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Aerosol Medications for Treatment of Mucus Clearance Disorders

Aerosol Medications for Treatment of Mucus Clearance Disorders

Aerosol for Treatment of Clearance Disorders

Bruce K Rubin MEngr MD MBA FAARC

Introduction Composition and Physiologic Role of Mucus Mucoactive Medications Bland Aerosols and Bicarbonate Expectorants Mucolytics Mucokinetic Medications Mucoregulatory Medications Fibrinolytics and Factor Inhibition Delivery Devices and Importance of Drug-Device Combination Nasal Delivery Order of Aerosol Administration and Administration During Conclusions

Airway mucus hypersecretion and secretion retention can result from inflammation, , stimulation, or mucus-producing tumors. Secretion clearance can be furthered hampered by ciliary dysfunction and by weakness or restrictive disease, leading to an ineffective . There are a number of different mucoactive medications that have been used to reduce hypersecretion, make secretions easier to transport, or increase the efficiency of cough or mucus clearance. In this paper, I review the pathophysiology of secretory hyper-responsiveness and mucus hypersecretion and discuss the different aerosol medications that can be used to augment secretion clearance. Key words: mucus; ; ; ; bicarbonate; mucolytics; expectorants; . [Respir Care 2015;60(6):825–832. © 2015 Daedalus Enterprises]

Introduction hypertrophy. Products of inflammation (including neutro- phil-derived deoxyribonucleic acid [DNA] and filamen- The airway mucosa responds to acute infection and in- tous actin), effete cells, , and cell debris all con- flammation with mucus hypersecretion and secretion () retention. With chronic exposure, there is mu- cous (goblet) cell and submucosal hyperplasia and Dr Rubin discloses relationships with Novartis, GlaxoSmithKline, In- spiRx, Philips Respironics, Boehringer Ingelheim, the National Institutes of Health, the Cystic Fibrosis Foundation, and the Denny Hamlin Foun- Dr Rubin is affiliated with the Department of Pediatrics, Virginia Com- dation. monwealth University School of Medicine, and the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, Correspondence: Bruce K Rubin MEngr MD MBA FAARC, Department Virginia. of Pediatrics, Children’s Hospital of Richmond at VCU, 1001 East Mar- shall Street, PO Box 980646, Richmond, VA 23298. E-mail: Dr Rubin presented a version of this paper at the 53rd RESPIRATORY CARE [email protected]. Journal Conference, “Aerosol Drug Delivery in Respiratory Care,” held June 6–7, 2014, in St Petersburg, Florida. DOI: 10.4187/respcare.04087

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Table 1. Aerosol Mucoactive Medications

Drug Device Indication Notes Albuterol/salbutamol , pMDI , COPD No evidence that it improves mucus clearance in patients with lung disease Dornase alfa (Pulmozyme) Nebulizer (see Table 2) CF Used only for CF Hyperosmolar 3% Nebulizer None No longer indicated for bronchiolitis Hyperosmolar 7% saline Nebulizer CF No evidence for use other than for CF, should not be given via vibrating mesh nebulizer (Bronchitol) DPI CF, Not cleared for use in the United States N-acetylcysteine (Mucomyst) Nebulizer None No evidence for use in any lung disease Anticholinergics pMDI, DPI Asthma, COPD Does not dry secretions pMDI ϭ pressurized metered-dose inhaler DPI ϭ dry powder inhaler CF ϭ cystic fibrosis

tribute to sputum purulence.1 Mucus is usually cleared by In the distal airways, secretions are pumped by tidal ciliary movement, and sputum is cleared by cough. Mu- , moving them to airways of larger diameter and coactive medications are intended to increase the ability to lower resistance. In the conducting airways, ciliated cells expectorate sputum or to decrease mucus hypersecretion, propel secretions by the metachronal beating of cilia. Mu- and these medications are classified based on their pro- cus clearance depends, in part, on ciliary beat frequency, posed method of action. Here, I review the use of aerosol ciliary power, ciliary coordination, and the surface prop- mucoactive medications for treating patients with chronic erties of airway secretions where they touch the cilia or airway diseases associated with poor mucus clearance and non-ciliated epithelial cell. When there is secretion reten- with mucus hypersecretion and present the evidence, how- tion or secretory hyper-responsiveness especially in asso- ever limited, of their effectiveness. ciation with inflammatory damage to the ciliated epithelial surface, secretions in the proximal airways may be cleared Composition and Physiologic Role of Mucus by cough. Sputum clearance by cough expectoration de- pends on cough power, airway dynamics with the equal Mucus is the normal airway-lining fluid that prevents pressure point moving with air flow, and the properties of dehydration of the airway surface, protects the airway from secretions, with more viscous and less adhesive secretions inhaled particles, and aids in clearance of inflammatory being more easily cleared by cough.4 mediators, effete cells, debris, inhaled particulates, and pollutants. With inflammation, the secretion is called Mucoactive Medications phlegm. Phlegm contains products of inflammatory cells, including Curschmann’s spirals and Charcot-Leyden crys- Medications used to promote mucus clearance have been tals in patients with respiratory eosinophilia, and DNA and categorized by their presumed mechanisms of actions (Ta- filamentous actin polymers when there are neutrophil ex- ble 1).5 The focus here will be on those delivered by tracellular traps or necrosis of inflammatory cells. Phlegm aerosol . also contains bacteria, debris, and a soup of inflammatory mediators. When phlegm is expectorated, it is called spu- Bland Aerosols and Bicarbonate tum.2 In health, mucus consists primarily of water and a poly- Although bland aerosols have been administered in an mer of the -forming MUC5AC and MUC5B. attempt to improve secretion clearance, there is no evi- The mucus layer is secreted by mucous (goblet) cells at the dence of their effectiveness, and there is potential risk to airway surface and in the cartilaginous airways by submu- adding an airway fluid load in the presence of inflamma- cosal . The mucus layer rests atop a periciliary fluid tion.6 Although aerosolized or instilled sodium bicarbon- layer containing airway surface fluid and tethered mucins, ate can produce an effective cough, this is presumed to be principally MUC1 and MUC4. The mucus layer also con- caused by airway irritation. Bicarbonate is not effective in tains entrapped debris and peptides.3 Cilia breaking down secretions or promoting secretion clear- transmit force to the mucus without entanglement due, in ance, and because of irritation, I do not recommend the use part, to a surfactant layer separating the airway surface of aerosolized or instilled sodium bicarbonate for airway fluid from the mucus gel. hygiene.

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Expectorants airway surface and undergoes first-pass metabolism. Fur- thermore, it is irritating to the airway, with a pKa of 2.2 Secretagogues (expectorants) increase the volume of wa- and a foul sulfur odor. There are no randomized controlled ter and mucus in the airway.7 Although medications such trials demonstrating a benefit of inhaled N-acetylcysteine as guaifenesin are proposed to be expectorants, data sug- or similar mucolytic medications in the treatment of any gest that they are not clinically effective.8 airway diseases, and therefore, these drugs are not recom- Commonly used aerosol expectorants include hyperos- mended for clinical use.15,16 molar 7% saline and mannitol. Hyperosmolar saline is an Dornase alfa is a mucolytic that targets the effective expectorant in patients with cystic fibrosis (CF). DNA polymer network in the CF airway. Dornase has Key studies from Australia showed improvement in lung been shown to improve mucus clearance and pulmonary function but at a cost of bronchospasm, so pretreatment function in subjects with CF.17 Aerosolized dornase may with a is considered important.9 Hyper- also allow better aerosol targeting of other medications to tonic saline is thought to act by inducing water and mucus the conducting airway . Despite extensive study, secretion into the airway and by causing an irritant cough. dornase has not been shown to be effective in diseases It is inexpensive, but some studies suggest that it is less other than CF.18 Studies on COPD suggest an increased effective than dornase alfa (Pulmozyme, Genentech, South mortality in subjects inhaling dornase, and in subjects with San Francisco, California).10 There are no published data bronchiectasis, there was worsening of lung function and supporting the use of hypertonic saline in combination more frequent pulmonary exacerbations during a 24-week with dornase alfa or other mucoactive medications. .19 Dornase alfa cannot be recommended for Mannitol is a sugar that, when inhaled as a dry powder the treatment of any airway disease other than CF. formulation, will draw water and secretions into the air- way and act as an expectorant. It has been approved for Mucokinetic Medications use in Australia and Europe for the treatment of CF and non-CF bronchiectasis.11 Mannitol has a sweet taste, but at Mucokinetic medications improve secretion clearance the present time, inhalation of a large number of capsules by increasing ciliary beating and/or power, increasing cough is required for each treatment. Like hypertonic saline, man- air flow, or decreasing adhesion between mucus and cilia. nitol can cause bronchospasm, so it is recommended that Although medications such as ␤-agonist patients be pretreated with an aerosol short-acting bron- can increase ciliary beat frequency and may increase mu- chodilator such as salbutamol. cus secretion, they have not been shown to be clinically Stimulation of the P2Y purinergic pathway triggers chlo- effective as mucokinetic medications.20 Aerosolized sur- ride transport through a non-CF transmembrane regulator factant can decrease the adhesive interaction between the ion channel. The P2Y2 agonist has been studied ciliary tip and mucus layer when there is breakdown of the as an expectorant in subjects with CF, but results of the normal surfactant layer.21 second phase 3 clinical trial (TIGER-2) failed to show improvement in FEV1, so further studies were stopped in Mucoregulatory Medications 2011.12 Blocking the epithelial sodium channel can also retain water in the airway. The epithelial sodium channel Mucoregulatory medications decrease stimulated mucus inhibitor amiloride has not been shown to be effective in secretion without affecting normal baseline secretion.22 In- the treatment of CF, and there is some evidence that its use haled anticholinergics, including atropine, ipratropium bro- is associated with deterioration in lung function.13 mide, tiotropium, and glycopyrrolate, do not decrease nor- mal secretion volume or increase the viscosity of secretions, Mucolytics but they do decrease hypersecretion that is triggered by inflammatory activation of muscarinic receptors.23 Aero- Mucolytic medications degrade polymer . The clas- solized indomethacin has been shown to decrease hyper- sic mucolytics, with N-acetylcysteine being the prototype, secretion in subjects with chronic , diffuse pan- have free sulfhydryl groups that hydrolyze disulfide bonds bronchiolitis, or bronchiectasis, although the mechanism of mucins and other proteins. Peptide mucolytics degrade of action is not clearly known.24 the copolymer network of DNA and filamentous actin that forms in the course of airway inflammation.7 This polymer Fibrinolytics and Tissue Factor Inhibition network is particularly well described in CF, where secre- tions in the airway contain little intact .14 Thus, CF In patients with airway inflammation and activation of sputum has more in common with pus than with mucus. the fibrinogenic pathway, there can be severe airway ob- Aerosolized N-acetylcysteine has been used for many struction by branching mucus casts. This is called plastic years as a mucolytic. N-acetylcysteine is inactivated at the bronchitis, and these casts are most commonly seen in

RESPIRATORY CARE • JUNE 2015 VOL 60 NO 6 827 MUCOACTIVE AEROSOLS patients with congenital heart disease and single-ventricle Table 2. Aerosol Drug-Device Combinations (Fontan) physiology. Plastic bronchitis has also been re- ported to occur in subjects with sickle cell acute chest Device Medication syndrome and in some subjects with severe asthma.25 There PARI eFlow Aztreonam (Cayston) is evidence that inhibiting tissue factor with inhaled hep- PARI LC Plus Tobramycin (TOBI, Bramitob) arin may decrease the formation of these casts by decreas- Colistimethate ing fibrinogenesis.26 PARI LC Star Dornase alfa Hypertonic saline Delivery Devices and Importance of Drug-Device Colistimethate Prodose adaptive aerosol delivery Colistimethate (Promixin) Combination system I-neb adaptive aerosol delivery Colistimethate Devices for the administration of aerosol mucoactive system drugs target the airway mucus layer, usually in the more TOBI Podhaler Tobramycin dry powder proximal airways. However, with severe COPD, CF, and Turbospin Colistimethate dry powder other diseases associated with secretion retention, there is Colobreathe Colistimethate dry powder inhomogeneity of air flow, with the most severely affected Hudson T Up-draft II Dornase alfa airways obstructed by secretions.27 Unfortunately, this is Marquest Acorn II Dornase alfa the part of the airway that needs to be targeted with these PARI LC Jet Dornase alfa PARI Baby Dornase alfa medications. There are a number of devices that produce Durable SideStream Dornase alfa ultrafine particles with a mass median aerodynamic diam- Bronchitol inhaler device Mannitol dry powder (Bronchitol) eter of Ͻ 2 ␮m and that limit inspiratory flow to allow greater deposition of these particles in obstructed areas. From Reference 31, with permission. These devices include the AKITA (Vectura, Chippenham, United Kingdom), AERx (Aradigm, Hayward, California), and I-neb adaptive aerosol delivery system (Philips Health- 33 care, Andover, Massachusetts).28,29 These devices are dis- cations. Devices are now commercially available and cussed in greater detail in other articles in this issue of under development to enhance sinus targeting. These in- RESPIRATORY CARE. clude the PARI Sinus pulsating aerosol system and others. Many devices have been introduced to augment aerosol At present, there are no published data demonstrating that medication deposition. Although most of these devices are nasal administration of mucoactive medications is benefi- more expensive than off-the-shelf jet , in many cial, but there are small studies investigating nasal dornase cases, the medication being administered is far more costly, in subjects with CF that suggest an improvement in quality 34 making the use of an appropriate drug-device combination of life with nasal therapy. not only attractive but now essential for drug approval, safety, and effectiveness.30 Table 2 shows many of the Order of Aerosol Administration and Administration drug-device combinations now approved in the United During Airway Clearance Therapy States for mucoactive medications. Because of the large number of aerosol medications Nasal Delivery given to patients with CF, including bronchodilators, mu- coactive medications, inhaled antibiotics, and anti-inflam- Delivery of mucoactive aerosols targeting the and matory medications, there are guidelines available from is an area of active investigation. Tradi- different CF centers that recommend a specific order of tionally, water, saline, and occasionally medications have administration of medications.35 However, not only are been administered by using devices such these guidelines lacking empiric data from randomized as the Neti Pot, but this has not been shown to be effective controlled trials, many of these guidelines recommend that in treating sinus disease and can carry risks.32 aerosol medications be given in a sequence that is quite Non-pressurized metered-dose pumps are used to de- different from other guidelines. Thus, the order of admin- liver antihistamines, , and corticosteroids to istration of CF aerosol medications in association with the nose but not necessarily to the sinuses. Nasal delivery airway clearance therapy is more of a belief system than can be enhanced using nebulizers such as the PARI SinuStar science. For example, small studies have not shown any (PARI Respiratory Equipment, Midlothian, Virginia), al- difference in effectiveness when dornase was given be- though sinus deposition is still minimal. Data suggest that fore, during, or after other aerosol therapy.36 For patients superimposing pulsatile flow or humming with nasal aero- using airway clearance therapy with high-frequency chest- sol will significantly enhance the sinus delivery of medi- wall compression, there is no contraindication to receiving

828 RESPIRATORY CARE • JUNE 2015 VOL 60 NO 6 MUCOACTIVE AEROSOLS inhaled mucoactive therapy simultaneously. Although cur- 16. Tam J, Nash EF, Ratjen F, Tullis E, Stephenson A. Nebulized and rent data cannot support any specific order of aerosol ad- oral thiol derivatives for pulmonary disease in cystic fibrosis. Co- ministration, a general principal is that fewer medications chrane Database Syst Rev 2013;7:CD007168. 17. Laube BL, Auci RM, Shields DE, Christiansen DH, Lucas MK, result in better adherence to therapy, and good adherence Fuchs HJ, Rosenstein BJ. Effect of rhDNase on airflow obstruction probably trumps the order of administration. and in cystic fibrosis. Am J Respir Crit Care Med 1996;153(2):752-760. Conclusions 18. Rubin BK. Who will benefit from DNase? Pediatr Pulmonol 1999; 27(1):3-4. 19. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idio- There are a variety of different medications that have pathic bronchiectasis with aerosolized recombinant human DNase I. been proposed for the treatment of airway mucus secre- rhDNase Study Group. Chest 1998;113(5):1329-1334. tion. Work is in progress to develop guidelines for the use 20. O’Riordan TG, Mao W, Palmer LB, Chen JJ. Assessing the effects of these drugs and to find effective aerosol therapy for of racemic and single enantiomer albuterol on airway secretions in chronic rinosinusitis. long-term intubated patients. Chest 2006;129(1):124-132. 21. Anzueto A, Jubran A, Ohar JA, Piquette CA, Rennard SI, Colice G, et al. Effects of aerosolized surfactant in patients with stable chronic REFERENCES bronchitis: a prospective randomized controlled trial. JAMA 1997; 1. Kater A, Henke MO, Rubin BK. The role of DNA and actin poly- 278(17):1426-1431. mers on the polymer structure and of cystic fibrosis sputum 22. Rubin BK, Priftis KN, Schmidt HJ, Henke MO. Secretory hyperre- and depolymerization by gelsolin or thymosin beta 4. Ann NY Acad sponsiveness and mucus hypersecretion. Chest 2014;146(2):496-507. Sci 2007;1112:140-153. 23. Bateman ED, Rennard S, Barnes PJ, Dicpinigaitis PV, Gosens R, 2. Rubin BK. Mucus, phlegm, and sputum in cystic fibrosis. Respir Gross NJ, et al. Alternative mechanisms for tiotropium. Pulm Phar- Care 2009;54(6):726-732; discussion 732. macol Ther 2009;22(6):533-542. 3. Voynow JA, Rubin BK. Mucus, mucins, and sputum. Chest 2009; 24. Tamaoki J, Chiyotani A, Kobayashi K, Sakai N, Kanemura T, Tak- 135(2):505-512. izawa T. Effect of indomethacin on bronchorrhea in patients with 4. Rubin BK. The role of mucus in cough research. Lung 2010;188(Suppl chronic bronchitis, , or bronchiectasis. Am 1):S69-S72. Rev Respir Dis 1992;145(3):548-552. 5. Rubin BK. The pharmacologic approach to airway clearance: mu- 25. Madsen P, Shah SA, Rubin BK. Plastic bronchitis: new insights and coactive medications. Paediatr Respir Rev 2006;7(Suppl 1):S215- a classification scheme. Paediatr Respir Rev 2005;6(4):292-300. S219. 26. Eason DE, Cox K, Moskowitz WB. Aerosolised heparin in the treat- 6. Kallstrom TJ, AARC. Clinical practice guideline. Bland aerosol ad- ment of Fontan-related plastic bronchitis. Cardiol Young 2014;24(1): ministration–2003 revision and update. Respir Care 2003;48(5):529- 140-142. 533. 27. Laube BL, Links JM, LaFrance ND, Wagner HN Jr, Rosenstein BJ. 99 7. Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Homogeneity of bronchopulmonary distribution of mTc aerosol in Respir Care 2007;52(7):859-865. normal subjects and in cystic fibrosis patients. Chest 1989;95(4): 8. Hoffer-Schaefer A, Rozycki HJ, Yopp MA, Rubin BK. Guaifenesin 822-830. has no effect on sputum volume or sputum properties in adolescents 28. Rubin BK. Pediatric aerosol therapy: new devices and new drugs. and adults with an acute infections. Respir Care Respir Care 2011;56(9):1411-1421; discussion 1421-1423. 2014;59(5):631-636. 29. Rubin BK, Williams RW. Emerging aerosol drug delivery strategies: 9. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks from bench to clinic. Adv Drug Deliv Rev 2014;75:141-148. GB, et al. A controlled trial of long-term inhaled hypertonic saline in 30. Rubin BK. Air and soul: the science and application of aerosol patients with cystic fibrosis. N Engl J Med 2006;354(3):229-240. therapy. Respir Care 2010;55(7):911-921. 10. Suri R, Grieve R, Normand C, Metcalfe C, Thompson S, Wallis C, 31. Williams R, Rubin BK. Aerosol therapy for the therapy of CF. In: Bush A. Effects of hypertonic saline, alternate day and daily rhDNase Bush A, Bilton D, Hodson, M. Hodson and Geddes’ cystic fibrosis, on healthcare use, costs and outcomes in children with cystic fibro- 4th edition. London: Taylor & Francis; 2015:279-297. sis. Thorax 2002;57(10):841-846. 32. Kassel JC, King D, Spurling GK. Saline nasal irrigation for acute 11. Daviskas E, Rubin BK. Effect of inhaled dry powder mannitol on upper respiratory tract infections. Cochrane Database Syst Rev 2010; mucus and its clearance. Expert Rev Respir Med 2013;7(1):65-75. (3):CD006821. 12. Moss RB. Pitfalls of drug development: lessons learned from trials of 33. Laube BL. Devices for aerosol delivery to treat . J Aerosol denufosol in cystic fibrosis. J Pediatr 2013;162(4):676-680. Med 2007;20(Suppl 1):S5-S17; discussion S17-S18. 13. Burrows EF, Southern KW, Noone PG. Sodium channel blockers for 34. Mainz JG, Schien C, Schiller I, Scha¨dlich K, Koitschev A, Koitschev cystic fibrosis. Cochrane Database Syst Rev 2014;4:CD005087. C, et al. Sinonasal inhalation of dornase alfa administered by vibrat- 14. Henke MO, Renner A, Huber RM, Seeds MC, Rubin BK. MUC5AC ing aerosol to cystic fibrosis patients: a double-blind placebo-con- and MUC5B mucins are decreased in cystic fibrosis airway secre- trolled cross-over trial. J Cyst Fibros 2014;13(4):461-470. tions. Am J Respir Cell Mol Biol 2004;31(1):86-91. 35. Flume PA, Robinson KA, O’Sullivan BP, Finder JD, Vender RL, 15. Black PN, Morgan-Day A, McMillan TE, Poole PJ, Young RP. Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: Randomised, controlled trial of N-acetylcysteine for treatment of airway clearance therapies. Respir Care 2009;54(4):522-537. acute exacerbations of chronic obstructive pulmonary disease. BMC 36. Dentice R, Elkins M. Timing of dornase alfa inhalation for cystic Pulmon Med 2004;4:13. fibrosis. Cochrane Database Syst Rev 2013;6:CD007923.

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Discussion with CF who were using aerosol ei- deposition through the Aerobika de- ther before or after the HFCWC (high- vice for nebulized delivery on inhala- DiBlasi: Bruce, that was an amaz- frequency chest-wall compression) tion compared with the Acapella, the ing presentation, as usual. There seems vest that suggested better aerosol de- data we produced3 actually married up to be a proliferation of new devices position with the vest. To my knowl- with the data you produced in vitro. that are being introduced to the mar- edge, this has never been published or So it does depend on the pathway. If ket, and a number of these are high- replicated clinically. If somebody the pathway for nebulizer delivery via frequency devices that patients can could show us data that this improved the PEP/OPEP device is not altered breathe spontaneously through while lung function or deposition or something appreciably, the in vitro deposition receiving a treatment. Do you think clinically meaningful, I think it would doesn’t differ, although it should be there’s any potential for these devices be great. Until then, we are telling pa- proved clinically. Another question is to provide some of that drug farther tients to do whatever is most comfort- the downside for combining, say, hy- down in the , especially in those able, so they’ll do it consistently. pertonic saline nebulized delivery via airways that are obstructed? It seems a PEP/OPEP device if you know you like the Acapella (Smiths Medical, Berlinski: I want to address that can deliver the same amount and you Ashford, United Kingdom) and Aero- question as well. There were actually can shorten the treatment time for a bika (Monaghan Medical, Plattsburgh, 2 studies published this year: one CF patient. Is there a downside to that? New York) are very attractive options in vivo study that Jim Fink coau- 1 Rubin: The only downside is not for this, but there aren’t a lot of data thored and one in vitro study from 2 having the data. I think most clini- to support using this combined ther- my lab. We found when the vibrating cians would agree with you, but only apy in our patient population. I’ve al- PEP (positive expiratory pressure) de- if there were clinical data to support ways been under the impression that vice (Acapella) was concomitantly what you are saying. you give the bronchodilator and then used with a nebulizer, the aerosol ex- do CPT (chest percussive therapy) or perienced a size selection when it † Fink: So, in our study that Ariel airway clearance next, but maybe it’s traveled through the housing of the (Berlinski) refers to, we took a look at the other way around because there device. In fact, the particle size de- placing the nebulizer where the man- ␮ are conflicting reports where people creased from 4 to 1.2 m. There was ufacturer said to put it,1 and then we give the bronchodilator first and then also a decrease in the amount of drug, put it between the device and mouth- do CPT, or they combine the therapy. with a loss of 70-80%. I was very piece, and we got better deposition. What is your feeling about providing pleased to find that it was also the That was true also when we looked at bronchodilators and other drugs using case in an in vivo study in which the the Hill-Rom device, the MetaNeb. It’s these devices, which essentially per- authors put the nebulizer in the back the first device I’ve ever measured with cuss the airway? of the Acapella, and they found a 70% virtually no aerosol delivered during decrease in the amount of intrapulmo- use, but placing the nebulizer between Rubin: Great question, Rob. First, nary deposition measured with radio- the manifold and mouthpiece gave I’ll speak to the order of delivery; this labeling. The conclusion is that it good aerosol delivery. Core to the is more of a religion then a science, should not be used as concomitant de- question, I think, is that most of this with each clinician having his/her own livery for that type of device. In my isn’t due to better response to bron- way of doing this. For example, first in vitro study, I also looked at a PARI chodilators or whatever drug because you open the airways with the bron- device that doesn’t interfere with the of the oscillation; it’s based on 20-year- chodilator, then you give the muco- flow, and it did not show any changes old data showing there’s an improved lytic and be sure that it gets down in particle size at all.2 We’re not sure response to bronchodilators when given there, then you do airway clearance to what happens with intrapulmonary de- with PEP. And these devices create PEP clear it out, then you give them in- position, but at least from the particle- as well as oscillation. haled antibiotics so it can stay down size characterization, it doesn’t inter- there...butthere are no data suggest- fere with the production of the aerosol. ‡ MacIntyre: I’m going to switch ing that one order is better than any gears from devices. I’d like to go back other. The idea of giving these simul- * Suggett: Just a comment on that to my patient I described earlier when taneously is attractive primarily be- point because it’s the Acapella device Marcos (Restrepo) was up there. So cause it decreases the amount of time that has the more torturous inhalation the patient is stuck on the ventilator. for these therapies. There was one un- flow path; the PARI PEP obviously This is a real case; I saw him yester- published study done by Bonnie Das doesn’t, and neither does the Aero- day. He is doing better except for the Gupta some 20 years ago looking at bika OPEP (oscillating PEP) device. I fact that he’s got these secretions that radioaerosol deposition in subjects think when you look at the in vitro make everybody scared to remove the

830 RESPIRATORY CARE • JUNE 2015 VOL 60 NO 6 MUCOACTIVE AEROSOLS tube. Marcos talked me out of putting ies show no benefit when it’s used as would think there would be an initial an aerosolized antibiotic in there, you an aerosol. Part of the problem is that increase, but I don’t know for sure. talked me out of putting N-acetylcys- we may not be dealing with actual teine down there, and you’ve talked mucus but rather purulent secretions Willson: Bruce, another comment me out of putting dornase alfa down that might not dissolve as easily. Also, or approach to trying to clear out se- there...it sounds like maybe an anti- in patients with asthma, it might have cretions down the airways—but not cholinergic might be useful under these irritant effects, too. Are we delivering mine—is dilute bicarbonate. Would circumstances? Maybe surfactant? it the wrong way, is there something you comment on that? wrong with our methodology, or is Rubin: Maybe. Rubin: Okay. You know from work- there just nothing to it once we try to ing with John Hunt that the airway is ‡ MacIntyre: Should I grab some aerosolize it into the lungs? acidified and that increasing pH within Exosurf and squirt it down there Mon- Rubin: Again, I can only speculate, the airway to normalize it will decrease day morning when I’m back in the but if you have a bronchoscope and a inflammation, perhaps. They’re using unit? suction channel and you’re liquefying bicarbonate as a mucolytic, and it’s pretty darn irritating. I don’t think there Rubin: I no longer have a North it and pulling it straight back, then are any data to support that, and I think Carolina license, so I’ll defer about you’re doing a world of good. If you’re it’s potentially harmful, so I probably Monday. “Maybe” means we have liquefying it and not sucking it out would not use it. In the ICU, folks often some small studies that have been done immediately and the patient doesn’t shoot it down as a liquid into the air- once; there are no replicated studies. have a great cough because he/she’s way. Parenthetically, there are also peo- They were carried out with a specific sick as sin, it’s just going to go down ple who do suctioning all the way down nebulizer with a specific surfactant. there and pool like stagnant water at to the alveolus, leading to all kinds of So I wouldn’t just squirt it down there. the bottom of a pool that’s been aban- granulomas and things like that. They I’d love to see people do that study. doned. This will do more harm than figure that if you’re not getting a good Doug (Willson) and I have been toy- good. The data suggest that it is no chunk of liver with each suction, you’ve ing with ideas like that, but you know better than placebo. It could be due to not gone far enough. There are even as well as I do that you can’t extrap- any one of a number of reasons; my people who will take saline and squirt it olate good clinical practice. guess is that thinning secretions just isn’t all that it’s cracked up to be in down to loosen up secretions, but first ‡ MacIntyre: I’m just trying to fig- terms of coughing things out. bag it! And I’m thinking, you’ve loos- ure out what I’m going to do on Mon- ened everything, now you’re pushing it day morning with this guy. † Fink: Another issue is that just down as deep as it will go into the air- like antibiotics and so many drugs that way, and then you want to try and get it Rubin: Transfer to UNC Chapel we give to the lungs for effect, it isn’t out? So there are many strange things Hill? just that you nebulized it, but it’s the done ‘neath the midnight sun. concentration that actually reaches Hill: Thank you for that great talk. where you want it to go. There’s a DiBlasi: What’s your stance on the The question I have is related to N-ace- difference between pouring 3 cc use of perfluorocarbons for mucus re- tylcysteine. I don’t think we need an through your scope onto a glob of mu- moval? It seems to be the buzz in Eu- RCT (randomized controlled trial) to cus and taking 3 cc and getting 3% of rope right now. demonstrate that it’s a great mucolytic ex vivo. You know, during bronchos- it with a jet nebulizer spread out in the Rubin: We did earlier work with copy, you put some N-acetylcysteine entire 70 square meters of the lung. perflubron when it was still being stud- solution on mucus in a dish, and it You’re probably not getting a high ied as a means of liquid ventilation, dissolves like magic. Actually—some enough target dose or concentration and we got involved because people may shudder at this, but perhaps oth- to get the effect. were getting all sorts of garbage up ers use it—mucus plugs disappear and Hill: Do you know what it does to with its use. We saw similar results are much easier to remove by suction ciliary function? when surfactant was instilled. Indeed, if you wash them with 5 to 10 mL of perfluorocarbons have very low sur- a 10% solution of N-acetylcysteine. I Rubin: Because it has a low pH, I face tension. The surface tension of make it by mixing a vial of 20% N-ace- would think it would initially increase perflubron is 10 dyne/cm, and like sur- tylcysteine with equal parts saline. Pa- it. Anything that irritates the cilia, be factant, it may help unstick and re- tients seem to tolerate this very well. it or other irritants, will ini- move secretions from the airways. I Obviously, this reduces mucus viscos- tially increase ciliary beat frequency like the concept, and I think it would ity. Yet, as you pointed out, the stud- and then will eventually slow it. So I be great to study. I haven’t seen any

RESPIRATORY CARE • JUNE 2015 VOL 60 NO 6 831 MUCOACTIVE AEROSOLS publications showing that it’s effec- suction more than every hour, you REFERENCES tive, but I think it would be well worth ought to leave the tube in. looking at. 1. Mesquita FO, Galindo-Filho VC, Neto JL, Hess: Well, after 10 years, some- Galva˜o AM, Branda˜o SC, Fink JB, Dor- Hess: I’d like to get back to Neil’s times it’s not good to keep listening to nelas-de-Andrade A. Scintigraphic assess- patient. My question for you, Neil, is your old lines. ment of radio-aerosol pulmonary deposi- rather than to try to affect the volume tion with the Acapella positive expiratory * Jason A Suggett PhD MBA, Mon- pressure device and various nebulizer con- of secretions that are being produced figurations. Respir Care 2014;59(3):328- if the patient has a good cough, why aghan Medical. † James B Fink PhD RRT FAARC, 333. not just take the tube out and let the 2. Berlinski A. In vitro evaluation of posi- patient cough out the secretions? Or James B Fink LLC, San Mateo, Cal- tive expiratory pressure devices attached use a cough assist machine to clear ifornia, and Division of Respiratory to nebulizers. Respir Care 2014;59(2): the secretions and not get hung up on Therapy, Georgia State University, At- 216-222. 3. Suggett J, Mitchell J, Avvakoumova V, Ali the fact that there are a lot of secre- lanta, Georgia, representing Aerogen. R, Schneider H. Combining inhalation by a tions in the airway? ‡ Neil R MacIntyre MD FAARC, Division of Pulmonary and Critical breath-actuated nebulizer (BAN) with ex- halation with oscillating positive expiratory ‡ MacIntyre: Well, Dean, you and Care Medicine, Duke University, Dur- pressure device (OPEP) offers potential for I were both on the guidelines commit- ham, North Carolina, representing simultaneous therapy Eur Respir J 2013; tee, and we wrote that if you have to InspiRx. 42(Suppl 57):P2115.

This article is approved for Continuing Respiratory Care Education credit. For information and to obtain your CRCE (free to AARC members) visit www.rcjournal.com

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