Considering the role of NPPV, PEEP, and other interventions Managing acute severe asthma: What therapies to try, part 2 key words: Asthma, Leukotriene modifiers, Mechanical ventilation

Time is a major factor in the management of acute severe asthma. Because the patient's condition is not static, continuing clinical evaluations must be made while a number of different therapeutic interventions are administered.

In the February 2007 issue of The Journal of Respiratory Diseases, we discussed the initial assessment of the patient and the use of ß₂- agonists, anticholinergics, and corticosteroids. In this article, we focus on other therapies, such as aminophylline, leukotriene modifiers, and noninvasive positive pressure ventilation (NPPV).

Aminophylline

Although aminophylline and its derivatives have been used for the treatment of bronchospasm for at least 5 decades, over the past few years the role of these medications has become unclear. Three meta-analyses showed no clear benefit of the use of aminophylline compared with placebo in patients with acute asthma who were treated with ß₂-agonists.^1-3

Aminophylline and other methylxanthines have significant adverse effects and drug-drug interactions (for example, with ciprofloxacin). In our experience, the use of aminophylline is reserved for patients in whom other agents have failed.⁴

Leukotriene-modifying drugs

Leukotrienes are inflammatory mediators that induce pathophysiological responses similar to those associated with asthma.^5,6 Therefore, leukotriene receptor antagonists and inhibitors of leukotriene synthesis could potentially be used to manage asthma.^5-8 These agents have a complementary anti-inflammatory effect together with corticosteroids in patients with asthma.^5,6 Zileuton, zafirlukast, and montelukast have been approved for the treatment of chronic asthma in the United States.

In a multicenter, randomized, placebo-controlled trial in emergency settings, the addition of high-dose zafirlukast resulted in a 34% reduction in the need for hospitalization among patients with acute asthma.⁹ These data suggest that leukotriene-modifying drugs may have a role in the treatment of acute severe asthma; however, additional studies are required to determine the indications for and dosages of these drugs.

Antibiotics and hydration

Antibiotic therapy is not routinely indicated for patients with acute severe asthma unless pneumonia or other evidence of bacterial infection is present. Clinicians must be aware that in patients with asthma, the presence of purulent sputum may not indicate infection but may be due to eosinophils in respiratory secretions.^10-12

Contrary to common belief, patients who have acute severe asthma are not typically dehydrated, and intravenous fluids should be administered only if clinically indicated. Moreover, there is no evidence that intravenous fluids alter the consistency or viscosity of sputum in asthmatic persons or promote its clearance.¹³

Magnesium sulfate

Since the 1930s, magnesium sulfate has been used for the treatment of patients with asthma.¹⁴ In 1938, Haury¹⁵ demonstrated the bronchodilating effects of magnesium sulfate in guinea pig lungs. In addition to its bronchodilating effects, magnesium sulfate may also increase the responsiveness of the ß₂-receptor.¹⁶ Conflicting results have been reported when patients receive intensive ß₂-agonists and magnesium sulfate, ranging from no benefit at all to an immediate improvement in forced expiratory volume in 1 second (FEV₁) and forced vital capacity.^17-19

In a multicenter, randomized, controlled trial of intravenous magnesium sulfate in the treatment of acute severe asthma, Silverman and colleagues²⁰ concluded that the administration of 2 g of intravenous magnesium sulfate improved pulmonary function. Even though this agent did not decrease the total number of patients admitted to the hospital, it clearly improved pulmonary function in patients with acute severe asthma. Many clinicians use magnesium sulfate routinely for these patients.

Other medications

The following agents have been used in investigational and selective cases.

•Glucagon: It is well known that glucagon produces smooth muscle relaxation by stimulating cyclic adenosine monophosphate production. Wilson and Nelson²¹ demonstrated the ability to reverse bronchospasm with a mean peak expiratory flow rate (PEFR) increase of 113 L/min in 57% of 14 patients treated with 1 mg of intravenous glucagon within 10 minutes of its administration.

•Nitroglycerin: This agent may produce bronchodilatation in patients who are unresponsive to conventional therapy.²² Prostacyclin production in endothelial cells and stimulation of adenyl cyclase have resulted in bronchodilatation and have been postulated as possible mechanisms.

•Calcium channel blockers: Calcium has been shown to be an important trigger in the release of mast cell mediators in asthma. Calcium channel blockers prevent the entry of calcium into the cell via voltage-dependent channels and therefore may be of benefit. Although nifedipine does not modify the basal bronchial tone in patients with asthma, it does prevent exercise-induced asthma.²³ Verapamil used via inhalation in high doses (10 to 20 mg) can dilate the bronchi of asthmatic patients and healthy persons, but obtaining verapamil for inhalation may be difficult.²⁴

•Inhaled diuretics: Changes in bronchial osmolarity can induce bronchoconstriction in patients who have asthma. An experimental study has demonstrated that furosemide may be an effective bronchoprotective agent against a number of bronchoconstrictor stimuli.²⁵ This bronchoprotective effect may be of added benefit in the patient with acute asthma.

•Inhaled heparin: Since heparin is a nonspecific blocker of inositol triphosphate receptors, it has been postulated that heparin may block these receptors on mast cells, thus modulating degranulation and mediator release. Studies have shown that heparin may attenuate the bronchoconstrictor response to antigens as well as exercise-induced bronchoconstriction, although its use in acute exacerbations of asthma is unclear.²⁶

•Clonidine: This agonist of central and peripheral a₂-adrenergic receptors, when inhaled via a nebulizer, improves the basal respiratory function as well as reduces the inflammatory reactions induced by allergens in persons with extrinsic asthma. Unfortunately, the hypotensive effect of this medication tends to limit its use.²⁷

Noninvasive positive pressure ventilation

Inspiratory and expiratory indices of airway obstruction and considerable dynamic compliance (hyperinflation) are seen in patients with acute severe asthma. When the FEV₁ decreases to 50% of baseline, there is an associated 7- to 10-fold increase in inspiratory muscle work.²⁸ At this point, assisted ventilation is required.

In patients with obstructive lung disease who have acute respiratory failure, NPPV has been shown to be effective in reducing the work of breathing, improving oxygenation, and reducing the need for intubation.^29,30 In acute severe asthma, continuous positive airway pressure decreases the work of breathing, causes bronchodilatation, decreases airway resistance, reexpands atelectatic lung, promotes removal of secretions, relaxes the diaphragm and inspiratory muscles, decreases the adverse hemodynamic effects of large negative-peak and -mean inspiratory pleural pressures, and may offset intrinsic positive end-expiratory pressure (PEEP).^29-33 Meduri and coworkers³⁴ have shown that NPPV can be safely used in a patient with severe asthma and hypercapnia whose condition has not improved despite aggressive medical management.

NPPV should be tried before intubation in alert, cooperative patients who have not improved with aggressive medical therapy.³⁴ However, NPPV should not be attempted in patients who are rapidly deteriorating or in those who are somnolent or confused. Furthermore, NPPV should be avoided in patients who are hypotensive (systolic blood pressure less than 90 mm Hg), have myocardial ischemia or significant ventricular dysrhythmias, are unable to protect their airway, or have life-threatening hypoxemia (oxygen saturation less than 90% or PaO₂ less than 60 mm Hg on a rebreathing face mask).

Endotracheal intubation with assisted mechanical ventilation

The decision to intubate an asthmatic patient is difficult and should never be made lightly. The timing of intubation is essentially based on clinical judgment. Although hypercapnia (PaCO₂ greater than 40 mm Hg) is a worrisome finding in patients with acute asthma, after evaluation, most of these patients will not require intubation. A high PaCO₂ alone is not an indication for intubation if the patient is alert and cooperative. Mountain and Sahn³⁵ reported that only 5 of 61 patients with acute severe asthma and hypercapnia required intubation. Indications and goals for mechanical ventilation in patients who have acute severe asthma are listed in Table 1.^36-39

Mechanical ventilation of patients with acute asthma is difficult because severe airflow obstruction results in a prolonged expiratory time with incomplete exhalation even at low ventilator rates.⁴⁰ This, in turn, results in progressive dynamic hyperinflation and the development of auto-PEEP.^38,41-43 Therefore, these patients must be ventilated with low tidal volumes with a reduced respiratory rate.⁴⁴

Some authors suggest the use of PEEP (extrinsic PEEP) in patients with acute severe asthma.³² PEEP has been demonstrated to reduce the work of breathing and dyspnea in patients with obstructive lung disease.⁴⁵ We recommend the measurement of intrinsic PEEP and the exhaled tidal volume to avoid significant air trapping and to determine which patients may benefit from PEEP. A low inspiration- expiration ratio (long expiration) should always be used.

Permissive hypoventilation (permissive hypercapnia) should be used in patients who have severe airway obstruction that persists after intubation; however, the arterial pH should be kept above 7.2.^{36,39,41,46,47} Sodium bicarbonate should be avoided because it may increase intracellular carbon dioxide and acidosis caused by the fixed carbon dioxide elimination.

General anesthetics

Various general anesthetic agents, both inhalational and intravenous, have been used in the management of refractory asthma.

Several inhalational anesthetic agents have intrinsic bronchodilator properties.⁴⁸ Of these agents, isoflurane is most suitable for asthma because of its bronchodilator effects and minimal arrhythmogenic potential. One study showed a decrease in auto-PEEP and airway resistance with isoflurane.⁴⁸

Ketamine, a dissociative intravenous anesthetic, has bronchodilator effects believed to be caused by endogenous catecholamine release. In one study, ketamine improved stethoscope examination findings but not spirometric lung mechanics.⁴⁹

Other anesthetic agents that have been tried successfully include ether, droperidol, and enflurane. Data for most of these agents are only anecdotal.

Helium

Studies have indicated that the inclusion of helium, a low-density gas, in inhaled gas mixtures lowers airway resistance and decreases the work of breathing. Inhalation of helium-oxygen mixtures (heliox) may be associated with temporary improvement in patients who have airway obstruction caused by asthma; chronic obstructive pulmonary disease; bronchiectasis; pulmonary fibrosis; and obstructive lesions of the trachea, larynx, and bronchi. The lower density of heliox decreases frictional resistance to turbulent gas flow.

Shiue and Gluck⁵⁰ reported that within 20 minutes of administration of helium-oxygen mixtures to intubated patients, a significant reduction was noted in peak airway pressures as well as in PaCO₂. Heliox delivery to intubated patients requires considerable expertise. To maximize benefit, the fraction of inspired oxygen should be kept as low as possible to achieve oxygen saturation greater than 90%.

In clinical practice, heliox is a blend of helium and oxygen (80:20, 70:30, or 60:40), with a gas density approximately one third that of air. The use of heliox in acute severe asthma has been the subject of considerable debate. However, the administration of helium-oxygen mixtures to patients who present to the emergency department (ED) with moderate to severe acute asthma exacerbations is not supported by existing evidence.^51-54

Extracorporeal membrane oxygenation

Although extracorporeal membrane oxygenation has been used in patients with acute severe refractory asthma, it should not be needed, since oxygenation is rarely a problem and even severe respiratory acidosis is usually well tolerated in these patients.⁵⁵

Bronchoscopy

The use of bronchoscopy in acute severe asthma is controversial. Although data are anecdotal, bronchoscopy has been used to remove mucous plugs in mechanically ventilated patients with severe asthma. Bronchoscopy may be considered if the patient's condition does not improve after several days of mechanical ventilation, especially if atelectasis is noted on the chest radiograph.⁵⁶

Indications for ICU admission

Patients with acute severe asthma who have trouble talking because of breathlessness, altered mental status, an FEV₁ or PEFR less than 25% of predicted, or a PaCO₂ greater than 40 mm Hg after aggressive treatment in the ED should be admitted to an ICU (Table 2).^57-59

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