AARC Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients

Assessment of Evidence

This guideline focused on the effectiveness, harmful effects, and cost associated with the use of aerosolized medications for airway clearance therapy in hospitalized adult and pediatric patients without cystic fibrosis (CF); adult and pediatric patients with neuromuscular disease (NMD), respiratory muscle weakness, or impaired cough; and postoperative adult and pediatric patients. We sought to determine whether the use of these medications changes sputum properties, improves oxygenation, decreases ventilator time, decreases ICU stay, decreases readmissions or emergency department visits, improves pulmonary function, improves quality of life, or decreases infection frequency compared with usual care. We also sought to determine what harmful effects and complications might accompany the use of these drugs. The medications considered are listed in Table 1. Similar to what was described in the nonpharmacologic airway clearance therapy clinical practice guideline,⁶ no high-level evidence was available. Because the recommendations are based on low-level evidence, we did not use a formal guideline development process. Rather, the recommendations are based on a consensus of the committee, informed by a systematic review of the literature⁵ and clinical experience. The systematic review helped frame the issues and allowed the identification of potential harmful effects.

Hospitalized Adult and Pediatric Patients Without Cystic Fibrosis

Trauma, inhalation injury, viral infections, asthma, bronchitis, and COPD can result in airway inflammation, mucus secretion, edema, and airway epithelium damage, which contribute to air-flow obstruction, air trapping, atelectasis, and ventilation/perfusion mismatch.^8–11 Hypoxemia and increased work of breathing can contribute to respiratory insufficiency and failure, and intubation with mechanical ventilation can further compromise mucus clearance. Table 1 lists several medications often used to improve secretion clearance. These inhaled medications include bronchodilators, mucolytics to thin secretions, mucoregulators to reduce inflammation and mucus secretion, and expectorants to aid in cough clearance.¹²

In this systemic review, we found that the evidence from randomized controlled trials (RCTs) was weak and insufficient to support the use of medications to improve airway clearance, improve oxygenation, reduce ventilator time, reduce hospital stay, change sputum properties, improve quality of life, or improve respiratory mechanics compared with usual care.⁵ A retrospective cohort study in pediatric subjects evaluated the use of both heparin and N-acetylcysteine in mechanically ventilated burn subjects. The results from this single-center study suggest that 5,000 units of aerosolized heparin alternating with 3 mL of 20% N-acetylcysteine every 2 h for the first 7 d of injury lessen the need for re-intubation, ventilator time, and mortality in pediatric burn subjects.¹³ An RCT of 20 male subjects with chronic bronchitis or asthmatic bronchitis comparing aerosolized N-acetylcysteine and isoproterenol reported decreased sputum viscosity (subjectively assessed), but no significant change in pulmonary function or daily sputum volume.¹⁴ The lack of high-level evidence from the studies included in this review does not support a recommendation for these therapies.

Guidelines from other groups support the use of medications such as inhaled short- and long-acting bronchodilators and inhaled corticosteroids for symptom relief in patients with symptomatic chronic obstructive pulmonary disorders. However, with respect to mucolytics and airway clearance, dornase alfa is not recommended for patients with non-CF bronchiectasis.^15,16 Trials with clinically important outcome measures are needed to establish the evidence for mucoactive medications outside of CF.¹⁷

Adult and Pediatric Patients With Neuromuscular Disease, Respiratory Muscle Weakness, or Impaired Cough

Respiratory complications are the leading cause of morbidity and mortality in patients with NMD and respiratory muscle weakness.^18,19 Secretion retention is common in these patients and is primarily due to an inability to generate an effective cough. Cough is composed of 3 phases: inspiration, compression through glottic closure and contraction of abdominal and thoracic muscles, and forced exhalation.²⁰ The interaction of these elements provides for a functional cough and expectoration of secretions. Inspiratory and abdominal muscle paralysis or weakness can inhibit the development of sufficient lung volumes and expiratory flow, respectively.²¹ Patients with NMD or stroke may also be unable to close the glottis to obtain adequate intrathoracic pressures, or breath stack for sufficient inspiratory volumes.

Compromised cough is common in many primary neurologic conditions and spinal cord injuries, but patients with spinal cord injuries may also suffer from mucus hypersecretion and an increase in bronchial tone. In cervical spinal cord injuries, parasympathetic overstimulation resulting from sympathetic denervation to the lungs leads to both an abnormal quantity and quality of mucus in the initial stages following injury.²²

Although mucus clearance is preserved in NMD,²³ patients with chronic respiratory infections from aspiration or retained secretions may develop a cycle of infection and inflammation that can impair ciliary function, cause airway remodeling,²⁴ and alter the physical properties of secretions.^12,25

Infants and children have chest-wall instability, lower functional residual capacity, and smaller airway diameter, which provide additional challenges for clearing airway secretions even in the absence of diseases that impair cough reflexes.²⁶ The presence of NMD or motor neuron disease increases the propensity for pulmonary complications, morbidity, and mortality in this population.

No RCTs or other studies were found, of any quality, on the use of inhaled medications to enhance airway clearance in these patients. Although some organizations have recommended nonpharmacologic airway clearance therapies,^27–29 only 2 guidelines recommend the use of inhaled medication for this purpose.^29,30 Clinical practice guidelines from the Consortium for Spinal Cord Medicine recommend the use of mucolytics for secretion management when other modalities are insufficient.²⁹ These guidelines also suggest isotonic saline for thick or dehydrated secretions, with no literature support or level of evidence provided for either recommendation. The British Thoracic Society recommends nebulized normal saline for children with NMD and tenacious secretions, although this was not based on any reported evidence.³⁰ Included with this recommendation is the administration of a pre-dose bronchodilator to minimize bronchospasm and an initial trial to determine patient safety. However, the American College of Chest Physicians' practice guidelines on pharmacologic protussive therapy specifically state, based on a good level of evidence, that these medications should not be prescribed to promote airway clearance in patients with NMD or impairment.³¹

Postoperative Adult and Pediatric Patients

Patients undergoing surgery are at risk for postoperative pulmonary complications, including atelectasis, pneumonia, pneumothorax, pleural effusion, pulmonary emboli, ARDS, empyema, exacerbation of existing lung disease, and respiratory failure.^32,33 These postoperative complications contribute to the risk of surgery, especially cardiothoracic and abdominal-wall surgery.³³ The incidence is higher for patients undergoing thoracic surgery (19–59%) than for those undergoing upper (16–20%) or lower (0–5%) abdominal surgery.³⁴ Atelectasis, including subclinical atelectasis, has been reported to occur in up to 90% of all anesthetized subjects.³⁵ It can persist for several days following surgery and, in addition to causing hypoxemia, can lead to retained secretions and pneumonia. Atelectasis can also aggravate or trigger the development of acute lung injury.^35,36 Retained secretions can plug airways, leading to distal gas absorption and alveolar collapse, and are one of the causes of atelectasis in the postoperative period.^37,38 Retained secretions are a primary reason given for ordering mucoactive medications.

In this systematic review, we found only 2 low-quality reports in the postoperative population; both involved the use of N-acetylcysteine.^39,40 The primary outcome of interest in each study was the incidence of atelectasis. A Danish RCT compared a course of preoperative oral N-acetylcysteine and postoperative intravenous N-acetylcysteine versus a similar strategy using a saline placebo in subjects undergoing elective upper laparotomy.³⁹ The authors found no difference in pulmonary function or incidence of atelectasis. The second report described 2 studies involving subjects undergoing abdominal surgery.⁴⁰ In the first study, subjects received either intratracheal N-acetylcysteine every 2 h or a saline placebo. The incidence of atelectasis was 45% (9/20) in the placebo group versus 10% (2/20) in the study group. The second study compared intratracheal versus nebulized N-acetylcysteine via an intermittent positive-pressure breathing device. The incidence of atelectasis was 20% (4/20) in both groups.

Two noncomparative studies of N-acetylcysteine in postoperative thoracic surgery subjects were not included in this systematic review, as they did not meet entry criteria.^37,41 One found no difference in the incidence of massive postoperative atelectasis in the nebulized N-acetylcysteine-treated group compared with the untreated group.³⁷ The other study found that the subjective impression of sputum viscosity and difficulty of expectoration decreased and the weight of expectorated sputum and S_pO2 improved in the nebulized N-acetylcysteine-treated group versus the saline-treated group during crossover.⁴¹

Physical and Financial Harmful Effects

The lack of evidence to support the benefit of any of the aerosolized medications listed in Table 1 does not imply that their use is benign. Adverse effects from administration of the drug or drug interactions contribute to morbidity and mortality. In addition, administering drugs that have little or no benefit to the patient contribute to the financial burden by increasing health-care costs.

Many of the studies included in the systematic review conducted by Sathe et al⁵ either were poor quality for reporting harm as an outcome variable or did not address adverse reactions associated with the interventional agent. Manufacturer package inserts are helpful and address the common side effects and adverse reactions. Health-care providers should be aware of these interactions with respect to the medications and assess patients for the opportunity to discontinue therapy.

Nausea, vomiting, stomatitis, fever, rhinorrhea, drowsiness, chest tightness, bronchial irritation, and, less frequently, bronchospasm in patients with known asthma are adverse effects associated with the administration of nebulized N-acetylcysteine.^4,42 Bleeding at the injection site was reported as an adverse outcome in a clinical trial comparing N-acetylcysteine administered via intratracheal instillation with nebulized N-acetylcysteine delivered via an intermittent positive-pressure breathing device in postoperative subjects.⁴⁰ This event was attributed to the invasive administration technique rather than the medication.

Adverse reactions to albuterol and ipratropium reported in the literature and by manufacturers are similar. Table 2 provides the adverse effects reported by the manufacturers on the package inserts. Less common adverse effects that have been reported in association with ipratropium bromide use include tachycardia, palpitations, eye pain, urinary tract infections, and urinary retention. Because ipratropium bromide is an anticholinergic drug, it is not recommended for patients with narrow-angle glaucoma, prostate hypertrophy, or bladder-neck obstruction.⁴³ Although the incidence is not reported, the manufacturer lists adverse reactions such as urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, atrial fibrillation, supraventricular tachycardia, and extrasystole after use of albuterol inhalation solution. Repeated dosing of this medication has been associated with decreases in serum potassium.⁴⁴

Although hypertonic saline is recommended for patients with CF, there are no studies demonstrating effectiveness in other hospitalized patient populations. Research indicates that a single treatment with hypertonic saline (most studies used 3%) can induce bronchospasm; significantly decrease FEV₁ (> 20%) and S_pO2; and increase vascular permeability, neutrophil adhesion, and gland secretion (neurogenic inflammation) in normal lung tissue and with pulmonary disease.^45–48 These effects can occur despite pretreatment with β agonists.^46–52 The safety of giving even one treatment of hypertonic saline depends on pretreatment with β agonists, baseline pulmonary function, previous overuse of short-acting β₂ agonists, nebulizer output, saline concentration, and treatment duration and frequency.^47,48 Administration of bronchodilators before mucolytic administration is time-consuming, and research is lacking to establish safety, stability, and efficacy of admixtures using both agents.⁵³

Evidence suggests that there are opportunities to constrain health-care costs without incurring adverse health consequences.⁵⁴ The use of care paths, guidelines, and/or protocols provides caregivers with the opportunity to reduce unnecessary resource use and improve the value of care provided to patients by matching the therapy to patient need. When guidelines, protocols, or care paths are used, these tools establish recommendations for the initiation, titration, evaluation, and discontinuation of medications. In an assessment of the impact of the national guidelines for the treatment of hospitalized patients with bronchiolitis, McCulloh et al⁵⁵ reported outcomes after the national guidelines for bronchiolitis were implemented at 2 academic medical centers. Fewer children received a trial of racemic epinephrine (17.8% vs 12.2%, P = .006) or albuterol sulfate (81.6% vs 72.6%, P < .001), and albuterol sulfate was discontinued more often after guidelines were instated (28.6% vs 78.9%, P < .001). Corticosteroid use in children without a history of asthma decreased with guideline use (26.5% vs 17.5%, P < .001).⁵⁵ The use of such tools improves the cost effectiveness and care coordination by targeting therapeutic interventions to the patients who would benefit the most.

Implications and Directions for Future Research

In theory, using medications to improve airway clearance should be an acceptable practice. However, the evidence supporting current practice is exceptionally limited.⁵ β agonists can increase ciliary beat frequency in healthy subjects, but the impact on mucus clearance in subjects with pulmonary disease is not significant.^56,57 As mucoregulatory agents, anticholinergic medications may reduce mucus secretion, but the evidence demonstrates no improvement in mucus clearance in patients with or without pulmonary disease.¹³ Some mucoactive medications improve mucus clearance when used in patients with CF, but the evidence does not support the use of these medications for patients with non-CF pulmonary disease.^58–61 Novel therapies to improve mucus clearance in unique situations, such as burns and inhalation injuries, have shown promise, but the amount of evidence is small, and more investigation is necessary before making definitive recommendations.⁷

The lack of high-level evidence has a significant impact on the respiratory therapist's ability to recommend for or against using inhaled medications to improve mucus clearance. Clinical decision making should be based on individual patient need, response to therapy, and potential for harm. Future research should be designed carefully with regard to subject population, outcome measures, and intervention.^62,63