2. Order of Therapy & Delivery Stacie Caddick-Dowty RRT, AE-C Hasbro Children’s Hospital Providence, RI

3. Stacie Caddick-Dowty RRT, AE-C
Presenter Disclosure
Stacie Caddick-Dowty RRT, AE-C
The following relationship(s) exist(s) related to this presentation:
No disclosures

4. OOT: Is there any Evidence?
There are few papers there refer to order of therapy and those that exist have slight variations in their suggestions. The suggested order of therapy is just that *suggested*. It is believed that therapy will give the most benefit if given in THIS order based on medication job function. The CF Education committee is in agreement and has approved an educational tool that was designed by myself and our education team at Hasbro Children’s Hospital (and then added to a tweaked in coordination with Mary Lester). It is that education project that this presentation is based from.
Breathe (Sheff) Jun; 11(2): 110–118

5. Bronchodilators Step 1: Readying the airways for therapy
What? albuterol (Proventil®, ProAir®, Ventolin®), levalbuterol (Xopenex®)
How? Inhaler or nebulizer
Why? To open up the airways by relaxing the muscles around them. This helps to widen the airway and make air flow easier into and out of the lungs. This assists other medications getting into the lungs better, and mucus to move out easier. Take minutes prior to other inhaled therapies.
First step in order of therapy is to open up those airways! Relaxing the smooth muscle surrounding the airways and opening them up helps get the rest of the medications IN deeper and the mucus OUT easier.
Recommendations is to take minutes prior to other therapies. **How many of our patients actually wait? (Our clinic is still trying to get patients to take their bronchodilators first)

6. Delivery of Bronchodilators
Use of valved holding chambers with or without mask (depending on age and ability) when delivering via MDI.
Use of small volume nebulizer kits with or without mask. “t-piece” style system, some medication gets wasted.
Nothing fancy. A standard small volume nebulizer or valved holding chamber is sufficient.
Using the same type of equipment in the hospital as well as at home.
*Bronchodilators are delivered in the same manner at home
as in the hospital.

7. Hydration What? hypertonic saline (Hypersal®, Pulmosal®)
Step 2: assisting airway clearance
What? hypertonic saline (Hypersal®, Pulmosal®)
How? nebulizer
Why? Draws water onto the airway surface making airway secretions less thick and sticky, and helps cilia have enough room to move.
Step 2 for Order of Therapy is Hydration. Hypertonic Saline draws water onto the airway surface through the surrounding tissues and gives cilia more room to move. Cilia are little hair like structures whose job is to move the mucus by moving together in a waving or beating pattern. Cilia help move the mucus up the system of airways toward the larger airways where mucus can be coughed out.

8. Hydration delivery
PARI LC Plus:
In the home, the following types of nebulizer kits are suggested to deliver Hypertonic Saline
A Respironics Sidestream (venturi system) or a PARI LC Plus (breath enhanced system) nebulizer kit is suggested for hydration therapy. This includes normal saline or any form of Hypertonic Saline.
Respironics Sidestream:
These efficent nebulizer kits offer less waste to the environment and more delivery to the lung using either a breath activated system or a venturi system.
Venturi design - Entrains room air during nebulization process to produce fast flow and greater output on inspiration.
BEN – Entrains air and nebulizes more medication on inspiration, wasting less to the atmosphere.
These are re-usable nebulizers manufactured to withstand frequent cleaning and disinfecting. Can last up to six months with proper care.
Delivery during and in patient hospital stay: Here is where things differ. Delivery of medications in the hospital settings varies from institution to institution.
Most hospitals use disposable nebulizer kits from varying manufacturers (some standard small volume nebs, venturi systems and BAN systems). I did hear from a couple RTs that their institution uses the CFF recommended Sidestream or PARI LC + and sends them home with patients along with cleaning and disinfecting instructions.

9. Mucolytics What? dornase alfa (Pulmozyme®), Acetylcysteine (Mucomyst®)
Step 3: assisting airway clearance
What? dornase alfa (Pulmozyme®), Acetylcysteine (Mucomyst®)
How? nebulizer
Why? Making mucus less sticky and thick will make it easier for you to move the mucus and cough it up and out. Less mucus means less chance for more bacteria to grow in the lungs.
Thinning the mucous is our next step in order of therapy. Thinning of the mucus happens quite fast. I’ve read articles that state 30 minutes to 1 hour prior to performing airway clearance. However during a bronchoscopy procedure we instilled 1.25mL (1.25mg) of Pulmozyme into the RUL which was packed with mucus. We withdrew the scope, waited 3-4 minutes and reentered the airway. The mucus had (what I can only describe) as “melted” from the airway. From this point forward I’ve been convinced of the purpose of mucolytics, and I tell many families that it works just like the little lenticular images that shows a mucus plug in the test tube prior to therapy, and then liquified mucus after therapy from the Pulmozyme handout.
Think of step 2 and 3 as mediations to help get the mucous out of the way!

10. Mucolytic delivery Respironics Sidestream: eRapid™:
Respironics Sidestream – CFF recommended - Reusable, meaning it can be used up to six months without replacing by cleaning and disinfecting at home.
Venturi design - Entrains room air during nebulization process to produce fast flow and greater output on inspiration.
Again using nebulizer kits manufactured to withstand cleaning and disinfection process. Can last up to 6 months with proper care.
The eFlow system with the eRapid handset is approved for use with Pulmozyme. Of Note: The handset has a 1cc residual volume which is equivalent to a standard small volume nebulizer.
eFlow system and eRapid handset (same eFlow system as the Altera – if a patient has an Altera eflow base and eRapid can be used) These eRapid handsets if not covered by insurance are $146 each. Not cheap! Use with patients who can use a mouthpiece ONLY. Should be replaced every 90 uses, currently no data to support using it longer due to appropriate dose delivery.
**Patient who need a mask should use a PARI LC Plus with PARI BABY mask conversion kit.
Just like with Hydration delivery… Delivery of these medications in the hospital settings varies from institution to institution. Most hospitals use disposable nebulizer kits from varying manufacturers (some standard small volume nebs, venturi systems and BAN systems). I did hear from a couple RTs that their institution uses the CFF recommended Sidestream or PARI LC + and sends them home with patients along with cleaning and disinfecting instructions.

11. Airway Clearance Step 4: What? Moving mucus up and out!
How? Chest percussion, OPEP (AerobiKa®, Acapella®, Flutter valve®) PEP device
Breathing techniques: autogenic drainage, active cycle breathing, huff cough
Vest systems: TheVest®, inCourage®, Smart Vest®, Afflo Vest® Monarch®
Other: percussor or Vibralung®
Why? Moving mucus up and out of the lungs is the most important component of your airway clearance therapies. After all the hard work you’ve done taking your mediations, huff and cough that mucus up and out.
SOOooo… now that your patients have inhaled a bronchodilator to open up the airways readying them for additional therapies, added depth to the surface liquid in the airway with hydration and thinned the mucus with a mucolytic; ITS TIME TO PERFORM AIRWAY CLEARANCE. Whatever form that may be…

12. HUFF AND COUGH
Always huff and cough after airway clearance. Mucus won’t come out on its own!!

13. Inhaled antibiotics
Step 5: Medication that needs to stay in the lungs
What? aztreonam (Cayston®), tobramycin (TOBI®), TOBI® Podhaler™, Bethkis®, Kitabis Pak®), colistimethate (Colistin®)
How? nebulizer
Why? Antibiotics help to kill the bacteria that can grow in the mucus. Always take ALL of the antibiotics that the doctor has told you to take.
Now we move on to step 5 (this step and finally step 6) are the medications that needs to stay in the airway to do their job.

14. Variability of delivery devices
The PARI LC+ was used in the pivotal trials for safety and efficacy. The chart above is from Vecellio et al. comparing 20 jet nebulizers with varying compressors or compressed air from the wall running at 8L. There was no relationship between the compressed air source and nebulizer performance, but rather the nebulizer cup itself was the primary driver of respirable particle mass. Theory re: the difference in performance include residual volume as well as wasted medication due to open system nebulizers. PARI LC +: contains valves that direct inspiratory flow through the bow of the cup, increasing nebulization resulting in more delivery to the lung and less leakage to the atmosphere.
The main Conclusion I want you to see here is that DELIVERY DEVICES MATTER!

15. Delivery matters Mean Sputum Concentrations ug/g
Pivotal studies compared the PARI LC to the Sidestream in In 2002 Gellar compared the PARI LC+ to the other two well known devices. The graph above shows Tobramycin Sputum concentrations following the delivery of 300mg TOBI in 5mL.
We all know delivery matters. Reviewing delivery devices and order of therapies at the RT annual review is essential. Patients get into bad habits (drooling into neb cups, cleaning practices lax, etc…). The one thing we can have an impact on is educating our patients and letting them know which devices are going to be the most effective delivering appropriate amount of drug to the lung.

16. Inhaled tobramycin TOBI; 300mg 2XD PARI LC Plus – CFF recommendation
No mixing required
Standard cleaning and disinfection required
Breath enhanced design delivers more to the lungs
Less waste to the environment in the home
Some hospitals use the Pari LC Plus nebulizer kit and send it home with the patients for disinfection and use for the next 6 months.

17. Tobi Podhaler™ No need for cleaning and disinfection.
Dispose Podhaler™ on a weekly basis.
Easily portable, external power not needed.
Quick delivery (4 minutes vs. 15 minutes)
Pulmosphere technology takes variable PIFR out of the delivery equation, ↓ing variability of distribution.
Can cause coughing/bronchospasm.

18. Inhaled colistin
Usual dose for adults with CF is 75mg twice a day via nebulizer
Colobreathe - Used in Europe, not FDA approved. (125 mg; 2XD; DPI)
Inject 2mL of sterile water into the colistin vial, while gently rotating and swirling the bottle (to prevent foaming) until all the white powder has dissolved. DO NOT shake vigorously.
Withdraw 1mL (75mg) of the colistin and place it into the nebulizer.
Draw up 2mL of normal saline and add into the nebulizer.
Place the remaining mixed colistin (1mL) into the refrigerator for future use.
DO NOT mix colistin with any other medications

19. Cayston® 75mg; 3XD; Altera eflow system by Pari.
Altera handset is drug specific only approved for delivery of Cayston®.
Quick delivery time (2-3 minutes)
Cleaning and disinfection slightly more involved
Mixing med with diluent
Storage (must be refrigerated)
Patients who use Cayston are generally required to bring their Altera/eFlow system and medication in with them. The Altera handset has no residual volume at the end of treatment. The patient is then responsible for cleaning, disinfecting and care of their device during the admission.

20. Inhaled corticosteroids
Step 6: Medication that needs to stay in the lungs
What? Inhaled steroids: budesonide (Pulmicort®), beclomethasone (Pulmicort, QVar®), fluticasone (Flovent®, mometasone (Asmanex®) cliclesonide (Alvesco®)
Inhaled corticosteroid and long acting bronchodilator: (fluticasone and salmeterol (Advair®), budesonide and formoterol (Symbicort®), fluticasone and vilanterol (Breo®), mometasone/formoterol (Dulera®).
How? inhaler/nebulizer
Why? Airways can have swelling in them from mucus and recurrent infections. Corticosteroids will help reduce swollen inflamed airways. Don’t forget to rinse your mouth after taking them!
Step 6. Inhaled CorticoSteroids. This last step is also a medication that needs to stay in the lung to do it’s job.

21. ICS delivery Aerosol with w/BAN
DPI (Twisthalers, Turbuhalers, Ellipta)
MDI w/ VHC
Many Many delivery options for ICS. They come in many forms. DPI, Respimat, MDI, Liquid requiring nebulization…
Respimat

22. Other inhaled medications
Vancomycin - Staphylococcal (Staph) or Streptococcal (Strep) mg vancomycin twice daily by nebulization. Powder form – 500mg vial - dilute with 10mL sterile water, add 5mL of vancomycin and 5mL of 0.9% NS to neb. Can lead to wheezing, coughing, and dyspnea. Take bronchodilator first.
AeroVanc (MRSA; Phase 2 results show decrease MRSA density in sputum samples)
Levofloxacin – Inhaled Levaquin approved for use in Europe and Canada; 240 mg 2XD
Quinsair™ studies discontinued and no there are no plans for further clinical development in CF.
Amikacin - NTM /P. aeruginosa; 500mg vial (2mL) + 1mL 0.9%NS via nebulizer.
Arikase (studies discontinued and no there are no plans for further clinical development.)
Ceftazidime - B. cepacia/P. aeruginosa; saline diluent; 1g 2XD via Jet Nebulizer
Lidocaine - cough suppression (chronic cough, refractory cough, habit cough, intractable cough, persistent cough)
There are so many medications out there being used to treat infections or cough symptoms however I can’t go through them all in detail. However some are used “off label” and some are in the development pipeline at varying phases of study.

23. Cont...
Drug development pipeline – there is always something in the works! As RTs it is out job to stay up to date and knowledgeable in CF care and inhaled therapy, as it is changing rapidly!

24. Thank You!
Stacie Caddick-Dowty Pediatric Pulmonary Lab Coordinator Hasbro Children’s Hospital Respiratory & Immunology Center Pulmonology, Cystic Fibrosis, Asthma/Allergy, & Ventilator Integration Program 593 Eddy St. Providence RI