Reactive airway disease was responsible for 388 000 pediatrie hospital izations in 1982, and occurs in approximately 10% of children in the United States. Thus, it is important for the pediatrician to manage both acute and chronic asthma effectively. The goal of therapy in acute severe asthma is the immediate reversal of airway obstruction and restoration of normal pulmonary function, best achieved through the use of a combination of medications. The purpose of this brief review is to answer specific questions that may arise as the pediatrician decides how to treat the patient with acute severe asthma in the office, emergency room, or hospital setting.
ASSESSMENT OF ACUTE ASTHMA
The patient's past and present history can alert the physician as to the need for aggressive therapy. A brief history should contain possible precipitating factors, history of past attacks, and dosage and timing of all medications. The duration of current symptoms is important, because those present 1 2 hours or longer respond less well to bronchodilator therapy. In addition, risk factors that have been associated with a more severe episode and possible hospitalization include frequent asthma attacks, recent attacks of severe asthma, recent hospitalization, need for intensive care, long delay in seeking medical care, and recent use of high dose steroids.
The initial physical exam should evaluate the overall status of the patient including, alertness, anxiety, fluid status, and general health, as well as the degree of airway obstruction. Wheezing results from turbulent airflow and occurs first on expiration alone, progressing to both inspiration and expiration. If airway obstruction is severe, the chest may be quiet, thus making wheezing an unreliable sign of degree of obstruction.
Hyperinflation of the chest occurs during a progressive acute attack from air trapped behind occluded small airways. Air trapping depresses the diaphragm, making it a less efficient muscle of inspiration and forcing the use of expiratory muscles. This use of accessory muscles has been associated with severe obstruction. In a study of 62 asthmatic children, Commey and Levison1 reported that dyspnea, subjective wheezing, and auscultatory findings did not correlate with outcome. However, all patients with forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximum expiratory flow volume (MEFR) of less than 50% of predicted values had sternocleidomastoid contraction with inspiration.
Pulsus paradoxus is a drop in systolic blood pressure of 10 mmHg or more with inspiration and has been shown to correlate with a worsening clinical asthmatic condition. Galant et al2 found a significantly greater pulsus paradoxus (mean 22 mmHg) in children with a PaCO2 greater than 40 mmHg compared with those with a PaCO2 less than 40 (mean 12 mmHg).
Additional Tests to Determine Severity
Chest radiograph findings in acute asthma are nonspecific and add little to the clinical assessment. Brooks et aP compared x-ray findings with clinical assessment in 128 children admitted for asthma. Despite finding seven patients with abnormal radiographs, no significant alterations in treatment were made as a result of the x-ray findings.
Measurement of peak expiratory flow rate (PEFR) may be performed in any child 5 years or older using a Wright® peak flow meter with a low range of 60 liters per minute and is helpful in assessing initial asthma severity and response to bronchodilators.
Blood gas measurements are the "gold standard" for assessing the severity of an asthmatic attack but are only necessary in patients who fail to respond to initial therapy or in those requiring hospitalization. In acute asthma, hypoxemta is invariably present due to ventilation/perfusion (V/Q) mismatching, with the degree of hypoxemia correlating with the severity of airway obstruction. Oxygen saturation may be measured noninvasively with a pulse oximeter and will provide an estimate of the degree of hypoxemia.
Because of the V/Q mismatch and the presence of hypoxemia, oxygen is indicated in every patient having an acute asthmatic attack. Humidified oxygen, given by mask, nasal cannula, or hood will relieve the hypoxemia and decrease the work of breathing. Asthmatics are not at risk for developing hypercarbia from oxygen therapy.
Administration of Sympathomimetics
The first drug administered to an asthmatic during an acute attack should be sympathomimetics, as they are the most potent bronchodilators. Comparisons of theophylline and ß-agonists in stable asthmatics have demonstrated that the ß-agonists are more potent bronchodilators. Rossing et al,4 comparing the efficacy of inhaled isoproterenol, subcutaneous epinephrine, and intravenous aminophylline as the initial therapy of acute asthma in 48 patients, found both of the sympathomimetics to be superior to aminophylline. This finding was confirmed by tanta et al,5 who found that patenterai and inhaled adrenergics were superior to aminophylline for the relief of acute bronchospasm in emergency room visits for acute asthma. Because theophylline is a less potent bronchodilator than the ß-agonists, it is not recommended for the initial management of acute severe asthma.
Several clinical investigations have shown that ß2 agonists administered by the inhaled route provide as great or greater bronchodilation with fewer systemic side effects than parenteral administration. Concerns have been raised as to the adequacy of penetration of aerosol throughout the bronchial tree in acute asthma. However, multiple clinical trials in children and adults have proven that the inhaled route is as effective as parenteral sympathomimetics and is associated with fewer side effects.6'7 Thus, in the management of acute asthma in the emergency room or physician's office, an aerosolized ß2-agonist is as effective as epinephrine or terbutaline injection and provides a wider margin of safety with greater patient acceptance.
The bronchodilating effect of ß-agonists is related to their ß2 effect, which relaxes smooth muscle; therefore, using the most specific ß2 agent is desirable. Currently, albuterol inhalation solution (5 mg/mL) offers the most ß2 selectivity with the longest duration of action (Table 1). Robertson et al8 found the administration of frequent small doses (0.05 mg/kg per dose every 20 min) of nebulized albuterol to be safe and superior to hourly dosing (0. 15 mg/kg/dose), producing a smoother rise in FEV1 with an earlier peak response without deterioration between doses.
Because of the hypoxemia that occurs in acute asthma, it is preferable to nebulize albuterol with oxygen via mask or mouthpiece and repeat as frequently as necessary, while monitoring the pulse to keep it less than 180 maximum.
Anticholinergics are potent bronchodilators and have been used to treat asthma for centuries. When compared with the ß2-agonists, anticholinergìcs (atropine sulfate, atropine methonitrate, ipratropium bromide [Atrovent®]) have a slower onset of action, with a peak effect not occurring for 60 minutes. The exact role of the anticholinergics in acute asthma is still unclear. Karpel et al9 reported the ß-agonists to be superior to anticholinergics for bronchodilation in acute asthma, although other studies have shown no difference between the two therapeutic classes.10 In a study of 28 children with acute asthma, Beck et al11 demonstrated that inhaled ipratropium produced a significant additional inctease in FEV1 after the maximum effect of inhaled albuterol had been reached. The authors suggested that in childhood asthma there may be a significant cholinergic component that contributes to the residual airway obstruction seen after treatment with albuterol alone (Table 1).
Aerosolized Drugs for the Treatment of Acute Severe Asthma In Children*
Theophylline in Emergency Therapy
The combined use of theophyHine and ß-agonists arose from in vitro studies indicating that a phosphodiesterase inhibitor combined with an adenyl cyclase stimulator would produce synergistic smooth muscle relaxation. However, clinical studies have shown that inhaled ß-agonists will produce further bronchodilation in patients with therapeutic theophyHine levels, but theophylline will not increase the bronchodilation achieved by maximally effective doses of inhaled ß-agonists.12
The actual benefit of theophylline in the emergency room treatment of asthma has been controversial. Studies in the treatment of acute asthma have railed to demonstrate any benefit from adding theophylline to optimal inhaled ß-agonist therapy.5 There is currently no evidence in the medical literature to suggest that administering aminophylline to patients presenting to the emergency room improves outcome over adequate ß2-agonist therapy alone.
Systemic Drugs for the Treatment of Acute Severe Asthma In Children
Corticosteroids have potent anti-inflammatory activity and are extremely effective in controlling chronic asthma. However, their use in acute asthma is controversial. The anti- inflammatory effect of Corticosteroids occurs through new protein synthesis and is delayed 6 to 8 hours following administration of a single dose of Corticosteroids. Therefore, the initial benefit of Corticosteroids in acute asthma may be related to improving the response to endogenous catecholamines and exogenous ßz-agonists that occurs within 1 hour of corticosteroid administration. In patients with acute asthma, Corticosteroids have been documented to decrease airway obstruction, improve oxygénation, and increase the response to ß-agonists. Also, recovery time has been shortened by Corticosteroids13 and the need for hospitaliza! ion has been reduced,14 if steroids are given early in the management of acute severe asthma.
The dosages of corticosteroids used in the treatment of acute asthma are largely empiric, with 1 to 2 mg/kg of methylprednisolone an effective emergency room dose. 1^ Although it is customary to use corticosteroids intravenously in the emergency room, Harrison et al15 did not find an advantage of parenteral administration over oral delivery.
Outcome of Emergency Room Treatment
Undertreatment is the most common cause of a poor response to or death from asthma. Because asthma consists of both bronchospasm and inflammation, therapy directed at only one of these aspects may be insufficient.
A number of studies have attempted to determine which presenting clinical signs and symptoms best predict the outcome of the emergency room treatment of asthma. Fields and Newcomb16 reported that 70% of acute childhood asthma is successfully treated, 15% to 20% of patients require hospitalization, and 10% to 20% experience relapse within IO days of discharge from the emergency room. The most predictive test is pulmonary function measurement in conjunction with the response to initial treatment. Patients who present with an FEV1 of less than 30% of predicted values and do not improve at least 35% after the first hour of intensive therapy have been shown to be most likely to require hospitalization.17
HOSPITALIZATION FOR ASTHMA
The criteria for hospitalization of an asthmatic child include status asthmaticus or an asthmatic attack with impending respiratory failure. In the past, status asthmaticus described a patient who failed to respond to three injections of epinephrine, with or without an aminophylíine bolus. With more aggressive inhaled ß-agonist therapy, the point at which a patient is in "status" is not exact. Admission is indicated when a patient has signs of impending respiratory failure, including severe respiratory distress or exhaustion, alteration in consciousness, pulsus paradoxus, and severe retractions that are not quickly reversed by initial therapy. In addition, the presence of hypotension, hypercarbia, ECG abnormalities, or extrapleural air require admission. Also, a patient with more than two visits for acute asthma within a 24 to 48 hours is at high risk for hospitalization. In general, the same parameters that were assessed in the emergency room should be used in patients admitted to an ICU. A child should be on a continuous cardiac monitor to detect any arrhythmias or ischemie changes, with frequent blood pressure measurements. Patients requiring admission to the ICU are usually too ill to have serial pulmonary function testing (PFT), but serial measurements are very useful in the recovery phase of a severe asthma attack. The best objective measure of airway obstruction in the patient with severe asthma is measurement of arterial blood gases, which may require an indwelling arterial catheter. A chest x-ray should be obtained on all hospitalized asthmatics.
β-Agonist therapy is the cornerstone of asthma treatment, with inhalation as the preferred route of administration. Once a child is in the ICU, the question arises as to how frequently ß-agonist therapy can be safely given. The duration of action of aerosolized ß-agonists depends on the dose administered and the physiologic status of the patient. Patients with severe bronchoconstriction will have a decreased intensity and duration of response to any given dose. IS Nelson et al19 demonstrated that adult asthmatics with incomplete responses to lower doses of ß-agonists obtained significant bronchodilation from logarithmic increments in use.
In the past, only relatively nonspecific ß-agonists, such as epinephrine, isoproterenol, and isoetharine were available; these had significant cardiac side effects, which limited their frequent use. However, with the availability of more selective ß-agonists, such as terbutaline, albuterol, and fenoterol, more frequent administration is possible. Albuterol may be given as frequently as needed, and sometimes in severe asthma; continuous nebulization is required (Table 2).8
Although studies in the emergency room have failed to show benefit from the addition of aminophylíine, in an ICU setting it improves outcome in severe patients.20 In addition to its bronchodilating effects, aminophylíine can prevent diaphragmatic fatigue and improve the strength of a fatigued diaphragm. Doses are given in Table 2.
When a child is responding minimally to ß-agonist therapy and aminophylíine, anticholinergic therapy may be instituted. Atropine (0.05 mg/kg/dose) every 4 to 6 hours may be given separately or mixed in the same nebulizer with a ß-agonist. Because atropine sulfate is well absorbed orally, the patient should be carefully monitored for side effects (tachycardia, flushing, disorientation) from systemic accumulation of atropine with continued administration.
Intravenous ß-agonists have been advocated to prevent the need for mechanical ventilation21; however, this use is controversial.22 Intravenous isoproterenol is the most dangerous ß-agonist to administer to an asthmatic. Death from myocardial toxicity22 and myocardial necrosis23 have been reported in children receiving intravenous isoproterenol therapy.
Bohn et al24 administered intravenous albuterol to 16 asthmatics using the doses given in Table 2. In addition, bicarbonate was given for a pH below 7.20. In 16 episodes, 11 responded and did not require intubation. The mean duration of infusion was 36 hours and the mean infusion rate 1.7 u,g/kg/min, with a maximum of 4 pgfkg/mm. In responding patients, the infusion was maintained for at least 4 hours and gradually decreased over the next 36 hours. Patients who failed to respond were maintained on the infusion while being ventilated. As patenterai albuterol is not available in the United States, terbutaline may be used (Table 2).
Severe metabolic acidosis is a sign of very severe airway obstruction. Acidosis may produce a relative adrenergic blockage, thus 1 to 2 mg/kg of intravenous NaHCO3 over 20 minutes should be administered if pH is less than 7.20. Attempting to correct the acidosis completely is potentially dangerous and probably should be reserved for ventilated patients.
Ventilation of Asthmatics
The PaCO2 is the best indicator of ventilation in acute asthma, however a single elevated PaCO2 does not indicate respiratory failure. Before therapy is initiated, PaCO2 values as high as 55 to 65 mmHg may be present. However, a PaCO2 of 55 mmHg or greater after one or two hours of intensive bronchodilator therapy or a rise in PaCO2 of 5 to 10 mmHg per hour during aggressive therapy in a patient who is becoming fatigued are indications for mechanical ventilation.25 With aggressive medical therapy, only a small fraction of patients should require mechanical ventilation.
Mechanical ventilation in asthmatic patients is often very difficult and numerous complications may occur. Because of this, a pulmonologist should be consulted for any child requiring mechanical ventilation. Intubation may be difficult and should be performed only by a physician skilled in difficult intubations. Because of the risk of intrapleural air leak, any patient requiring mechanical ventilation should have ventilation controlled by paralyzing agents. General guidelines for ventilating asthmatic patients include a tidal volume of approximately 10 mL/kg body weight, a relatively short inspiratory time, and as long an expiratory time as possible. Because the expired time constants of alveolar units are increased, air trapping is the major problem. When a ventilated asthma patient develops hypercarbia and is wheezing throughout the inspiratory phase, increasing expiratory time by decreasing the rate may result in a fall in the CO2, instead of the normally expected rise. Positive end expiratory pressure (PEEP) in general should not be used in ventilated asthmatic patients, but occasionally the use of PEEP will prevent early airway closure and improve ventilation.
Another technique occasionally used is controlled hypo ventilation. Because barotrauma may result from measures to normalize the CO2, the patient's CO2 is allowed to rise to the 50s and sodium bicarbonate is administeted to correct the acidosis. With this technique , extremes in ventilator parameters are avoided and barotrauma is minimized.
Aggressive medical therapy should be continued with the goal to wean the patient off the ventilator. Parenteral medications should be administered as before ventilation. Inhaled medications should be continued in-line in the ventilator circuit. Because less inhaled medication is delivered by this method, dosage and frequency may need to be increased.
Weaning the Patient from Therapy
Asthma therapy should be weaned in the reverse order that it was instituted. The first step is to wean the patient from mechanical ventilation. Medical therapy should remain the same. When the patient is off the ventilator, parenteral ß-agonists should be weaned as tolerated. After that, nebulized therapy is decreased slowly. It is essential to follow objective measures during decreasing therapy. Arterial blood gases are the best measure of improvement and readiness to wean from therapy. If the patient is greater than 5 to 6 years of age, pulmonary function tests (peak flow rate and FEV1) should be sequentially measured as soon as the patient has improved enough to perform these tests.
After a severe asthma attack, it may take several weeks for maximal improvement in pulmonary function tests. Because of this and also the increase in nonspecific bronchial hyperreactivity following a severe asthma attack, the patient should continue to receive corticosteroids for at least 2 weeks and intensive bronchodilator therapy for 1 month.
An acute asthmatic attack represents a treatment failure - a chronic asthma maintenance program is essential to prevent further hospitalizations.
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Aerosolized Drugs for the Treatment of Acute Severe Asthma In Children*
Systemic Drugs for the Treatment of Acute Severe Asthma In Children