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WAITING TO INHALE: 115:48:07 DELIVERY OF MEDICATIONS TO THE LOWER AIRWAYS15:48:07 SPEAKER: Michael Rock, M.D.15:48:4715:48:47 DR. ROCK: Thank you, Ellen, for that15:48:49 introduction. It's a pleasure to be here this15:48:51 morning. With the title of today's talk, if you15:48:54 were expecting Whitney Houston to appear, I'm15:48:57 sorry to say that she could not make it, so I will15:49:00 be here instead.15:49:0215:49:02 This is really a very important topic, given that15:49:05 we deliver so many inhaled medications to the15:49:08 airway in children. I'm going to speak mostly15:49:11 about asthma, but of course I have an interest15:49:13 cystic fibrosis and there are some unique15:49:16 challenges in CF patients regarding medications15:49:19 that are available to deliver to the lower airway.15:49:2115:49:22 I know probably many people come in with15:49:24 preconceived notions as to what is the best way to15:49:27 deliver medications to the airway. This might be15:49:30 controversial. We'll see in the next 40 or 4515:49:33 minutes if the data that I'm going to show you15:49:36 might change your mind. I'll show you what's15:49:39 happening on a national basis with regard to15:49:42 medications delivered to the lower airway.

15:49:4415:49:46 So the learning objectives are to describe the15:49:49 different delivery devices for inhaled15:49:51 medications, learn of systematic reviews of the15:49:53 use of nebulized medications versus metered dose15:49:57 inhalers and the treatment of acute asthma, and15:49:59 learn of the use of valved spacer devices with15:50:01 metered dose inhalers.15:50:0315:50:03 I do have one disclosure. I am a member of the15:50:06 Cystic Fibrosis Foundation Data Safety Monitoring15:50:09 Board. We monitor several studies, and in my role15:50:13 I'm paid a very small amount for my time with15:50:18 monitoring those studies, and I will reference off15:50:21 label use of medications during this talk.15:50:2315:50:25 So we're going to start with a case report. This15:50:27 is a real case. I did not make this up. This is15:50:30 someone that I saw in the spring of this year.15:50:33 When I saw him in clinic, he was an 8‐month‐old15:50:36 that had had quite a bit of coughing and wheezing.15:50:39 He had had three to four emergency department15:50:41 visits. He was already on nebulized Albuterol and15:50:44 Pulmicort at home, and this is a direct quote from 215:50:47 my dictation to the primary care physician: "He15:50:50 wears a face mask, but the mother is finding it a15:50:52 bit more challenging to give these treatments. His

15:50:56 past medical history is significant, for last15:50:59 winter he was hospitalized here in our ICU with15:51:02 RSV and he required intubation and mechanical15:51:05 ventilation and he's had coughing and wheezing15:51:07 ever since then. The pertinent part of the exam15:51:10 was that he had audible expiratory wheezing and15:51:14 intercostal retractions. He had inspiratory and15:51:18 expiratory wheezing also on auscultation with a15:51:21 stethoscope."15:51:2115:51:22 So I stopped the nebulized Pulmicort and15:51:26 Albuterol, began Flovent 44 micrograms per puff,15:51:30 two puffs using spacer with a face mask twice a15:51:33 day. His intervention plan was Albuterol for15:51:37 puffs using spacer with mask as needed for cough15:51:39 or wheeze and repeat up to every four hours as15:51:41 needed. We received a phone call from the family15:51:44 five days later. He was doing very well. No15:51:48 wheezing. Very seldom coughing. So this is quite15:51:51 gratifying that in a very short time, this child15:51:54 that had audible wheezing when I saw him in15:51:57 clinic, he was totally clear by changing his15:52:00 modality of therapy from nebulized to metered dose15:52:04 inhaler.15:52:0515:52:07 So there are certainly challenges in delivering15:52:09 medications to the lower airway. We have all

15:52:12 evolved to try to keep the external environment15:52:16 from getting inside us, with the exception of15:52:20 obviously we have to breathe air all the time. So15:52:23 molecular oxygen, we want to get that down into15:52:25 our alveoli, but particles bigger than oxygen,15:52:28 it's not desirable. We have a torturous route in15:52:34 the upper airway. You consider the hairs in the15:52:36 nose, the nasal turbinates. The nose will filter15:52:41 out particles that go down as small as 1 micron in15:52:44 size. Even if one is breathing through the mouth,15:52:46 you certainly have a torturous route to go beneath15:52:49 the vocal cords with a 90‐degree turn in the back15:52:52 of the throat. And it's really thought that15:52:54 breathing through the mouth particles of 5 microns15:52:57 or larger are filtered out.15:53:0015:53:00 Once you get down into the lower airway, we all15:53:03 know that the airway branches over and over and15:53:05 over again. There is something call the Weibel15:53:09 model of airway branching where there are 23 315:53:11 generations of airways, and each time there's a15:53:13 branch point, that's a corner that medications15:53:19 have to negotiate to get down to the target15:53:21 region. In asthma we're certainly looking at15:53:23 delivering medications to smaller airways down15:53:25 here. The same could be said for cystic fibrosis.15:53:29

15:53:30 About the only time I could think that you would15:53:32 want a medication in the upper airway would be a15:53:34 child with croup and giving them nebulized racemic15:53:38 epinephrine. You certainly want that to work15:53:40 right in the sublatic region right beneath the15:53:42 vocal cords. So our challenge in delivering15:53:46 inhaled medications to the airway is to defeat15:53:49 these filtering mechanisms that should keep out15:53:53 particles from the lower airway.15:53:5615:53:58 In terms of talking about particles delivered by15:54:02 medical devices, be they nebulizers or metered15:54:05 dose inhalers or dry powder inhalers, the way to15:54:09 characterize the size of the particles is called15:54:11 the MMAD, and that stands for median mass15:54:15 aerodynamic diameter. That is a central tendency15:54:20 of the size of the particles; in other words, 50%15:54:23 of the particles are smaller, 50% are larger. As15:54:28 we just spoke about on the previous slide, the15:54:30 upper airway of the nose, the larynx, the trachea,15:54:33 certainly with the upper airway most of those15:54:35 larger particles are filtered out. To go beneath15:54:39 the vocal cords, one needs particles of less than15:54:42 5 microns in size, so the 2 to 5 micron size gets15:54:46 beyond the vocal cords into the airway.15:54:5215:54:52 Now, once you get into the airway, you have

15:54:54 different ways of particles settling on the15:54:56 airway. Particles that are greater than15:54:59 5 microns, and sometimes those do get beneath the15:55:02 vocal cords, they can slam into these branch15:55:04 points. They can slam into walls. That is called15:55:06 inertial impaction.15:55:0915:55:09 Particles of 1 to 5 microns in size, those can15:55:14 settle on airways by sedimentation. In other15:55:16 words, it's by gravity. And the longer the15:55:20 residence time in the airway, in other words, if15:55:23 one holds your breath, that gives those particles15:55:26 more time to settle out. And in fact, there have15:55:28 been estimations that with a 10‐second breath15:55:31 hold, that increases the amount of particles15:55:34 deposited in the airways by at least 10%. 415:55:4115:55:41 And then lastly, a way that particles can settle15:55:43 on the airways, particularly in the respiratory15:55:45 region, is by Brownian diffusion. Those are15:55:48 really like molecular forces of these particles15:55:50 interacting with each other. You might, in fact,15:55:56 you would want Brownian diffusion if you wanted to15:55:58 get particles into the distal distal bronchioles,15:56:02 even alveoli. Let's say you have a patient that15:56:05 you need pneumocystis prophylaxis, but they're15:56:08 allergic to TMP sulfa. They can be on nebulized

15:56:11 pentamidine once a month. You'll want that to go15:56:13 certainly as distal as possible, so you would be15:56:15 relying on Brownian diffusion for those patients.15:56:1815:56:21 There are a number of factors that determine15:56:24 aerosol deposition. Those that can divided into15:56:27 aerosol factors and patient factors. As we just15:56:31 spoke about, aerosol factors, the particle size15:56:35 distribution is very important and generally we15:56:37 say that the respirable range is less than15:56:40 5 microns.15:56:4115:56:42 Aerosol density is important, also. If you have15:56:44 many particles in close proximity to each other,15:56:47 those can coalesce, and then they're not greater15:56:50 than 5 microns in size anymore. There are15:56:54 hydroscopic properties. It's a humid environment15:56:58 in the airway, given that we warm and humidify the15:57:01 air with the upper airway down at the lower airway15:57:04 and particles can grow in size. And viscosity and15:57:07 surface tension also play a role in the size of15:57:10 the particles.15:57:1115:57:11 Just as important as the aerosol factors are the15:57:14 patient factors. Inspiratory flowrate is15:57:17 certainly important, and we'll see that in a slide15:57:20 here in a moment. And inspiratory flowrate is

15:57:24 device dependent. With dry powder inhalers, which15:57:28 we will talk about later, one needs a very fast15:57:32 inspiratory flowrate. You need to de‐agglomerate15:57:35 particles off of the carrier vehicle in dry powder15:57:39 inhalers.15:57:4015:57:40 That is in contrast to metered dose inhalers,15:57:42 where you want a slower inspiratory flowrate so15:57:45 that you don't have that inertial impaction. You15:57:48 don't want the particle slamming into those branch15:57:52 points in the airway.15:57:53 515:57:53 Title volume, respiratory rate, and breath holding15:57:56 time, those are all important in the hang time or15:57:59 the residence time in the airway, the amount of15:58:02 time the particles are in there that can settle15:58:09 out by sedimentation.15:58:1015:58:11 Certainly upper airway anatomy is important. If15:58:14 you have a toddler with large tonsils, they have a15:58:16 bigger anatomic challenge in their upper airway15:58:19 compared to a teenager who does not have large15:58:22 tonsils. Lower airway obstruction is certainly of15:58:25 issue. You can't get the particles to distal15:58:29 airways if there's quite a bit of obstruction.15:58:3115:58:31 And then lastly and very importantly, the ability

15:59:55 central distribution of these radioactive15:59:57 particles, compared to a slower inspiratory16:00:01 flowrate of 30 liters per minute where there's16:00:04 more equal distribution of the particles16:00:05 throughout the airways.16:00:0716:00:09 So the history of inhaled medications goes back to16:00:14 2000 BC in India. And back in that time, there 616:00:19 were herbal preparations such as the Datura plant16:00:23 that were used for medical purposes. The root of16:00:26 the Datura plant, Datura is Angel's Trumpets. It16:00:30 has alkaloids, which has potent anti‐cholinergic16:00:35 bronchodilator activity. They took these roots,16:00:38 they crushed them up, mixed them with ginger and16:00:40 pepper, smeared them on a reed, which was dried,16:00:43 and then that was smoked. So that was maybe the16:00:45 first reference to inhaled medications in history.16:00:5016:00:51 The first time that the term "inhaler" was ever16:00:53 used was by Dr. John Mudge in 1778. He published16:00:59 a book called "A Radical and Expeditious Cure of a16:01:03 Catarus Cough." He proposed inhaling opium vapor16:01:08 through this Mudge inhaler. You can barely see on16:01:12 here. There are some holes right here in the16:01:14 handle of this inhaler. The patient puts their16:01:17 mouth on this mouthpiece here. They inhale. Air16:01:20 is drawn through these holes, goes through the

16:01:23 bottom of this tankard, which is where the opium16:01:26 solution is at. So this is the first reference to16:01:29 the word "inhaler."16:01:3116:01:31 We go forward to more modern times and what's been16:01:38 around certainly for many, many years is16:01:41 compressors and jet nebulizers. And I brought one16:01:44 here. People have seen this before, but I'll just16:01:47 set this up here for a moment. We won't do the16:01:49 whole treatment. A ice lime green. They don't16:01:52 all come in a green color. Tubing, plug that in16:02:04 here. We'll talk about different nebulizers here16:02:05 in a moment. I just have some saline here. Twist16:02:09 this off. I'll squirt that in there. If anybody16:02:15 wants a saline breathing treatment this morning,16:02:17 you can come on down and get your breathing16:02:19 treatment. So it only goes one way. I just16:02:26 discovered something. That kind of makes sense.16:02:27 You've got this round part here. I tried to put16:02:29 it in there. That wasn't work. So you've got to16:02:31 go back this way. This round part is back here to16:02:35 the handle. A mouthpiece, and we'll plug this in16:02:43 here, and away we go. And you can see the fog16:02:48 coming out of the mouthpiece there. It's a little16:02:51 bit noisy, so we won't run it any further.16:02:5516:02:55 So what just happened there? What's the physics

16:02:58 or the physics behind this? When you have a gas16:03:01 source go through a small capillary tube, you have16:03:05 a high velocity right here at this outlet. There16:03:09 is one or two capillary tubes that go down into a 716:03:12 reservoir. There's something called Bernouilli's16:03:15 law. When you have a high gas source going16:03:18 through an opening, there's a decreased pressure16:03:20 right there. That causes the liquid to be sucked16:03:23 up through this capillary tube and then there are16:03:26 shearing forces on the surface of that liquid that16:03:31 turn this into various particles of different16:03:34 sizes.16:03:3516:03:35 What is not shown in these schematics or these16:03:38 nebulizers is there are a series of baffles here.16:03:40 There's a huge spread of particles that were just16:03:44 developed when we turned on the compressor. They16:03:47 range in size from .1 to 30 microns. Obviously,16:03:52 30 microns is a huge size. Inertial impaction,16:03:56 which we talked about earlier in the airways, that16:03:58 occurs in the nebulizers, also. Those larger16:04:01 particles impact against baffles in there. They16:04:06 rain back down to the reservoir and they get16:04:08 re‐nebulized over and over and over again. That16:04:10 is the fate of 99% of the particles. So only 1%16:04:15 of the particles actually are output to the16:04:18 patient.

16:04:1816:04:20 This is something called the mainstream nebulizer.16:04:23 Over here is something called the side stream16:04:25 nebulizer. That's actually a brand of nebulizer,16:04:28 and that's because the capillary tube comes in16:04:30 alongside the compressed gas source. You're16:04:34 sheering across a larger volume with this16:04:38 cross‐section here, compared to this here. So16:04:41 these, in some ways, can be more efficient.16:04:4316:04:45 The problem is all nebulizers were not created16:04:49 equal. This was a study done at National Jewish16:04:53 Hospital in 1994. Each one of these numbers here16:04:56 has a different grand of a nebulizer. There's 1716:05:00 available brands in the U.S. when they did this16:05:02 study. This shows time of nebulization to the16:05:07 point of eight‐fold decline in particle output.16:05:10 The diamonds are the 95% confidence intervals.16:05:14 The horizontal line is the mean. And each one of16:05:17 these boxes is the average determination of16:05:21 triplicate treatments with four different16:05:24 nebulizers, but of the same brand. So they had16:05:27 four nebulizers produced by the same company. For16:05:30 example, number two here is the Acorn They took16:05:33 four Acorn nebulizers. What's interesting is16:05:38 these three boxes here are together, but this one16:05:41 right here is quite different from those three, so 8

16:05:43 that tells you the manufacturing process of these16:05:44 nebulizers, even though they try to make them16:05:48 precise, there's variability in the output of16:05:51 these nebulizers.16:05:5216:05:53 The other variability you see amongst the16:05:55 different brands of nebulizers here, this one16:05:58 takes forever to get down to an eight‐fold16:06:01 decrease in particle output. And you can see the16:06:04 other variability with the other brands of16:06:06 nebulizers.16:06:0816:06:11 This is delivery of particles in the respiratory16:06:12 range in milliliters per minute. And again, you16:06:16 can see some variability. Some of the better16:06:19 nebulizer brands are this one right here. Number16:06:22 three is called the Aqua Tower. Numbers 12 and16:06:27 13, this is the Peri‐LC. Number 13 is a Peri‐LC16:06:31 Jet Plus, which is the nebulizer that I had here.16:06:35 And number 15 is the Side Stream.16:06:3816:06:38 By the way, we're talking about brands of16:06:41 nebulizers. It looks like maybe the medical16:06:44 students are off today. I often hear on the wards16:06:47 people say, "A child got an Albuterol nebulizer."16:06:51 Grammatically, that is incorrect. It's Albuterol16:06:54 by nebulization. There's no such thing as an

16:06:57 Albuterol nebulizer. There is a Peri‐LC16:06:59 nebulizer; there is an Acorn nebulizer; there's an16:07:03 Aqua Tower, but there is no such thing as an16:07:05 Albuterol nebulizer so just semantics here, but16:07:10 it's grammatically incorrect.16:07:1216:07:12 Because of this variability in nebulizers, the FDA16:07:16 requires on package inserts that in phase three16:07:18 studies, the recommended use of that medication is16:07:24 with a particular nebulizer and compressor that16:07:27 was done in the studies. In the case of16:07:30 Pulmicort, which was what the child was on in the16:07:34 case presentation, I don't know what kind of16:07:36 nebulizer he was using. I think it probably would16:07:39 have been useless for me to ask the family,16:07:41 because they would not know, either. If you look16:07:43 at the package insert for Pulmicort, it says a16:07:47 Peri‐LC Jet Nebulizer with a pericompressor. It16:07:51 also says that other nebulizer and compressor16:07:54 combinations have not been tested and safety and16:07:57 efficacy are unknown.16:07:5916:08:00 The other interesting issue about Pulmicort, that 916:08:03 was an eight‐month old infant that was on16:08:05 Pulmicort. I sent them a disclosure slide that I16:08:08 talk about off label indications in this talk.16:08:11 Pulmicort is only approved by the FDA down to 12

16:08:14 months of age. Certainly it doesn't mean that16:08:16 it's necessarily unsafe, but it is an off label16:08:20 use of Pulmicort.16:08:2116:08:22 There are certainly many, many challenges in16:08:24 nebulizers. I plugged it in before everyone got16:08:27 here. I connected the tubing. I put the16:08:30 medication in the cup. I put the top on there16:08:33 initially backwards. The actual time to nebulize16:08:37 takes, what, 10, 15 minutes? The nebulizer goes16:08:41 until it starts sputtering and then once finished16:08:45 with the treatment. That does not mean that all16:08:48 of that drug has been nebulized. There is16:08:51 residual volume or dead volume in nebulizers,16:08:54 which generally ranges about one milliliter.16:08:57 Considering that a unit dose of Albuterol is 2.516:09:01 milliliters, that's almost half of unit dose that16:09:03 remains behind in the nebulizer.16:09:0616:09:06 There's certainly other forms of waste with16:09:08 nebulizers. This runs continuously for the 10 or16:09:11 15 minutes. The child is not breathing in during16:09:14 all of that time, so there's waste during16:09:17 nebulization. Need to be near an electrical16:09:21 outlet, when I've already mentioned. It's not16:09:23 portable. So it's really many, many challenges16:09:25 with nebulizer treatments.

16:09:2616:09:31 So ideally, you have a happy toddler that's16:09:33 sitting on a parents' lap and you certainly do16:09:36 need to use a face an mask. People have taken16:09:40 corrugated tubing, aimed it at the child's mouth,16:09:44 and have done the blow by method. That does not16:09:46 work very well. You really don't get appreciable16:09:49 drug into the lower airways.16:09:5016:09:51 So this child is nice and cooperative, but what16:09:53 happens when they do not cooperate? I've heard16:09:56 the argument, well, if a child is crying during a16:09:59 breathing treatment, they're taking in big breaths16:10:01 and it's going to enhance the breathing treatment16:10:03 even more. We've all seen children cry, but how16:10:08 much have we really considered what happens during16:10:10 crying? How much time do they spend in16:10:13 inspiration versus expiration? Well, we'll take a16:10:18 look at a crying child. And we actually have 1016:10:20 inspiration/expiration labeled for you.16:10:4516:10:45 So that was a 20‐second video clip, and of that 2016:10:50 seconds I would guess that, what, maybe four or16:10:53 five seconds at the most was an inspiration? Most16:10:56 of the time was spent in expiration.16:10:5916:11:00 A study was performed to look at can you deliver

16:11:04 medications to the lower airway or I should16:11:06 actually say how does it compare to delivering16:11:09 medications to the lower airway in a child that's16:11:11 distressed, in other words, crying versus not16:11:14 crying, not distressed? This was looking at16:11:19 chromalin, which is an asthma medication back from16:11:21 the seventies and eighties which we really don't16:11:23 use anymore, because it's not a very good16:11:25 medication for asthma. P16:11:2816:11:28 Chromalin is absorbed across the respiratory16:11:30 epithelium and it undergoes hepatic and renal16:11:34 metabolism. They looked at the amount of16:11:36 chromalin in urine in 15 infants that were either16:11:39 distressed or not distressed. The not distressed16:11:43 infants excreted 0.43% of chromalin in their urine16:11:48 versus zero.11% in the distressed infants. And16:11:55 they are actually surprised with this finding.16:11:56 They stated in the last sentence before their16:11:58 methods section, "We expected that with larger16:12:01 title volumes, we would have better delivery of16:12:04 drug in crying infants, but the opposite was16:12:07 true."16:12:0816:12:08 It makes sense when we think that have video clip16:12:10 that we just looked at. Children, when they're16:12:13 crying, they're not spending very much time in

16:14:51 and their phase three studies were with the eFlow.16:14:5516:14:55 In September of this year, we expected the FDA to16:14:57 approve Aztreonam for inhalation. The phase three16:15:02 studies showed that it was safe. It was16:15:04 effective. And very surprisingly, the FDA denied16:15:07 the application. I don't know why. It's really16:15:10 never been made public. The FDA has said that16:15:14 they want more studies. And we're still in limbo16:15:16 as to whether we're going to have Aztreonam16:15:20 ventilation. If it had come out, the package 1216:15:22 label would have said "Deliver with the eFlow16:15:25 nebulizer."16:15:2616:15:26 Right now there's only one tobramycin solution for16:15:30 inhalation and that's Toby delivered with an LC16:15:33 jet nebulizer. There is another company that's16:15:36 developing a tobramycin solution for ventilation16:15:40 using the eFlow, but they're in very early16:15:42 development.16:15:4316:15:43 As you can see, these other two products are16:15:45 cheaper, but I don't know that there's really any16:15:47 FDA indications of using these products with any16:15:50 medications. There's a journal called Respiratory16:15:51 Care, and in the December 1st issue this month,16:15:55 there was a study in there looking at Dianase

16:15:59 delivered about the Omron compared to Dianase16:16:02 delivered with a Peri‐LC jet nebulizer. It was16:16:06 equivalent, in fact, better with the Omron. It16:16:09 was more efficient. The respirable particles were16:16:13 delivered in a much better range than the Peri‐LC16:16:16 Jet Nebuliser. This is one of those laboratory16:16:20 studies and it's there. Perhaps using this for16:16:24 Dianase would be useful, but I don't foresee that16:16:28 the package label is going to change from this16:16:30 small in vitro study.16:16:3216:16:32 These products are very, very nice. They make the16:16:35 treatments go much, much more quickly. If we had16:16:38 with Aztreonam for inhalation approved by the FDA,16:16:41 the treatment would have been perhaps three to16:16:44 five minutes versus the ten to 12 to 15 minutes16:16:48 with a conventional jet nebulizer and a16:16:51 compressor.16:16:5216:16:54 So we go on to metered dose inhalers. In 1955,16:16:59 there was a 13‐year‐old with asthma. And she16:17:02 complained to her father that there should be a16:17:04 better way to get asthma medications, somewhat16:17:07 analogous to her mother's hair spray.16:17:1116:17:11 Her father was the former chair of the Department16:17:13 of Pharmacology at Boston University, and he was

16:17:16 the president of a company called Riker16:17:18 Laboratories. He put together a team to develop16:17:23 metered dose inhalers, and within one year they16:17:26 had a new drug application with the FDA. So that16:17:29 was 1956. We just celebrated recently the16:17:32 50th anniversary of the metered dose inhaler.16:17:36 1316:17:36 These devices have a propellant in the canister16:17:39 with the drug. There needs to be surfactant in16:17:43 this solution, also, so that it keeps the drug and16:17:45 the propellant homogeneous.16:17:4816:17:48 If you zoom in on the guts of this device, you16:17:54 have a metering chamber here. The size of that16:17:58 determines the amount of drug that is delivered.16:18:00 There's a metering valve with a hole in it that16:18:03 when the canister is depressed, that delivery16:18:09 valve with the hole goes into the metering chamber16:18:13 that forces the air out of the actuator nozzle,16:18:16 and this comes out at a very, very high velocity.16:18:19 You've got a plume of medication that comes out16:18:21 the inhaler, and there's something called the16:18:25 flashing process where the particles rapidly16:18:28 become smaller. Particles initially, when they16:18:31 come out, are 35 microns in size. And the initial16:18:35 speed of the particles coming out of the inhaler16:18:38 is in the range of 15 to 30 meters per second.

16:18:41 That's about one‐tenth of the speed of a bullet16:18:45 coming out of a gun. Within 0.1 seconds, that16:18:49 speed decreases by half. These particles come out16:18:53 in a rapid string. They become smaller over time16:18:55 and then this is delivered to the airways.16:18:5916:19:01 So the problem, as I just mentioned, and the16:19:04 particles coming out in a rapid stream, there is16:19:08 multiple issues with putting the inhaler directly16:19:10 in your mouth. You have to coordinate pressing16:19:13 down and breathing at the same time. You don't16:19:14 have that much distance between the mouthpiece and16:19:17 the posterior pharynx and most of the particles16:19:20 will just impact against the posterior pharynx.16:19:23 And particularly if you inhale quickly, you may16:19:26 not give the particles time for them to get16:19:28 smaller in size, which does happen with time. So16:19:32 there's really a ballistic quality of metered dose16:19:37 inhalers.16:19:3816:19:38 To combat that, valved holding chambers were16:19:42 developed. There are different brands. This one16:19:44 is the Opti‐Chamber. These are the Aero Chambers.16:19:47 This allows having the particles slow down in the16:19:54 holding chamber.16:19:5516:19:56 Some studies have been done taking radioactive

16:19:59 labeled aerosols in these metered dose inhalers,16:20:02 comparing, giving the inhaler, just directly16:20:05 placing it in your mouth, compared to using the 1416:20:07 holding chamber. There is a 10‐ to 17‐fold16:20:10 decrease in radioactivity in the posterior pharynx16:20:13 when you use valved holding chambers.16:20:1716:20:18 There certainly are issues of using valved holding16:20:21 chambers, somewhat similar to issues with the16:20:24 nebulizer treatments. These are somewhat bulky.16:20:28 They're big and teenagers may not want to carry16:20:31 these around.16:20:3116:20:31 There's also somewhat of a more practical issue,16:20:35 which we normally don't think of. When you take16:20:38 these plastic inhalers right out of the box,16:20:41 there's a static electric charge on the walls of16:20:44 these inhalers, and you can have patients you16:20:47 start on a medication, they call you a week later16:20:49 and say, I'm not any better. That static electric16:20:52 charge can attract the medication to be on the16:20:56 walls of the inhaler. You can easily avoid that16:20:59 by, when you first take these devices right out of16:21:03 their box, you wash it with a dishwasher solution16:21:07 and that gets rid of the static electric charge16:21:09 for at least 30 days.16:21:11

16:21:11 Alternatively, there's this vortex device. This16:21:14 is a metal inhaler that does not have the static16:21:16 electric charge. This is likely more expensive16:21:18 than these. I have no practical experiences with16:21:21 this vortex inhaler.16:21:2316:21:28 So we'll take a quick diversion here and talk16:21:30 about atmospheric science, because this is16:21:33 important with metered dose inhalers. Ozone is16:21:35 both friend and foe. We've heard of ozone alert16:21:37 action days in the summertime when there's no16:21:40 wind. Ozone is irritating to our airways when it16:21:45 is here at ground level, but up in the16:21:46 stratosphere, ozone is very important for the16:21:50 health of us and all living creatures on earth.16:21:53 It's earth's natural sunscreen.16:21:5616:21:56 The World Health Organization estimates that if16:21:59 the ozone layer decreased by 10%, annually there16:22:03 would be an increase of 300,000 non‐melanoma16:22:06 cancers and 4500 melanoma cancers per year in the16:22:10 world. If you had just a 1% decrease in the ozone16:22:14 layer, then you'd have an increase of cataracts of16:22:18 0.5%. So the ozone layer filters out the UVB16:22:24 radiation from the sun.16:22:25 1516:22:27 Back in the 1970's, some scientists discovered the

16:22:30 catalytic reaction, which they received a Nobel16:22:33 Prize for in chemistry in 1995. And everyone16:22:38 knows where I'm going with this. This has to do16:22:40 with chlorofluorocarbons, which was the propellant16:22:44 in metered dose inhalers until fairly recently.16:22:47 The way the catalytic reaction works is that16:22:50 sunlight reacts with the chlorofluorocarbon16:22:54 molecule to knock off a chlorine atom. That16:22:57 interacts with ozone, which is 03. That yields an16:23:01 oxygen molecule and chlorine monoxide. That,16:23:05 then, interacts with an oxygen atom to yield16:23:09 another oxygen molecule and freeze up that16:23:11 chlorine to once again destroy another ozone16:23:14 molecule.16:23:1416:23:15 One chlorine atom can destroy 150,000 ozone16:23:20 molecules. And bromine is 45 times as potent as16:23:24 chlorine. So this certainly could be ‐‐ is a16:23:29 real issue, and in fact, studies have been done16:23:32 looking at what's called the ozone hole over the16:23:36 Antarctic. These are depictions of this ozone16:23:40 hole. It's measured in something called Dobson16:23:42 units. Less than 220, which is the more blue and16:23:46 purple area, defines the ozone hole. This is in16:23:49 September of 1980 and here's September of 2008.16:23:5316:23:54 This is due to our activity here on earth with

16:23:57 chlorofluorocarbons. Now, granted, certainly16:24:00 metered dose inhalers can be a small fraction of16:24:03 this, but as a result of this really startling16:24:07 occurrence that we brought on ourselves, in 198716:24:11 the Montreal Protocol was developed. That was a16:24:14 protocol in which, initially, the U.S. and 2916:24:17 countries signed on. Since 1987 there have been a16:24:20 number of other countries that have signed on.16:24:23 Now I believe it's 191 countries have signed onto16:24:25 this in which the production of ozone‐depleting16:24:32 substances is to be phased out in all of these16:24:35 countries that have signed on with the Montreal16:24:36 Protocol. And in fact, the original protocol16:24:40 stated that the ozone depleting substances needed16:24:44 to be decreased by half by 1998.16:24:4716:24:48 In another 13 days, we have a very significant16:24:50 date here in the U.S., because December 31st,16:24:53 2008, is the last date that we can have CFC's as16:24:58 propellants in metered dose inhalers. The16:25:01 changeover has already occurred and there's a16:25:04 color handout back there that looks at the 1616:25:06 different Albuterol preparations and then Xopenex16:25:10 or leave Albuterol, which you can see they have to16:25:14 be primed in how often you wash the actuator16:25:20 plastic part of it.16:25:21

16:25:21 There is actually one change of this which just16:25:23 occurred within the last week. The first16:25:24 medication ProAir HFA, it now has an FDA16:25:30 indication down to 4 years of age. So you can16:25:31 cross out the 12 and older and make that age 4.16:25:3416:25:35 So here's another off label reference in my talk.16:25:38 That patient I talked about at the very beginning,16:25:41 I switched them off of Pulmicort and put them on16:25:44 Flovent and Albuterol. Those medicines are16:25:47 medications are not approved by the FDA for16:25:49 patients less than age 4. Certainly we and people16:25:52 all around the country use these medications in16:25:55 infants and toddlers.16:25:5616:25:58 Getting back to the Montreal Protocol, the former16:26:01 Secretary General of the United Nations, Kofi16:26:04 Annan, said that this was the best example of16:26:07 international cooperation ever.16:26:0916:26:13 So there are differences between the16:26:15 chlorofluorocarbons and the HFA. The plume is16:26:18 different for the HFA. It's a softer plume. You16:26:21 also don't get the cold freon effect with the HFA16:26:25 inhalers. HFA stands for hydrofluoroalkane. So16:26:30 those now the propellants in metered dose16:26:33 inhalers.

16:26:3416:26:36 And lastly, we have dry powder medications. It is16:26:40 possible in the manufacturing process to make dry16:26:44 powder preparations that are less than 5 microns16:26:46 in size, but those have very strange aerodynamic16:26:50 properties and really don't go into the airway16:26:53 well. So what drug manufacturers had to do was to16:26:56 create an excipient that the particles were16:26:59 latched onto, and that's generally lactose. In16:27:03 these preparations, one needs a high inspiratory16:27:07 flowrate. That creates turbulence, which16:27:10 separates the excipient from the actual drug16:27:13 particle. The excipient or the lactose rams16:27:16 against the posterior pharynx, whereas the16:27:19 particles go down into the airways.16:27:2016:27:21 Now, before using this inhaler, because this is a16:27:23 dry powder, these particles need to be protected 1716:27:27 from the environment, because humidity can render16:27:30 them useless. This shows the innards of the16:27:33 discus. There are certainly other inhalers that16:27:36 are more linear stubby devices that either have16:27:39 medications in line or one needs to load a gelatin16:27:42 capsule, and that is pierced. With the discus,16:27:46 there is a strip of medications. When one16:27:49 advances the thumb wheel, that medication is16:27:52 pierced and it's brought in line with the

16:27:53 mouthpiece.16:27:5516:27:55 As I mentioned earlier, you need a deep, fast16:27:58 inspiration to separate the excipient from the16:28:02 drug. So the dry powder inhalers, they certainly16:28:06 can be useful. They're not as bulky as carrying16:28:09 around an inhaler with a valved chamber, but you16:28:12 can't have infants and toddlers use these. You16:28:14 have to have a child that's older, that can16:28:16 cooperate with a deep, fast inspiration. So I16:28:20 would say generally above age 6, 7, or 8 at the16:28:24 minimum to use a dry powder inhaler.16:28:2616:28:30 So let's get on to the meat of this. We've talked16:28:33 about different modalities of giving medications.16:28:37 What about comparing these head to head? This is16:28:39 one of the more pivotal studies. It is a16:28:41 meta‐analysis of studies. They did a MEDLINE16:28:46 search and there were three requirements to be16:28:48 included in this meta‐analysis. Children had to16:28:50 be less than age 5. They had to have been seen in16:28:54 the emergency department. And they had to have16:28:56 received ‐‐ it had to be a randomized controlled16:28:59 trial in which patients either received beta16:29:02 agonist by metered dose inhaler with a valved16:29:05 holding chamber or by nebulizer.16:29:07

16:29:07 And after they sifted through hundreds of studies,16:29:10 there were six that fit these criteria. They16:29:13 looked at what was better. The primary outcome16:29:17 was discharge from the emergency department. The16:29:20 line in the middle with one is neutral. If you're16:29:23 to the left of that, it favors metered dose16:29:26 inhaler with valved holding chamber. If you're to16:29:29 the right of that, it favors nebulizer. They16:29:32 found when they did this meta‐analysis that16:29:34 metered dose inhalers with valved holding chambers16:29:36 was superior. It decreased admissions from the16:29:40 emergency department by 50%. They also looked at16:29:43 secondary indicators, such as clinical scores.16:29:46 That was improved, also. 1816:29:4816:29:51 This is another large meta‐analysis in which16:29:54 randomized control trials were looked at, and they16:29:58 divided this into different categories. Delivery16:30:01 of short acting beta agonists in the emergency16:30:03 department, nebulizers, and metered dose inhalers16:30:06 with spacers are equally effective. Delivery of16:30:09 short acting beta agonists in the hospital16:30:11 setting. No difference in pulmonary function16:30:13 response between nebulizers and MDI with spacers.16:30:17 And the outpatient setting, no difference between16:30:20 MDI and dry powder inhalers. They said the use of16:30:23 nebulizers has not been adequately studied in

16:30:25 randomized control trials. And lastly, with16:30:28 inhaled corticosteroids, no difference between16:30:31 metered dose inhalers and dry powder inhalers, but16:30:34 there aren't any pediatric studies.16:30:3716:30:37 It's certainly easy to study acute asthma in that16:30:40 you have a sick patient. You can listen to16:30:43 wheezing. You can develop clinical scores. If16:30:45 they're old enough you can do pulmonary functions.16:30:47 A little bit more challenging with well‐controlled16:30:51 asthma on a chronic basis. How do you separate16:30:53 out one modality versus another?16:30:5616:30:57 And then lastly, a Cochran Database Systematic16:31:00 Review looked at the various studies that included16:31:06 2,066 children, 614 adults, and 25 trials. They16:31:10 found that the method of delivery beta agonist did16:31:13 not affect the hospital admission rate. In16:31:16 children, length of stay in the ED was16:31:18 significantly shorter for MDI with spacer. And16:31:22 their bottom line was metered dose inhalers with16:31:24 spacers produced outcomes that were at least16:31:27 equivalent to nebulizer delivery. Spacers may16:31:30 have some advantages compared to nebulizers in16:31:32 children with acute asthma.16:31:3316:31:35 Now, I realize this issue is very, very

16:31:37 polarizing. There are certainly medical personnel16:31:43 that swear by nebulizers are superior to any other16:31:47 modality of therapy. I would contend that the16:31:51 evidence actually is contrary that they're16:31:54 equivalent. There are certainly many advantages16:31:58 to metered dose inhalers and that it's much, much16:32:00 faster. And I really like this quote from a16:32:02 respected pediatric pulmonologist in Houston. I16:32:06 took this off of the pediatric e‐mail listserve16:32:10 probably at least three or four years ago. "For a 1916:32:13 variety of reasons, including economic cost,16:32:16 routine beta agonist administration at Texas16:32:18 Children's Hospital was changed from nebulization16:32:20 to MDI about three years ago in the OR, in the16:32:25 ICU, in the emergency department, and on the16:32:27 floors. It has been almost universally accepted.16:32:30 We still have many senior clinicians in the16:32:33 community who, via the old dogma, advise nebulizer16:32:36 therapy based on the theory of more deposition due16:32:39 to less need for cooperation in young ones. For16:32:43 my personal practice, the greatest evidence for16:32:46 the superiority of MDI has been the testimony of16:32:49 the vast majority of mothers of infants and16:32:51 toddlers. They almost all tell me the same story.16:32:54 It is quite difficult to impossible to get such16:32:58 children to sit still and wear a mask for 10 to 2016:33:00 minutes. However, all mothers can hold their

16:33:03 child and get their cooperation for two to four16:33:05 puffs via valved holding chamber. Overall, it16:33:09 takes less time, but when I explain the bare16:33:11 minimum about aerosol deposition, these mothers16:33:14 convince themselves and me that their children get16:33:17 more beta agonist or inhaled corticosteroid16:33:20 deposited in their airways. It takes less time16:33:24 and both children and mothers are happier."16:33:2616:33:26 A second very helpful development is that we are16:33:28 no longer demonstrating an alternate model when16:33:31 sick asthma patients come into the ER and receive16:33:34 nebulized treatment while we are trying to teach16:33:37 them in clinic to use an MDI. So perhaps one16:33:40 might say this is a zealot and I'm a little bit of16:33:43 a zealot, too, but to try to get the pulse of the16:33:46 pediatric pulmonology community, I placed a survey16:33:50 on this pediatric pulmonology Listserv earlier16:33:52 this week. I had 182 responses to five questions.16:33:56 This is one of the five questions.16:33:5816:33:58 "For outpatient therapy of asthma, what is your16:34:01 preferred mode of medication delivery?" Two, the16:34:05 182 said nebulizer. You've got about 28% MDI with16:34:12 valved holding chamber. About 5% with dry powder16:34:16 inhaler. And then this was an either/or MDI or16:34:20 dry powder inhaler.

16:34:2116:34:22 I put another question on the survey, which I16:34:24 don't have a slide for. I asked this group, "For16:34:28 your institution, do you have a policy encouraging16:34:32 MDI valved holding chambers?" The responses could16:34:35 be yes, no, or no, but we'd like to move in that 2016:34:40 direction. And it broke out 30%, about one‐third,16:34:43 one‐third, one‐third. One‐third yes, have a16:34:45 policy. One‐third don't. And one‐third would16:34:48 like to move in that direction.16:34:4916:34:50 Similar to Dr. Mallory in Seattle, there was a16:34:53 place on the survey for extra comments. I16:34:55 received a comment yesterday from Seattle16:34:57 Children's Hospital. They have also converted to16:35:00 MDI's with spacers in their hospital. They look16:35:03 at their quality indicators of length of16:35:05 admission. They're just as good as when they were16:35:08 using nebulizers.16:35:0916:35:10 There's a statement in the Cochran systematic16:35:12 review of the nebulizer culture, and I really like16:35:16 that phrase. In my imagination, I see petri16:35:19 dishes in the microlab with little nebulizers16:35:23 growing on them. But putting that out of my mind,16:35:25 how do you change the nebulizer culture? This is16:35:28 a really interesting study that was done in

16:35:30 Australia in which they looked at the available16:35:34 evidence. They convened a group of caretakers in16:35:37 the ER: Physicians, nurses, respiratory16:35:40 therapists. They looked at best practices and16:35:42 developed a guideline for using MDI's with valved16:35:46 holding chambers. Their guideline was anybody16:35:49 less than critical asthma, they needed to go to16:35:52 the ICU, got an MDI with a valved holding chamber.16:35:56 I'm really not even sure about that rationale, but16:35:58 be that as it may, they had an intense education16:36:01 period over three months in which they taught16:36:03 everyone in all the shifts about this guideline.16:36:07 They wanted to teach the public about this, so16:36:09 they placed ads on television and the newspaper.16:36:13 They developed education guidelines. Four16:36:17 families explained the rationale for changing from16:36:19 nebulizers to metered dose inhalers with spacers.16:36:22 How to use MDI's with spacers. How to clean them.16:36:25 And then they implemented this. They've16:36:28 prospectively evaluated 200 perspective patients.16:36:31 The guideline was followed appropriately for 95.5%16:36:37 of the chain, so it can go done.16:36:3916:36:40 There was an excellent, excellent commentary that16:36:43 accompanied this article. I wanted to read a few16:36:45 paragraphs from this commentary. "In the second16:36:48 century AD, Ptolemy, the Greek astronomer and

16:36:52 mathematician, postulated that the sun rotated16:36:54 around the earth. His theory remained 2116:36:57 unquestioned for 1200 years. In the year of his16:36:59 death, Copernicus published his Copernicun system,16:37:04 showing clearly that Ptolemy was wrong and that,16:37:07 in fact, the earth and other planets orbited the16:37:10 sun. Galileo agreed with Copernicus, but was16:37:10 forced by the Inquisition to recant his support of16:37:14 the Copernicun system almost a century after it16:37:18 had been scientifically proven.16:37:2016:37:20 "The benefits of spacer devices over nebulizers in16:37:24 childhood asthma may not be as earth shattering as16:37:27 whether the sun or the earth is the center of the16:37:30 solar system, but it addresses an important issue16:37:32 in one of the commonest childhood disorders of our16:37:35 time. How many of us can honestly say that spacer16:37:37 devices have mainly taken the place of nebulizers16:37:39 in our emergency rooms and in our pediatric wards?16:37:43 For this reason, I think the paper of my pal and16:37:46 his colleagues is immensely important. It shows16:37:49 in an exemplary way what managerial steps need to16:37:52 be taken to adopt scientifically proven research16:37:56 results. For true consensus to occur, much16:37:59 explanation and discussion is needed. Didactic16:38:02 decisions will inevitably result in failure,16:38:05 because colleagues and their views, have not been

16:38:08 treated with respect."16:38:0816:38:09 So I really like that commentary. It's not going16:38:12 to work if Mike Rock says we need the change in16:38:16 AFCH to all MDI's with valved holding chambers.16:38:20 It really needs to be a collaboration. I don't16:38:22 know if we're there. I don't know if we're ready16:38:24 to go there or not. I think the evidence in this16:38:26 talk says that we should. In the meantime, for16:38:29 the general pediatricians in the office, you could16:38:31 consider doing this in your office. For the16:38:34 residents here, if your continuity clinic director16:38:38 is not here, you could have discussions when you16:38:39 see a child with asthma. Well, how about putting16:38:42 them on an MDI with a valved holding chamber? I16:38:44 think it's a win/win situation and we all want to16:38:48 be winners in the end.16:38:5116:38:52 [Applause.]16:39:0116:39:01 This text is being provided in rough draft format.16:39:01 Communication Access Real‐time Translation (CART)16:39:01 is provided in order to facilitate communication16:39:01 accessibility and may not be a totally verbatim16:39:01 record of the proceedings. 22