, careful monitoring of liver and kidney function, as well as serum fluoride concentration, is helpful for avoiding toxic levels of sevoflurane. [48]

Other agents

Neuromuscular blockers may be used with caution in patients who are well sedated but exhibiting severe anxiety and tachycardia, as well as in those who are intolerant of intubation. [3, 24]

In isolated case reports, nitric oxide has also been used in the treatment of status asthmaticus and has been effective when mechanical ventilation is not adequate. [49, 50]

Additionally, the use of nebulized lidocaine in combination with albuterol or levalbuterol is effective in helping the vocal cord dysfunction that may accompany status asthmaticus (this is an unpublished observation by an author in clinical practice). Data have shown that lidocaine in asthma may have efficacy. [51, 52] It helps in reducing the cough component and has been shown to be an eosinophilic apoptotic agent with clinical efficacy in chronic cough.

Extracorporeal Life Support

Mikkelsen and colleagues reported the successful use of extracorporeal life support in patients with status asthmaticus and severe secondary asphyxia in any patient who otherwise was not responsive to aggressive pulmonary support. [53]

The role of extracorporeal life support has been studied and implemented in several institutions and should be considered in patients at high risk of developing refractory status asthmaticus. [54, 55] This includes, but is not limited to, patients with a history of multiple intubations, respiratory failure requiring intubation within 6 hours of admission, hemodynamic instability, neurologic impairment at the time of admission, and duration of respiratory failure greater than 12 hours despite maximal medical therapy. [56]

Noninvasive Ventilation

Noninvasive ventilation, such as bilevel positive airway pressure, can be considered in patients with impending respiratory failure, in order to avoid intubation. In contrast to patients with chronic obstructive respiratory disease exacerbation and respiratory failure, however, asthma patients tend to require more invasive means of ventilation with intubation when they are in status asthmaticus. The presence of severe bronchoconstriction with multiple secretions and inflammatory processes are contributors to the need for more aggressive ventilation. [56]

Ram et al demonstrated that the effectiveness of noninvasive positive pressure ventilation was affected by meta-analysis. [57] Ueda et al reported using noninvasive positive pressure ventilation to wean a patient with refractory status asthmaticus who also had developed atelectasis. [58]

Steinack et al report that venoocclusive extracorporeal membrane oxygenation (ECMO) was effective in a 25-year-old pregnant woman. [59] The patient failed to respond to the usual therapeutic modalities for status asthmaticus, including the typical medications discussed as well as pressure control ventilation with high inspiratory pressures. ECMO as mentioned should always be considered with status asthmaticus and respiratory failure with inadequate response to pressure control ventilation, antimuscarinic drugs, intravenous beta-agonists, intravenous methylprednisolone, and magnesium sulfate. Continuous positive airway pressure therapy has been used for support of status asthmaticus. Noninvasive positive-pressure ventilation has been shown to "splint" the airways, allowing for better exhalation and emptying. [60]

Leatherman et al reported that prolongation of the expiratory time can decrease dynamic inflation in patients with status asthmaticus and may have a minor positive effect on weaning in these patients. [61]

One should also consider that noninvasive ventilation may have a significant role in managing patients with status asthmaticus. This has been shown to be mostly effective in the pediatric population. [62]

Mechanical Ventilation

Consider mechanical ventilation as a salvage therapy in patients with status asthmaticus. Mechanical ventilation in patients with asthma requires careful monitoring, because these patients have high end-expiratory pressure and, therefore, are at high risk for pneumothorax.

Indications for intubation and mechanical ventilation include the following:

• Apnea or respiratory arrest

• Diminishing level of consciousness

• Impending respiratory failure marked by significantly rising PCO2 with fatigue, decreased air movement, and altered level of consciousness

• Significant hypoxemia that is poorly responsive or unresponsive to supplemental oxygen therapy alone

Mechanical ventilation, when used in patients with asthma, is usually required for less than 72 hours. In occasional patients with severe bronchospasm, however, mechanical ventilation can be prolonged. In these situations, consultation with a pulmonologist or another expert in mechanical ventilatory techniques is recommended.

Because asthma is a disease of airway obstruction (ie, increased airway resistance), resulting in prolongation of the time constant (the time needed for lung units to fill and empty), low ventilator rates are usually needed.

Considerations in mechanical ventilation

The decision to intubate a patient with asthma should be made with extreme caution. Positive pressure ventilation in a patient with asthma is complicated by the severe airway obstruction and air trapping, which results in hyperinflated lungs that may resist further inflation and places the patient at high risk of barotrauma. Therefore, mechanical ventilation should be undertaken only in the face of continued deterioration despite maximal bronchodilatory therapy.

In the face of high peak airway pressures, the principle of mechanical ventilation in status asthmaticus is controlled hypoventilation with toleration of higher levels of PCO2 in order to minimize tidal volume and peak inspiratory pressures. Permissive hypercapnia can be tolerated as long as the patient remains adequately oxygenated. A longer inspiration/expiration (I/E) ratio, often greater than 1:3-4, helps to allow time for optimal exhalation, facilitating ventilation and avoiding an excessive amount of further air trapping (auto–positive end-expiratory pressure [auto-PEEP]).

Keep in mind, however, that patients may be uncomfortable and air hungry while ventilated with low respiratory rates, prolonged exhalation times, and hypercapnia due to a strategy of controlled hypoventilation.

The use of positive end-expiratory pressure (PEEP) is controversial. A patient with status asthmaticus who is in respiratory failure and on mechanical ventilation usually has a significant amount of air trapping that results in intrinsic PEEP, which may be worsened by maintaining PEEP during exhalation. However, some patients may benefit from the addition of PEEP, perhaps owing to the maintenance of airway patency during exhalation. Thus, in a patient who remains refractory to the initial ventilatory settings with no or very low PEEP, cautiously increasing the PEEP may prove beneficial.

Traditionally, slow, controlled ventilation with heavy sedation, often with muscle relaxation, has been used to ventilate patients with status asthmaticus. Caution is warranted, however, as the use of muscle relaxants with high-dose corticosteroids has been associated with the development of prolonged paralysis.

Alternatively, some practitioners report ventilating children with status asthmaticus with pressure support alone. This strategy may allow the patient to set his or her own respiratory rate as determined by the physiologic time constant, while assisting ventilation and relieving the fatigue due to significantly increased work of breathing.

Invasive mechanical ventilation is associated with increased hospital resource use, with prolonged length of stay and even a higher risk of developing pneumonia. The research for noninvasive ventilation should help in minimizing the frequency of invasive mechanical ventilation. [63] In addition, a single case report showed that status asthmaticus in a 12-year-old boy with subcutaneous emphysema and pneumomediastinum resulted in worsening of both of the conditions with noninvasive ventilation. Further research is needed in this area. [64] When in doubt, mechanical invasive ventilation should be considered first in patients with significant respiratory distress who are not responding to the usual aggressive pharmacological and appropriate oxygenation. It is considered the safest approach in a patient who is in severe status asthmaticus, particularly with secondary respiratory failure. It is not, however, without adverse effects or complications. Pneumothorax and idiopathic hemothorax have both been reported. [65]

Monitoring and support

Patients require supportive measures and monitoring during mechanical ventilation. Ideally, monitor flow-volume loops to ascertain if adequate time is provided for exhalation to avoid breath stacking, which occurs if the next breath is delivered before exhalation is completed. Monitoring exhaled tidal volume and auto-PEEP is also important.

Fluids and electrolytes should be monitored. Before arrival in the hospital, children with status asthmaticus have often had diminished oral intake and may have been vomiting because of respiratory difficulty or adverse effects from their medications. This leads to decreased intravascular volume status that may be potentiated by the effects of positive pressure ventilation. Moreover, serum electrolyte levels should be monitored because medications used to treat asthma can result in significant kaliuresis.

In addition, cardiac output may be decreased because of decreased preload that results from air trapping and auto-PEEP. This decreased cardiac output and intravascular volume may be accompanied by metabolic acidosis. Intravascular fluid expansion is needed to treat hypoperfusion, hypotension, or metabolic acidosis.

In addition, diastolic hypotension may occasionally result from high doses of beta-agonists. A vasoconstrictor (ie, norepinephrine, phenylephrine) may be considered if significant diastolic hypotension in the face of adequate intravascular volume persists.

Catheter placement

Placement of an indwelling arterial catheter may be considered for blood gas sampling and continuous blood pressure measurement in patients with mechanical ventilation but is not generally recommended. The arterial waveform can also be used for measurement of pulsus paradoxus.

Heliox

Other treatments have been used in patients with severe acute asthma, but none is well proven. A combination of helium and oxygen known as heliox (ie, 30/70 mixture) has been studied, but this treatment should only be considered in patients who are able to take deep breaths, because the treatment is dependent on inspiratory flow. [66]

Helium is an inert gas that is less dense than nitrogen. The administration of a heliox reduces turbulent airflow across narrowed airways, which can help to reduce the work of breathing. This, in turn, can result in improved gas exchange and improve pH and clinical symptoms. [67, 68] It does not improve the caliber of the narrowed airway. Because of its low density, helium is more fluid under conditions of turbulence. This results in minimizing airway pressure and facilitating reoccurrence of laminar flow. Therefore, oxygenation becomes easier in the presence of increased airway resistance.

Some data suggest that nebulized-size particles may be more uniformly distributed in the distal airways when nebulization treatments are administered via heliox than with a standard oxygen-nitrogen mixture. [69]

Heliox can be administered via a well-fitting face mask at flows high enough to prevent entrainment of room air. The effectiveness of heliox in reducing the density of administered gas and improving laminar airflow depends on the helium concentration of the gas. The higher the helium concentration, the more effective the result. Therefore, an 80/20 mixture of helium-oxygen is most effective.

Heliox loses most of its clinical utility when the FiO2 is greater than 40%, reducing the percentage of helium to less than 60%. Therefore, the limitation to the use of heliox is the amount of supplemental oxygen the patient requires to maintain adequate oxygen saturation.

Heliox has also been used with mechanical ventilation to lower the dynamic peak inspiratory pressures.

Heliox is a low-density gas that allows better oxygenation into the small airways. It should be considered in patients who are not adequately responding to conventional pharmacological therapy, and it may aid in preventing intubation. [70]

Deterrence and Prevention

Status asthmaticus can usually be prevented if patients are compliant with their medications and avoid triggers and stress factors. However, this condition can occur even when patients are compliant and doing well as outpatients. In such situations, search for an occult infection (eg, respiratory syncytial virus [RSV] in children but rarely in adults or an occult sinus infection).

Prevention of status asthmaticus may be aided with monitoring forced oscillation test results rather than spirometry findings. This is particularly true for children younger than 12 years. However, adults with reactive airways may be undertreated if the criterion for stability and normality is a spirometric FEV1 of greater than 80% of the predicted value.

Among the important preventive considerations are home medications, such as anti-inflammatory agents. Corticosteroids are now considered the mainstays of asthma maintenance therapy. Studies indicate that the underuse of anti-inflammatory agents is related to more severe asthma. This is thought to be due to airway remodeling and the persistence of inflammatory changes.

Identify specific patients who are at risk for asthma exacerbation, such as younger children and adults older than 60 years. Bronchodilators are recommended for acute exacerbations. Environmental management is also necessary in children with environmental allergies.

A retrospective analysis showed that the severity of asthma at baseline and the age of the patient are the most important determining factors in the risk for recurrent status asthmaticus and for predicting the severity of the attack. [71] In other words, patients older than 60 years who are also characterized as having either moderate persistent asthma or severe persistent asthma are at high risk of developing status asthmaticus.

Therefore, compliance with the National Institutes of Health (NIH) guidelines for the treatment and management of patients with asthma should theoretically be an effective prophylaxis against the development of status asthmaticus.

Inpatient education by trained lay volunteers in patients who are admitted with status asthmaticus was associated with improvement in posthospitalization and better adherence to their inhaler management. [1]

In a study by Miller et al, [72] an asthma protocol developed by the hospital and based on the guidelines of the National Institutes of Health in children with status asthmaticus resulted in improved time to treatment and better outcome. This was studied in children aged 3-11 years.

Consultations

Consult allergists or pulmonologists because these specialists can provide comprehensive follow-up care with the appropriate therapy, allergy testing (if indicated), control of environmental factors, and consistent follow-up testing and manipulation of medications, as required. Consultation with a surgeon may be required if the child can benefit from fundoplication.

Hospital admission for asthma should be considered the result of a failure of outpatient management. Better outpatient therapy is necessary to prevent subsequent admissions.

Consultation with a member of social services can provide support in the complex management of a chronic illness. Adolescents who have severe, uncontrolled asthma and are nonadherent or have depression or significant behavioral issues may require the services of a psychiatrist or psychologist.

Long-Term Monitoring

Appropriate follow-up is important, as is checking the patient's peak flow meter and forced expiratory volume in 1 second (FEV1) at home or in the office, respectively.

Children with asthma commonly present with normal (FEV1), and, accordingly, more sensitive lung function testing should be undertaken with regular impulse oscillometry system (IOS) assessments. Medication titration may be usefully guided by IOS resistance and reactance values.

Outpatient follow-up and continued care of a patient who has been hospitalized in the pediatric ICU because of severe status asthmaticus is important in optimizing long-term outcome and quality of life and in minimizing recurrent episodes of severe asthma exacerbation. Follow-up is best provided by a specialist in the treatment of asthma. The subgroup of patients who are poor perceivers of dyspnea are at increased risk for future exacerbations. An at-home peak flow meter may be valuable in this poor-perceiver population. [8]

Complications

In adults with status asthmaticus, the clinical presentation with overt acidemia was significantly associated with higher rate of invasive ventilation and prolonged hospital stay with complications and mortality. This was based on a retrospective analysis in patients aged 33-70 years. [73] Hypokalemia was noted in a minority of these patients but, for the most part, did not require supplementation. [74]

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Author

Constantine K Saadeh, MD President, Allergy ARTS, LLP; Principal Investigator, Amarillo Center for Clinical Research, Ltd

Constantine K Saadeh, MD is a member of the following medical societies: American Academy of Allergy, Asthma and Immunology, American College of Rheumatology, American Medical Association, Southern Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

John J Oppenheimer, MD Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

John J Oppenheimer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, New Jersey Allergy, Asthma and Immunology Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Amgen; GSK; Aquestive; Aimmune<br/>Clinical Adjudication/Data Safety Monitoring Board for AZ, GSK, Abbvie, Sanofi; Executive Editor for Annals of Allergy, Asthma & Immunology; Editor for Medscape; Reviewer for UpToDate; Honoraria from American Board of Allergy and Immunology.

Acknowledgements

Michael R Bye, MD Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami, Leonard M Miller School of Medicine; Medical Director, Palliative Care Team, Director, Pediatric Critical Care Transport, Holtz Children's Hospital, Jackson Memorial Medical Center; Medical Manager, FEMA, Urban Search and Rescue, South Florida, Task Force 2; Pediatric Medical Director, Tilli Kids – Pediatric Initiative, Division of Hospice Care Southeast Florida, Inc

G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Heart Association, American Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Barry J Evans, MD Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center

Barry J Evans, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Michael Goldman Professor of Internal Medicine, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Helen M Hollingsworth, MD Director, Adult Asthma and Allergy Services, Associate Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care, Boston Medical Center

Helen M Hollingsworth, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, and Massachusetts Medical Society

Disclosure: Nothing to disclose.

Jan Malacara, PA-C Consulting Staff, Allergy ARTS, LLP

Disclosure: Nothing to disclose.

Adam J Schwarz, MD Consulting Staff, Critical Care Division, Pediatric Subspecialty Faculty, Children's Hospital of Orange County

Adam J Schwarz, MD is a member of the following medical societies: American Academy of Pediatrics and Phi Beta Kappa

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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