1. Small Volume Nebulizer

   The use of a small volume nebulizer and related compressor is considered medically necessary durable medical equipment (DME) for any of the following indications:

   1. To administer antibiotics (gentamicin, amikacin, or tobramycin,***) to members with cystic fibrosis or bronchiectasis
   2. To administer beta-adrenergics (albuterol, isoproterenol, isoetharine, levalbuteral, metaproterenol), anticholinergics (ipratropium), corticosteroids (budesonide), and cromolyn for the management of obstructive pulmonary diseases (chronic bronchitis, emphysema, asthma, etc.);* or
   3. To administer dornase alfa (Pulmozyme)** to members with cystic fibrosis or primary ciliary dyskinesia (Note: the use of Pulmozyme for other non-cystic fibrosis indications (e.g., asthma, chronic bronchitis, Niemann-Pick type C, and post-lung transplantation [not an all inclusive list]) is considered experimental and investigational); or 
   4. To administer formoterol (Perforomist) or arformoterol (Brovana) for the management of chronic obstructive pulmonary disease when medical necessity criteria in Pharmacy Clinical Policy Bulletin on "Long-Acting Beta Agonists" are met; or
   5. To administer iloprost (Ventavis) via a controlled dose inhalation drug delivery system (i.e., the I-neb or the Prodose nebulizer) to members with pulmonary hypertension; or 
   6. To administer mucolytics (other than dornase alpha) (acetylcysteine) for persistent thick or tenacious pulmonary secretions; or
   7. To administer pentamidine to members with HIV, pneumocystosis, or complications of organ transplants.

   8. To administer aztreonam inhalation solution (Cayston) to persons with cystic fibrosis with Pseudomonas aeruginosa.†

   Small volume nebulizers and related compressors are considered experimental and investigational for all other indications because their effectiveness for indications other than the ones listed above has not been established.

   * For criterion (a) to be met, the physician must have considered use of a metered dose inhaler (MDI) with and without a reservoir or spacer device and decided that, for medical reasons, it was not sufficient for the administration of needed inhalation drugs.

   ** More than 1 nebulizer may be considered medically necessary for members who are prescribed nebulized dornase alpha (Pulmozyme) plus other nebulized medications.  The Food and Drug Administration (FDA)-approved product labeling of dornase alpha instructs that it should not be diluted or mixed with other drugs in the nebulizer.  The labeling explains that mixing of dornase alpha with other drugs could lead to adverse physicochemical and/or functional changes in dornase alpha or the admixed compound.

   *** Note on the Pari-C Plus Vented Jet Nebulizer: Aetna considers the Pari-C Plus breath-enhanced or vented jet nebulizer medically necessary for pulmonary administration of aerosolized tobramycin because there is some evidence from direct comparative studies with standard unvented jet nebulizers to suggest that the Pari-C Plus vented jet nebulizer is necessary to deliver adequate concentrations of tobramycin to the lung (e.g., Coates et al, 1998; Campbell and Saiman, 1999; Weber et al, 1994; Eisenberg et al, 1997; Ramsey et al, 1999).  Consensus guidelines from the Cystic Fibrosis Foundation recommend use of the Pari-C Plus Jet Nebulizer for delivery of tobramycin to individuals with cystic fibrosis (Campbell and Saiman, 1999).  Aetna does not consider the Pari-LC Jet Plus brand of nebulizer medically necessary for nebulization of budesonide inhalation suspension (Pulmicort Respules).  The Pari-LC Jet Plus Nebulizer was used in controlled clinical trials of nebulized budesonide for FDA approval.  However, subsequent studies have demonstrated that brands of jet nebulizers other than Pari-LC Jet Plus are also capable of delivering a clinically effective dose of inhaled budesonide (Szefler, 1999).  By contrast, ultrasonic nebulizers have been found in clinical studies to be inefficient at delivering inhaled budesonide and are not recommended for this indication (Nikander, 1994; Nikander, 1999). 

   † Note on the Altera Nebulizer System: Aetna considers the Altera Nebulizer System medically necessary only to administer aztreonam inhalation solution (Cayston) to persons with cystic fibrosis with Pseudomonas aeruginosa.  The FDA-approved labeling for Cayston states that it should only be administered with the Altera Nebulizer System.

2. Large Volume Nebulizer:

   A large volume nebulizer, related compressor, and water or saline are considered medically necessary DME to deliver humidity to a person with thick, tenacious secretions, with any of the following indications:

   1. Administration of pentamidine for members with HIV, pneumocystosis, and complications of organ transplants;
   2. Bronchiectasis;
   3. Cystic fibrosis;
   4. Tracheobronchial stent;

   5. Tracheostomy.

   A large volume nebulizer and related compressor is considered experimental and investigational for all other indications because their effectiveness for indications other than the ones listed above has not been established.

3. Ultrasonic Nebulizers:
   

   The use of ultrasonic nebulizers is considered medically necessary DME for delivery of tobramycin (Tobi) for members with cystic fibrosis who meet the criteria for a standard nebulizer.

   Because there is no proven medical benefit to nebulizing particles of other drugs to diameters smaller than achievable with a pneumatic model, ultrasonic nebulizers are considered medically necessary only when all of the following criteria are met:

   1. The member meets the criteria for a standard nebulizer; and
   2. The primary care physician and specialist indicate that the member has been compliant with other nebulizer and medication therapy; and

   3. The use of a standard nebulizer has failed to control the member's disease and prevent the member from utilizing the hospital or emergency room.

   Ultrasonic nebulizers are considered experimental and investigational for all other indications because their effectiveness for indications other than the ones listed above has not been established.

4. Battery Powered Compressors:

   A battery-powered compressor is rarely medically necessary.  Accompanying documentation must be submitted justifying its medical necessity.

5. Accessories:

   1. Disposable large volume nebulizers are considered convenience items.  A non-disposable unfilled nebulizer filled with water or saline by the member/caregiver is an acceptable alternative.

   2. Note: Kits and concentrates for use in cleaning respiratory equipment are not covered.  This is consistent with Medicare's policy.

6. Replacement:

   For members with DME benefits, replacement of nebulizers is considered medically necessary on an individual basis if both of the following criteria are met:

   1. The primary care physician and/or specialist confirm that the member has been compliant with the nebulizer and anticipate the need for continued use to prevent a hospital admission or emergency room visits; and

   2. The warranty has expired.

   The following table lists the usual maximum frequency of replacement for accessories that is considered medically necessary.

   1. Administration set, small volume filtered pneumatic nebulizer: 1/month
   2. Administration set, small volume non-filtered pneumatic nebulizer, disposable: 2/month 
   3. Administration set, small volume non-filtered pneumatic nebulizer, non-disposable: 1 per 6 months
   4. Aerosol mask, used with DME nebulizer: 1/month
   5. Corrugated tubing, disposable, used with large volume nebulizer: 100 feet/2 months
   6. Corrugated tubing, non-disposable, used with large volume nebulizer: 10 feet/year
   7. Dome and mouthpiece, used with small volume ultrasonic nebulizer: 2/year
   8. Face tent: 1/month
   9. Filter, disposable, used with aerosol compressor: 2/month
   10. Filter, non-disposable, used with aerosol compressor or ultrasonic generator: 1 per 3 months
   11. Immersion external heater for nebulizer: 1 per 3 years
   12. Nebulizer, durable glass or autoclavable plastic, bottle type, not used with oxygen: 1 per 3 years
   13. Small volume non-filtered pneumatic nebulizer, disposable: 2/month
   14. Tracheostomy mask or collar: 1/month

   15. Water collection device, used with large volume nebulizer: 2/month.

7. Nebulized Opioids

   The use of nebulized morphine or other opioids is considered experimental and investigational for the relief of cancer-related dyspnea, or dyspnea in persons with chronic obstructive pulmonary diseases because the effectiveness of this approach has not been established.

8. Nebulized Corticosteroids for the Treatment of Nasal Polyps

   The use of nebulized corticosteroids for the treatment of nasal polyps, including in the pre- and post-polypectomy periods, is considered experimental and investigational because of insufficient evidence of the clinical value of nebulized corticosteroids over established forms of nasal corticosteroid administration (e.g., nasal spray, metered-dose nasal inhaler).

9. Nebulized Lidocaine as Pain Relief for Nasogastric Tube Insertion in Children

The use of nebulized lidocaine as pain relief for nasogastric tube insertion in children is considered experimental and investigational the effectiveness of this approach has not been established.

See also CPB 0593 - Aerosolized or Irrigated Anti-infectives for Sinusitis.

In this policy, the actual equipment (i.e., electrical devices) are referred to as either a compressor (when nebulization of liquid is achieved by means of air flow) or as a generator (when nebulization of liquid is achieved by means of ultrasonic vibrations).  The term nebulizer is generally used for the actual chamber in which the nebulization of liquid occurs and is an accessory to the equipment.  The nebulizer is attached to an aerosol compressor or an ultrasonic generator in order to achieve a functioning delivery system for aerosol therapy.

The plan of care must contain the specific condition of the patient justifying the medical necessity of each item.  The order for any drug must clearly specify the type of solution to be dispensed to the patient and the administration instructions for that solution.  The type of solution is described by a combination of (i) the name of the drug and the concentration of the drug in the dispensed solution and the volume of solution in each container, or (ii) the name of the drug and the number of milligrams/grams of drug in the dispensed solution and the volume of solution in that container.

A narrative diagnosis and/or an ICD-9 diagnosis code describing the condition must be present on each order.  An ICD-9 code describing the condition that necessitates nebulizer therapy must be included on each claim for equipment, accessories, and/or drugs.  The patient's medical record must contain information that supports the medical necessity for all equipment, accessories, drugs and other supplies that are ordered.

Chronic infection with Pseudomonas aeruginosa is associated with progressive deterioration in lung function in cystic fibrosis (CF) patients.  Nebulized antibiotics/anti-infectives (e.g., colistin and tobramycin) have been used in the management of these patients.

In a prospective double-blind placebo-controlled study, Jensen et al (1987) assessed the effects of colistin inhalation in 40 patients with CF and chronic broncho-pulmonary P. aeruginosa infection.  Active treatment consisted of inhalation of colistin 1 million units twice-daily for 3 months and was compared to placebo inhalations of isotonic saline.  Significantly more patients in the colistin inhalation group completed the study as compared to the placebo group (18 versus 11).  Colistin treatment was superior to placebo treatment in terms of a significantly better clinical symptom score, maintenance of pulmonary function and inflammatory parameters.  The authors recommended colistin inhalation therapy for CF patients with chronic P. aeruginosa lung infection as a supplementary treatment to frequent courses of intravenous anti-pseudomonas chemotherapy.

Pai and Nahata (2001) noted that aerosolized tobramycin doses ranging from 80 mg 2 or 3 times daily to 600 mg 3 times daily have been used in various clinical trials.  At an 80-mg dose, preservation of pulmonary function with little or no improvement over the baseline was reported.  Tobramycin, nebulized at 600 mg 3 times daily, significantly improved clinical and pulmonary functions and reduced the density of P. aeruginosa in the sputum.  No ototoxicity or nephrotoxicity was reported at either dose.  An increased risk of emergence of resistant strains of P. aeruginosa was noted at all doses, after prolonged use.

Tobramycin solution for inhalation (TOBI) received U.S. Food and Drug Administration approval for the maintenance therapy of patients 6 years or older with CF who have between 25 % and 75 % of predicted forced expiratory volume in 1 second (FEV(1)), are colonized with P. aeruginosa, and are able to comply with the prescribed medical regimen.  TOBI was not approved for the therapy of acute pulmonary exacerbations in patients with CF, nor was it approved for use in patients without CF (Prober et al, 2000).

In a randomized clinical trial, Hodson et al (2002) evaluated the safety and effectiveness of tobramycin nebulizer solution (TNS) and nebulized colistin in CF patients chronically infected with P. aeruginosa.  A total of 115 patients, aged 6 yrs or older, were randomized to receive either TNS or colistin, twice-daily for 4 weeks.  The primary end point was an evaluation of the relative change in lung function from baseline, as measured by FEV(1) % predicted.  Secondary end points included changes in sputum P. aeruginosa density, tobramycin/colistin minimum inhibitory concentrations and safety assessments.  TNS produced a mean 6.7 % improvement in lung function (p = 0.006), while there was no significant improvement in the colistin-treated patients (mean change 0.37 %).  Both nebulized antibiotic regimens produced a significant decrease in the sputum P. aeruginosa density, and there was no development of highly resistant strains over the course of the study.  The safety profile for both nebulized antibiotics was good.  Tobramycin nebulizer solution significantly improved lung function of patients with CF chronically infected with P. aeruginosa, but colistin did not, in this study of 1-month's duration.  Both treatments reduced the bacterial load.

In a review on the role of nebulized antibiotics for the treatment of respiratory infections, Klepser (2004) stated that data regarding this topic are scarce.  At this time, data support the use of aerosolized tobramycin solution for inhalation in CF patients infected or colonized by P. aeruginosa.  Apart from this situation, widespread aerosolized administration of other agents in CF and non-CF patient populations should not be advocated.

There is a lack of adequate evidence supporting the use of nebulized opoids for dyspnea.  Foral et al (2004) performed a structured review of the evidence for the use of nebulized morphine for the relief of dyspnea in persons with chronic obstructive pulmonary disease.  The investigators concluded that there is inadequate evidence from placebo-controlled studies to support the use of nebulized morphine for the relief of dyspnea in patients with chronic obstructive pulmonary disease (COPD).  These investigators reported that published studies vary considerably in the dose, opioid used, administration schedule, and methodology.  One study found improved exercise capacity in 11 patients not reproducible in a larger sample, and another study found benefit in 54 terminal patients.  All other studies found no benefit.  These investigators noted, furthermore, that recently published Global Initiative for Lung Disease guidelines have specifically stated that opioids are contraindicated in COPD management due to the potential respiratory depression and worsening hypercapnia.  The authors concluded that nebulized opioids should be discouraged in COPD, as current data do not support their use.

In a systematic review, Viola et al (2008) assessed the effectiveness of 4 drug classes (opioids, phenothiazines, benzodiazepines, and systemic corticosteroids) for relieving dyspnea experienced by advanced cancer patients.  Search sources included Medline, Embase, HealthSTAR, CINAHL, and the Cochrane Library.  Four reviewers selected evidence using pre-defined criteria: controlled trials not limited to cancer and involving the specified drug classes for dyspnea treatment.  Three systematic reviews, 1 with meta-analysis, 2 practice guidelines, and 28 controlled trials were identified.  Most examined the effect of opioids, generally morphine, on dyspnea.  Although the results of individual trials were mixed, the systematic review with meta-analysis detected a significant benefit for dyspnea with systemic opioids; 2 small placebo-controlled trials in cancer patients found systemic morphine reduced dyspnea, and dihydrocodeine also significantly reduced dyspnea in 4 placebo-controlled trials.  Nebulized morphine was not effective in controlling dyspnea in any study or the meta-analysis.  No controlled trials examined systemic corticosteroids in the treatment of cancer patients, and of the other non-opioid drugs examined, only oral promethazine, a phenothiazine, showed some benefit in the relief of dyspnea.  Studies varied in methodological quality.  The authors concluded that systemic opioids, administered orally or parenterally, can be used to manage dyspnea in cancer patients.  Oral promethazine may also be used, as a 2nd-line agent if systemic opioids can not be used or in addition to systemic opioids.  Nebulized morphine, prochlorperazine, and benzodiazepines are not recommended for the treatment of dyspnea, and promethazine must not be used parenterally.

There is insufficient evidence of the clinical value of nebulized corticosteroids for the treatment of nasal polyps, including in the pre- and post- polypectomy periods, over established forms of nasal corticosteroid administration (e.g., nasal spray, metered-dose nasal inhaler).  Bikhazi (2004) stated that "no clinical studies have yet documented nebulized nasal steroid benefit".

There is inadequate evidence to support the use of nebulizers over spacers for delivery of beta-agonists in acute asthma.  In a Cochrane review that compared holding chambers (spacers) versus nebulizers for beta-agonist treatment of acute asthma (Cates et al, 2006a), it was found that MDIs with spacer produced outcomes that were at least equivalent to nebulizer delivery.  Spacers may have some advantages compared to nebulizers for children with acute asthma.

Evidence is limited to support the use of nebulizers over spacers for delivering inhaled corticosteroids in chronic asthma.  In a Cochrane review that compared holding chambers versus nebulizers for inhaled steroids in chronic asthma (Cates et al, 2006b), it was concluded that budesonide in high dose delivered by the particular nebulizer used in the only double-blinded study that could be included in this review was more effective than budesonide 1,600 ug via a large volume spacer.  However, it is unclear if this was an effect of nominal dose delivered or delivery system.  Cost, compliance and patient preference are important determinants of clinical effectiveness that still require further assessment.  Future studies are needed to ascertain the relative effectiveness of inhaled corticosteroids delivered by different combinations of nebulizer/compressor compared to holding chamber.  Moreover, further studies evaluating these delivery methods are needed in infants and pre-school children, as these are groups that are likely to be considered for treatment with nebulized corticosteroids.

Nasogastric tube (NGT) insertion is a common procedure in children that is very painful and distressing.  There is insufficient evidence to support the use of nebulized lidocaine for NGT insertion.  In a randomized, double-blind, placebo-controlled trial, Babl et al (2009) examined if nebulized lidocaine reduce the pain and distress of NGT insertion in young children.  Patients were eligible if they were aged from 1 to 5 yrs with no co-morbid disease and a clinical indication for a NGT.  Nebulization occurred for 5 mins, 5 mins before NGT insertion.  Video recordings before, during, and after the procedure were rated using the Face, Legs, Activity, Cry, and Consolability (FLACC) pain and distress assessment tool (primary outcome measure) and pain and distress visual analog scale scores (secondary outcome measures).  Difficulty of insertion and adverse events were also assessed.  A total of 18 subjects were nebulized with 2 % lidocaine and 18 subjects with normal saline.  Nebulization was found to be highly distressing; FLACC scores during NGT insertion were very high in both groups.  There was a trend in the post-NGT insertion period toward lower FLACC scores in the lidocaine group.  Visual analog scale scores for this post-insertion period were significantly lower in the lidocaine arm for pain and distress.  There were no significant differences between groups in terms of difficulty of insertion and the number of minor adverse events.  The study was terminated early because of the distress and treatment delay associated with nebulization.  The authors concluded that NGT insertion results in very high FLACC scores irrespective of lidocaine use.  They stated that nebulized lidocaine can not be recommended as pain relief for NGT insertion in children.  The delay and distress of nebulization likely outweigh a possible benefit in the post-insertion period.

Kuo et al (2010) performed a systematic review of current knowledge concerning the use of nebulized lidocaine to reduce the pain of NGT insertion in order to develop evidence-based guidelines.  In addition, a meta-analysis of appropriate randomized controlled trials (RCTs) was performed.  The databases included PubMed (1996 to 2009), ProQuest (1982 to 2009), CINAHL (1982 to 2009), and the Cochrane Central Register of Controlled Trials (2009), and reference lists of articles.  Experts in this field also were contacted.  Two investigators selected the research based on inclusion criteria and reviewed each study's quality according to the Jadad scale.  Five RCTs with 212 subjects were identified.  A total of 113 (58 %) subjects were women.  The mean age of treatment and control groups was 59.6 and 55 years, respectively.  The countries of studies were the United States, United Kingdom, Australia, Canada, and Thailand.  In the treatment groups, the use of lidocaine concentration was 4 % and 10 %.  The pooled effect size was 0.423 (95 % confidence interval: 0.204 to 0.880; Z = -2.301; p = 0.021), indicating that the use of nebulized lidocaine before NGT insertion can decrease pain by 57.7 %.  The authors concluded that there is insufficient evidence to recommend the dosage, concentration, or delivery method.  They stated that further research is needed to articulate a comprehensive clinical guideline.

Cayston (aztreonam for inhalation solution) has been approved by the FDA to improve respiratory symptoms in cystic fibrosis patients with Pseudomonas aeruginosa.  The FDA approval of Cayston was based on a randomized, double-blind, placebo-controlled, multi-center trial in 164 subjects.  Subjects received either Cayston (75 mg) or volume-matched placebo administered by inhalation 3 times a day for 28 days.  Patients were required to have been off antibiotics for at least 28 days before treatment with study drug.  The primary efficacy endpoint was improvement in respiratory symptoms on the last day of treatment with Cayston or placebo.  Statistically significant improvements were seen in both adult and pediatric patients, but were substantially smaller in adult patients.  The treatment difference at 28 days between Cayston-treated and placebo-treated patients for percent change in FEV1 was statistically significant at 10 %.  Improvements in FEV1 were comparable between adult and pediatric patients.  Two weeks after completion of drug treatment, the difference in FEV1 between Cayston and placebo groups had decreased to 6 %.

Cayston is supplied as a single-use vial of sterile, lyophilized aztreonam to be reconstituted with a 1-ml ampule of sterile diluent designed for administration via inhalation using an Altera Nebulizer System.  The recommended dose of Cayston for both adults and pediatrics 7 yrs of age and older is 1 single-use vial (75 mg of aztreonam) reconstituted with 1 ml of sterile diluent administered 3 times a day for a 28-day course (followed by 28 days off Cayston therapy).  Dosage is not based on weight or adjusted for age.  Doses should be taken at least 4 hours apart.

An UpToDate review on "Primary ciliary dyskinesia (immotile-cilia syndrome (Bergstrom, 2012) states that “Daily chest physiotherapy is important in compensating for diminished or absent mucociliary clearance.  The effectiveness of DNase and other mucolytic agents, such as hypertonic saline and acetylcysteine, has not been fully assessed in PCD, but may be tried, particularly in patients with recurrent infections or ongoing respiratory symptoms”.