1 00:00:16,135 --> 00:00:18,614 Hey, everybody. Welcome back to Palm Peeps. I'm 2 00:00:18,614 --> 00:00:20,954 excited today to be back with Luke Hedrick 3 00:00:21,015 --> 00:00:24,054 and doing another rapid fire journal club. We 4 00:00:24,054 --> 00:00:25,435 had a lot of fun discussing 5 00:00:25,815 --> 00:00:28,614 ARDS trials, a bunch of landmark trials, in 6 00:00:28,614 --> 00:00:30,295 ILD, I think was the last one we 7 00:00:30,295 --> 00:00:33,280 talked about. And we have, another great article 8 00:00:33,280 --> 00:00:35,059 to discuss today. Luke, how are you 9 00:00:35,359 --> 00:00:37,119 doing? Hey, Dave. I'm good. I'm happy to 10 00:00:37,119 --> 00:00:38,479 be back. It's been a minute, but I 11 00:00:38,479 --> 00:00:40,239 think this will be a nice addition to 12 00:00:40,239 --> 00:00:41,539 the journal club series. 13 00:00:41,920 --> 00:00:44,265 Yeah. And without further ado, we don't have 14 00:00:44,265 --> 00:00:46,265 to build up the suspense too much more. 15 00:00:46,265 --> 00:00:48,125 What trial are we gonna talk about today? 16 00:00:48,185 --> 00:00:49,945 Yeah. So today we're gonna be talking about 17 00:00:49,945 --> 00:00:52,104 the missed two trial, which was published in 18 00:00:52,104 --> 00:00:53,965 the new England journal in 2011. 19 00:00:54,744 --> 00:00:56,585 Great. Yeah. I think that this is a 20 00:00:56,585 --> 00:00:57,085 real, 21 00:00:57,480 --> 00:00:59,960 truly practice defining trial. We've talked about a 22 00:00:59,960 --> 00:01:02,039 lot that really shaped our practice and we'll 23 00:01:02,039 --> 00:01:03,640 dive into the details of what, but I 24 00:01:03,640 --> 00:01:05,980 think that this is one where very specifically 25 00:01:06,120 --> 00:01:08,200 the protocol and the trial has become a 26 00:01:08,200 --> 00:01:10,280 real standard of care. Let's talk about what's 27 00:01:10,280 --> 00:01:10,965 going on. 28 00:01:11,364 --> 00:01:12,724 So we know that there's gonna be some 29 00:01:12,724 --> 00:01:14,484 background since this is missed two and there 30 00:01:14,484 --> 00:01:16,084 was a missed one trial. So why don't 31 00:01:16,084 --> 00:01:18,164 you tell us what the background was leading 32 00:01:18,164 --> 00:01:19,944 up into this trial? Yeah. 33 00:01:20,484 --> 00:01:22,564 So we know that infections in the plural 34 00:01:22,564 --> 00:01:24,344 space are common and morbid 35 00:01:24,700 --> 00:01:26,719 and often require surgical intervention 36 00:01:27,099 --> 00:01:28,640 to definitively manage. 37 00:01:29,340 --> 00:01:30,159 And unfortunately, 38 00:01:31,020 --> 00:01:34,239 antibiotics and chest tube drainage alone often fail. 39 00:01:34,780 --> 00:01:36,939 The MIST-one trial, which was published in the 40 00:01:36,939 --> 00:01:38,880 New England Journal in 02/2005, 41 00:01:39,405 --> 00:01:40,864 studied intrapleural streptokinase, 42 00:01:41,724 --> 00:01:43,745 and unfortunately that showed no benefit. 43 00:01:44,364 --> 00:01:46,364 And so here, the MIS two trial was 44 00:01:46,364 --> 00:01:49,484 a study of intrapleural tPA and DNase to 45 00:01:49,484 --> 00:01:52,625 try to ease drainage of these infected effusions 46 00:01:52,844 --> 00:01:54,224 by breaking down septations 47 00:01:54,590 --> 00:01:56,530 and thinning the pleural fluid itself. 48 00:01:57,150 --> 00:02:00,109 Yeah, that's great. We've talked about complex pleural 49 00:02:00,109 --> 00:02:00,609 effusions 50 00:02:00,909 --> 00:02:03,549 previously on the show. We've talked about infected 51 00:02:03,549 --> 00:02:05,490 pleural spaces and empyema previously. 52 00:02:05,870 --> 00:02:08,530 This is a common problem that every pulmonologist 53 00:02:08,830 --> 00:02:10,604 is going to run into that you might 54 00:02:10,604 --> 00:02:12,205 see in the ICU, but you also might 55 00:02:12,205 --> 00:02:14,205 see in the clinic and the floor. And 56 00:02:14,205 --> 00:02:16,365 it's a really interesting one because it can 57 00:02:16,365 --> 00:02:18,764 affect people of all ages. I've definitely seen 58 00:02:18,764 --> 00:02:19,264 immunosuppressed 59 00:02:19,564 --> 00:02:22,569 people with really badly infected portal spaces, but 60 00:02:22,569 --> 00:02:25,230 I've also seen the young, really totally healthy 61 00:02:25,530 --> 00:02:27,069 who person who had pneumonia, 62 00:02:27,370 --> 00:02:30,510 maybe got therapy or maybe honestly muscled through 63 00:02:30,569 --> 00:02:32,810 and then developed a severe pleural infection. And 64 00:02:32,810 --> 00:02:34,810 so having guidance of how to manage it 65 00:02:34,810 --> 00:02:37,185 is super helpful. And we're really thinking about 66 00:02:37,185 --> 00:02:40,224 enzymatic therapy. I call this enzymatic therapy as 67 00:02:40,224 --> 00:02:40,884 its combination. 68 00:02:41,664 --> 00:02:42,805 Intrapleural tPA 69 00:02:43,104 --> 00:02:45,504 less, more, less of a pure enzyme than 70 00:02:45,504 --> 00:02:47,824 DNA ACE. The combination of them of trying 71 00:02:47,824 --> 00:02:49,044 to break down septations, 72 00:02:49,344 --> 00:02:51,669 thin the pleural fluid collection, and drain it 73 00:02:51,669 --> 00:02:52,169 appropriately 74 00:02:52,469 --> 00:02:54,330 is what can help make these people better. 75 00:02:54,710 --> 00:02:56,629 So how what was the study? They wanted 76 00:02:56,629 --> 00:02:58,550 to answer this question a little bit more 77 00:02:58,550 --> 00:03:00,790 thoroughly than and with a different protocol than 78 00:03:00,790 --> 00:03:03,030 in the first trial. So what study design 79 00:03:03,030 --> 00:03:04,090 did they come up with? 80 00:03:04,685 --> 00:03:05,905 Yeah. So the 81 00:03:06,205 --> 00:03:08,444 this study here was a double blind, double 82 00:03:08,444 --> 00:03:10,384 dummy, two by two factorial 83 00:03:10,685 --> 00:03:13,645 RCT that was run at 11 different hospitals 84 00:03:13,645 --> 00:03:14,384 in The UK 85 00:03:14,925 --> 00:03:18,120 from December 2005 to November 2008. 86 00:03:18,599 --> 00:03:20,519 And by double dummy, what I mean is 87 00:03:20,519 --> 00:03:22,759 that there was actually a sham placebo for 88 00:03:22,759 --> 00:03:24,599 each of the study drugs, which is pretty 89 00:03:24,599 --> 00:03:25,099 interesting. 90 00:03:25,560 --> 00:03:27,719 Yeah, it is really interesting. It really helps 91 00:03:27,719 --> 00:03:29,560 add to the validity of study that you're 92 00:03:29,560 --> 00:03:32,775 giving a placebo intervention. And these are very 93 00:03:32,775 --> 00:03:34,935 physical to give a placebo because you're thinking 94 00:03:34,935 --> 00:03:37,014 about going and instilling something into the chest 95 00:03:37,014 --> 00:03:38,954 tube. So really nice that we know 96 00:03:39,254 --> 00:03:41,495 everybody's really blind. So that's the patient, the 97 00:03:41,495 --> 00:03:42,555 treaters, the investigators. 98 00:03:43,909 --> 00:03:46,229 One thing that's really important with these infected 99 00:03:46,229 --> 00:03:49,110 pleural space infections is that outcome that we're 100 00:03:49,110 --> 00:03:50,169 looking for, because 101 00:03:50,469 --> 00:03:52,949 we're talking about a different set of outcomes 102 00:03:52,949 --> 00:03:55,030 than we may be in our classic ICU 103 00:03:55,030 --> 00:03:58,250 trials or our classic chronic pulmonary disease trials. 104 00:03:58,354 --> 00:04:00,754 So what were the primary and secondary outcomes 105 00:04:00,754 --> 00:04:03,094 that they wanted to, have some insights into? 106 00:04:03,875 --> 00:04:06,215 Yeah, the primary outcome here is. 107 00:04:06,914 --> 00:04:08,834 A little bit wordy, but it's the change 108 00:04:08,834 --> 00:04:10,294 in the percent of the hemithorax. 109 00:04:10,914 --> 00:04:13,074 That's taken up by the effusion on chest 110 00:04:13,074 --> 00:04:13,574 x-ray 111 00:04:14,050 --> 00:04:16,689 at day seven compared to day one, which 112 00:04:16,689 --> 00:04:18,550 is like a roundabout way of saying 113 00:04:18,930 --> 00:04:21,329 how much do we think we got out. 114 00:04:21,329 --> 00:04:23,889 We're not looking at just milliliters of fluid, 115 00:04:23,889 --> 00:04:25,670 but relative to 116 00:04:26,245 --> 00:04:28,104 that patient's own imaging. 117 00:04:28,884 --> 00:04:30,964 And then the key secondary outcomes that they 118 00:04:30,964 --> 00:04:32,904 looked at were referral to surgery, 119 00:04:33,365 --> 00:04:34,824 hospital length of stay, 120 00:04:35,365 --> 00:04:37,865 all cause three month and twelve month mortality, 121 00:04:38,500 --> 00:04:41,139 and then safety, any kind of adverse effects 122 00:04:41,139 --> 00:04:44,019 from instilling TPA and DNAs into the plural 123 00:04:44,019 --> 00:04:44,519 space. 124 00:04:45,060 --> 00:04:47,540 Totally. And I like this combination of outcomes 125 00:04:47,540 --> 00:04:50,180 because the primary outcome really gives us that 126 00:04:50,180 --> 00:04:52,519 functional, how did we do with this therapy? 127 00:04:52,824 --> 00:04:55,725 Did it have the intended physiologic effect 128 00:04:56,105 --> 00:04:59,145 that is represented by a radiographic finding that 129 00:04:59,145 --> 00:05:01,165 we were shooting for by giving this therapy? 130 00:05:01,464 --> 00:05:03,305 And then all of the secondary outcomes are 131 00:05:03,305 --> 00:05:04,985 the key ones that we care about for 132 00:05:04,985 --> 00:05:06,910 these patients. And I'll make a special note 133 00:05:06,910 --> 00:05:09,389 about the referral referral for surgery. This is 134 00:05:09,389 --> 00:05:12,529 often the endpoint of interest in these plural 135 00:05:12,670 --> 00:05:15,629 interventions for effective plural spaces because we know 136 00:05:15,629 --> 00:05:17,389 that there is a surgical option that can 137 00:05:17,389 --> 00:05:18,750 be done. You can always go in and 138 00:05:18,750 --> 00:05:21,089 open and clear out the the plural space, 139 00:05:21,185 --> 00:05:22,464 but you also wanna see if you can 140 00:05:22,464 --> 00:05:24,805 get away without doing that to decrease morbidity 141 00:05:24,865 --> 00:05:25,605 for the patients. 142 00:05:26,545 --> 00:05:27,985 All right. So we know what we're gonna 143 00:05:27,985 --> 00:05:29,824 be thinking about. Now we should think about 144 00:05:29,824 --> 00:05:31,745 who these patients are. So what were the, 145 00:05:31,904 --> 00:05:34,064 key inclusion criteria that we have for this 146 00:05:34,064 --> 00:05:34,564 study? 147 00:05:35,149 --> 00:05:37,790 Yeah. So the inclusion and exclusion criteria, I 148 00:05:37,790 --> 00:05:38,449 think we're 149 00:05:38,829 --> 00:05:41,490 aiming to cast a pretty broad net. So 150 00:05:41,709 --> 00:05:43,009 in terms of inclusion criteria, 151 00:05:43,550 --> 00:05:46,750 anyone with clinical evidence of infection that was 152 00:05:46,750 --> 00:05:50,345 assessed by the recruiting physician, so fever, CRP, 153 00:05:50,485 --> 00:05:51,545 white blood cell count. 154 00:05:52,084 --> 00:05:55,204 And then also had pleural fluid with any 155 00:05:55,204 --> 00:05:57,144 of grossly purulent drainage, 156 00:05:57,605 --> 00:06:00,084 a positive fluid culture or Gram stain, or 157 00:06:00,084 --> 00:06:02,245 a pH of less than 7.2. Any of 158 00:06:02,245 --> 00:06:05,160 those would get you included in the trial. 159 00:06:05,460 --> 00:06:07,300 And then in terms of exclusion, they were 160 00:06:07,300 --> 00:06:10,259 aiming to exclude people with increased bleeding risk 161 00:06:10,259 --> 00:06:12,520 because of the TPA that was being instilled 162 00:06:12,980 --> 00:06:15,379 or people who they didn't think could re 163 00:06:15,379 --> 00:06:18,020 expand the long after drainage, because that's really 164 00:06:18,020 --> 00:06:21,394 what drives the benefit other than source control. 165 00:06:21,774 --> 00:06:23,875 A lot of the benefit people get from 166 00:06:23,935 --> 00:06:25,935 drainage of effusions is from re expanding the 167 00:06:25,935 --> 00:06:27,535 lung. And so if you can't do that, 168 00:06:27,535 --> 00:06:29,854 you're unlikely to really benefit from the trial 169 00:06:29,854 --> 00:06:30,834 in the first place. 170 00:06:31,339 --> 00:06:33,580 And so there's exclusion criteria where an age 171 00:06:33,580 --> 00:06:34,319 18, 172 00:06:35,180 --> 00:06:37,120 if you had previously gotten intrapleural 173 00:06:37,500 --> 00:06:38,800 medications. So fibrinolytics, 174 00:06:39,259 --> 00:06:39,759 DNase, 175 00:06:40,220 --> 00:06:42,779 or both for an empyema, if you were 176 00:06:42,779 --> 00:06:44,639 allergic to any of the study drugs, 177 00:06:45,004 --> 00:06:47,404 if you had a coincidental stroke. And so 178 00:06:47,404 --> 00:06:49,745 really they're thinking about the hemorrhage risk. 179 00:06:50,365 --> 00:06:52,524 If you'd had major hemorrhage or trauma or 180 00:06:52,524 --> 00:06:54,845 major surgery in the last five days, if 181 00:06:54,845 --> 00:06:56,544 you'd had a previous pneumonectomy 182 00:06:56,845 --> 00:06:58,144 on the infected side, 183 00:06:58,699 --> 00:07:00,779 if you're pregnant or lactating and then the 184 00:07:00,779 --> 00:07:02,000 kind of usual catchall 185 00:07:02,699 --> 00:07:05,100 of expected survival less than three months from 186 00:07:05,100 --> 00:07:07,899 something other than what caused the plural problem 187 00:07:07,899 --> 00:07:08,959 in the first place. 188 00:07:09,660 --> 00:07:11,899 Yeah, that's great. I think casting a broad 189 00:07:11,899 --> 00:07:13,899 net, really capturing the people we wanna think 190 00:07:13,899 --> 00:07:17,264 about. A few interesting notes on this. I 191 00:07:17,264 --> 00:07:19,665 think that their inclusion about the plural fluid 192 00:07:19,665 --> 00:07:20,165 studies, 193 00:07:20,705 --> 00:07:23,824 it really shows us that in practice, there's 194 00:07:23,824 --> 00:07:24,324 sometimes 195 00:07:25,345 --> 00:07:26,324 less of a 196 00:07:27,040 --> 00:07:30,639 clinical distinction between complex, para pneumonic infusion and 197 00:07:30,639 --> 00:07:34,180 mpyema. The classic mpyema is that grossly purulent 198 00:07:34,240 --> 00:07:36,259 fluid that comes out of your pleural drainage. 199 00:07:36,319 --> 00:07:38,639 But then we also think about getting there 200 00:07:38,639 --> 00:07:41,139 with a really low pH or positive cultures 201 00:07:41,314 --> 00:07:43,634 or having a complex para pneumonic infusion that 202 00:07:43,634 --> 00:07:45,894 meets one of those criteria. And this is 203 00:07:45,954 --> 00:07:47,634 including all of those people because any of 204 00:07:47,634 --> 00:07:49,555 those people are those that might need to 205 00:07:49,555 --> 00:07:51,714 progress to surgery or might have really morbid 206 00:07:51,714 --> 00:07:53,954 outcomes if we don't end up fixing this 207 00:07:53,954 --> 00:07:56,180 pearl space. And then I'll just comment on 208 00:07:56,180 --> 00:07:57,079 the exclusion. 209 00:07:57,779 --> 00:07:59,459 There's a lot of debate about how much 210 00:07:59,459 --> 00:08:02,339 bleeding risk there is by instilling tPA into 211 00:08:02,339 --> 00:08:04,579 the pleural space. Obviously, some of this will 212 00:08:04,579 --> 00:08:06,899 have systemic effects. That being said, you're not 213 00:08:06,899 --> 00:08:09,305 giving IV tPA, but I think it's very 214 00:08:09,305 --> 00:08:12,025 reasonable within a child to be conservative and 215 00:08:12,025 --> 00:08:14,264 say that anybody who has an increased risk 216 00:08:14,264 --> 00:08:16,185 of bleeding, we're gonna exclude just so we 217 00:08:16,185 --> 00:08:18,925 have a true sense of how this intervention 218 00:08:18,985 --> 00:08:21,490 can help people in the purest sense. And 219 00:08:21,490 --> 00:08:23,329 so look, I always love that you summarize 220 00:08:23,329 --> 00:08:24,849 who these people are for us and we 221 00:08:24,849 --> 00:08:27,970 give a good blanket statement. So who, after 222 00:08:27,970 --> 00:08:30,209 we've done this inclusion exclusion, who are we 223 00:08:30,209 --> 00:08:31,269 really looking at? 224 00:08:31,810 --> 00:08:33,829 Yeah. So who they ended up including 225 00:08:34,289 --> 00:08:37,110 were middle aged, mostly male patients 226 00:08:37,784 --> 00:08:40,284 with complicated plural effusions or empyemas 227 00:08:40,825 --> 00:08:43,464 that occupied about one third to two fifths 228 00:08:43,464 --> 00:08:44,284 of the hemithorax 229 00:08:45,225 --> 00:08:48,184 with mostly small bore chest tubes for mostly 230 00:08:48,184 --> 00:08:49,565 community acquired infections 231 00:08:50,220 --> 00:08:52,620 and small bore here. They meant less than 232 00:08:52,620 --> 00:08:54,079 15 French in size. 233 00:08:55,019 --> 00:08:57,019 That's great. And I think this goes into 234 00:08:57,019 --> 00:08:59,980 some of the previous existing data on, pleural 235 00:08:59,980 --> 00:09:02,955 interventions and chest tube drainage. We've had prior 236 00:09:02,955 --> 00:09:05,195 trials that show that small bore chest tubes 237 00:09:05,195 --> 00:09:08,714 for complex paradigmatic effusion or empyemas are generally 238 00:09:08,714 --> 00:09:10,955 just as effective as surgical chest tubes, even 239 00:09:10,955 --> 00:09:13,355 though they have a smaller French caliber, whereas 240 00:09:13,355 --> 00:09:15,455 opposed to say maybe like a hemothorax, 241 00:09:15,889 --> 00:09:17,649 we're usually leaning a little bit more towards 242 00:09:17,649 --> 00:09:19,110 a larger bore chest tube. 243 00:09:19,730 --> 00:09:21,490 So that brings us to the intervention a 244 00:09:21,490 --> 00:09:23,169 little bit. You already mentioned it's small bore 245 00:09:23,169 --> 00:09:25,169 chest tubes, but I think the particulars of 246 00:09:25,169 --> 00:09:27,009 how they were actually doing this intervention is 247 00:09:27,009 --> 00:09:28,934 really important for how we could bring this 248 00:09:28,934 --> 00:09:31,654 trial into practice. So what were the specifics 249 00:09:31,654 --> 00:09:32,475 of the intervention? 250 00:09:33,335 --> 00:09:35,174 Yeah, so this was a two by two 251 00:09:35,174 --> 00:09:38,535 factorial trial. They took two ten patients and 252 00:09:38,535 --> 00:09:41,095 then randomized them about one to one of 253 00:09:41,095 --> 00:09:44,350 the following forearms. So either tPA and DNase, 254 00:09:44,570 --> 00:09:46,590 which were ten milligrams and five milligrams, 255 00:09:47,290 --> 00:09:48,350 tPA and placebo, 256 00:09:49,370 --> 00:09:51,790 DNase and placebo, or double placebo. 257 00:09:52,330 --> 00:09:54,889 And then those medications were both given twice 258 00:09:54,889 --> 00:09:56,509 a day for three days 259 00:09:56,934 --> 00:09:58,855 with clamping of the chest tube for an 260 00:09:58,855 --> 00:10:01,495 hour after each dose in an attempt to 261 00:10:01,495 --> 00:10:03,254 keep the drug on the pleural space and 262 00:10:03,254 --> 00:10:04,934 let it act for a little bit. And 263 00:10:04,934 --> 00:10:06,774 those drugs were not necessarily given at the 264 00:10:06,774 --> 00:10:09,254 exact same time. And so a lot of 265 00:10:09,254 --> 00:10:10,235 time at the bedside 266 00:10:10,615 --> 00:10:11,115 instilling 267 00:10:11,789 --> 00:10:14,509 medications and clamping tubes and then returning an 268 00:10:14,509 --> 00:10:16,209 hour later to unclamp. Yeah. 269 00:10:16,909 --> 00:10:18,269 And if you, I don't know if you've 270 00:10:18,269 --> 00:10:20,029 done this in Belgium, but I definitely remember 271 00:10:20,029 --> 00:10:22,269 doing it, going by putting the drug in, 272 00:10:22,269 --> 00:10:24,695 coming back, opening up, putting another drug in, 273 00:10:24,695 --> 00:10:26,134 or putting them in the combo. And I 274 00:10:26,134 --> 00:10:28,215 think this guidance is really helpful for what 275 00:10:28,215 --> 00:10:30,375 we do in practice, especially because we have 276 00:10:30,375 --> 00:10:32,375 these arms that compare it to what if 277 00:10:32,375 --> 00:10:34,295 you just used one drug. And we actually 278 00:10:34,295 --> 00:10:35,735 have a whole other trial of just what 279 00:10:35,735 --> 00:10:37,894 streptokinase did, as you mentioned, the missed one 280 00:10:37,894 --> 00:10:39,720 that didn't have this effect. The devil is 281 00:10:39,720 --> 00:10:40,460 in the details 282 00:10:41,080 --> 00:10:42,919 and we really like to focus on trying 283 00:10:42,919 --> 00:10:44,759 to do it exactly as they did in 284 00:10:44,759 --> 00:10:46,539 their combined intervention arm. 285 00:10:46,840 --> 00:10:48,840 So with that, what did they end up 286 00:10:48,840 --> 00:10:51,080 finding? What were the outcomes that they ended 287 00:10:51,080 --> 00:10:52,274 up seeing in the chart? 288 00:10:52,995 --> 00:10:55,335 Yeah, I think in general, it's worth just 289 00:10:55,394 --> 00:10:57,894 discussing the outcomes of that TPA and DNAs 290 00:10:58,035 --> 00:10:59,014 arm and combination. 291 00:10:59,555 --> 00:11:02,355 Because there was a highly significant interaction between 292 00:11:02,355 --> 00:11:04,434 the two for the primary outcome and the 293 00:11:04,434 --> 00:11:06,134 P of 0.002. 294 00:11:06,590 --> 00:11:08,929 And so first thinking about efficacy, 295 00:11:09,549 --> 00:11:12,529 that primary outcome of portal effusion size reduction 296 00:11:12,990 --> 00:11:14,690 was significant. They found 297 00:11:15,149 --> 00:11:16,850 a almost thirty percent reduction 298 00:11:17,389 --> 00:11:19,549 in the space in the hemothorax that was 299 00:11:19,549 --> 00:11:20,529 taken up at baseline 300 00:11:21,134 --> 00:11:23,054 versus a 7.9% 301 00:11:23,054 --> 00:11:23,554 reduction 302 00:11:23,855 --> 00:11:25,875 of a fusion size with the placebo. 303 00:11:26,654 --> 00:11:29,535 And interestingly, neither drug worked on their own 304 00:11:29,535 --> 00:11:32,274 in terms of just draining the fluid out. 305 00:11:32,975 --> 00:11:35,554 Yeah, that that's exactly really helpful. 306 00:11:36,240 --> 00:11:38,879 To hear about how the arms that we 307 00:11:38,879 --> 00:11:40,720 had of the single drugs really didn't give 308 00:11:40,720 --> 00:11:43,220 us that same reduction. And so if 309 00:11:43,519 --> 00:11:45,519 there ever was a time I remember one 310 00:11:45,519 --> 00:11:47,039 time I had a patient where there was 311 00:11:47,039 --> 00:11:48,639 gonna be a delay on the tPA, and 312 00:11:48,639 --> 00:11:50,340 they said, could we just do the DNAs? 313 00:11:50,399 --> 00:11:53,625 And obviously logistical things come into play, but 314 00:11:53,625 --> 00:11:55,865 this really showed that it's this combination, the 315 00:11:55,865 --> 00:11:57,964 synergistic effect that we're trying to capture. 316 00:11:58,264 --> 00:12:00,105 So that's great. We know we achieved this 317 00:12:00,105 --> 00:12:04,044 radiologic outcome that probably represents some physiologic significance. 318 00:12:04,519 --> 00:12:07,080 But what about clinically meaningful outcomes for these 319 00:12:07,080 --> 00:12:07,580 patients? 320 00:12:08,360 --> 00:12:09,720 Yeah. And so that kind of leads us 321 00:12:09,720 --> 00:12:11,740 to those key secondary outcomes. 322 00:12:12,279 --> 00:12:13,720 The big one, I don't wanna bury the 323 00:12:13,720 --> 00:12:16,039 lead too much here, was referral for surgery. 324 00:12:16,039 --> 00:12:18,684 So in the tPA and DNase arm, only 325 00:12:18,684 --> 00:12:21,084 four percent of patients were referred for surgery 326 00:12:21,084 --> 00:12:23,485 versus sixteen percent in the placebo arm. So 327 00:12:23,485 --> 00:12:25,485 an odds ratio of point one seven and 328 00:12:25,485 --> 00:12:27,264 a p value of point o three. 329 00:12:27,964 --> 00:12:31,164 The other secondary outcomes were generally neutral to 330 00:12:31,164 --> 00:12:33,800 favorable. So the hospital length of stay when 331 00:12:33,800 --> 00:12:36,440 you excluded a, like, nearly four hundred day 332 00:12:36,440 --> 00:12:39,639 outlier in the placebo group favored the tPA 333 00:12:39,639 --> 00:12:41,639 and DNAs. The mean length of stay was 334 00:12:41,639 --> 00:12:44,360 just under twelve days versus seventeen days. And 335 00:12:44,360 --> 00:12:45,580 then there was no mortality 336 00:12:46,040 --> 00:12:48,220 difference. And overall seems like it 337 00:12:48,575 --> 00:12:50,414 drained the fluid. People got out of the 338 00:12:50,414 --> 00:12:53,054 hospital quicker and a good chunk of them 339 00:12:53,054 --> 00:12:55,554 did not need surgery compared to the placebo 340 00:12:55,615 --> 00:12:57,695 group. Yeah. Yeah. I think you said, as 341 00:12:57,695 --> 00:12:59,134 you said, that's a lead. You're getting to 342 00:12:59,134 --> 00:13:01,554 avoid surgery for a healthy chunk of people. 343 00:13:01,750 --> 00:13:03,910 Sixteen percent is not a huge number, but 344 00:13:03,910 --> 00:13:05,910 going down from sixteen to four percent has 345 00:13:05,910 --> 00:13:07,910 a definitely a big impact. And I don't 346 00:13:07,910 --> 00:13:09,590 think it's so surprising we didn't see a 347 00:13:09,590 --> 00:13:12,950 mortality difference. We certainly have multiple treatments for 348 00:13:12,950 --> 00:13:15,450 these infected pleural spaces. These patients were closely 349 00:13:15,509 --> 00:13:17,595 monitored. So even the ones where it wasn't 350 00:13:17,595 --> 00:13:19,754 working, I'm sure are getting very good care. 351 00:13:19,754 --> 00:13:21,514 And so it makes sense that you might 352 00:13:21,514 --> 00:13:23,754 not see that mortality, but hospital length of 353 00:13:23,754 --> 00:13:26,715 stay, referral for surgery are certainly very clinically 354 00:13:26,715 --> 00:13:27,215 significant. 355 00:13:28,315 --> 00:13:30,269 And then you mentioned some of the concerns 356 00:13:30,269 --> 00:13:32,350 with the exclusion criteria about safety. We aren't 357 00:13:32,350 --> 00:13:34,829 doing an active drug therapy into this plural 358 00:13:34,829 --> 00:13:36,509 space, so we always have to think about 359 00:13:36,509 --> 00:13:39,070 adverse events for these patients. Was there any 360 00:13:39,070 --> 00:13:41,070 difference or signal in the adverse events between 361 00:13:41,070 --> 00:13:41,649 the groups? 362 00:13:42,215 --> 00:13:44,134 No. I think just to be succinct with 363 00:13:44,134 --> 00:13:46,295 it, there really was no difference in adverse 364 00:13:46,295 --> 00:13:49,095 effects between the groups. There were six serious 365 00:13:49,095 --> 00:13:49,595 events 366 00:13:50,134 --> 00:13:52,615 across all four arms that were mostly related 367 00:13:52,615 --> 00:13:55,175 to bleeding. There were some intrapleural bleeding, some 368 00:13:55,175 --> 00:13:56,554 GI bleeding, and some hemoptysis. 369 00:13:57,279 --> 00:13:59,679 And then the other adverse effects were made 370 00:13:59,679 --> 00:14:02,320 up of some combination of discomfort or pain 371 00:14:02,320 --> 00:14:03,539 with drug administration, 372 00:14:04,320 --> 00:14:06,480 so the actual, like, flushing into the pleural 373 00:14:06,480 --> 00:14:08,899 space. A couple of folks had some transient 374 00:14:08,960 --> 00:14:11,779 mental status changes and then a rash. But 375 00:14:12,044 --> 00:14:14,284 overall, there was no difference between the groups. 376 00:14:14,284 --> 00:14:15,725 And so it seemed like it was pretty 377 00:14:15,725 --> 00:14:17,105 well tolerated, all taken. 378 00:14:17,485 --> 00:14:19,565 Yeah. That's great. Certainly, the pleural space is 379 00:14:19,565 --> 00:14:21,404 very sensitive. There can always be pain with 380 00:14:21,404 --> 00:14:23,004 this, but we always have to balance the 381 00:14:23,004 --> 00:14:24,284 fact that there would be pain if you 382 00:14:24,284 --> 00:14:25,264 had to have a surgical intervention as well. 383 00:14:25,264 --> 00:14:25,440 And even the 384 00:14:29,519 --> 00:14:31,539 All right. So we've talked about the outcomes. 385 00:14:31,600 --> 00:14:33,200 We talked about who were the patients. It 386 00:14:33,200 --> 00:14:35,440 seems like we have a really positive effect 387 00:14:35,440 --> 00:14:36,179 in intervention. 388 00:14:36,720 --> 00:14:39,120 What's our gross takeaway? What are we using 389 00:14:39,120 --> 00:14:41,735 this trial to guide our practice about? Yeah. 390 00:14:41,735 --> 00:14:44,214 I think the newspaper headline version of this 391 00:14:44,214 --> 00:14:45,355 is that combination 392 00:14:45,735 --> 00:14:49,574 intrapleural enzyme therapy with TPA and DNAs improves 393 00:14:49,574 --> 00:14:52,375 drainage of infected pleural fluid and reduces the 394 00:14:52,375 --> 00:14:54,794 need for surgery and hospital length of stay. 395 00:14:55,460 --> 00:14:58,279 Yeah. Fantastic. I think a truly practice defining 396 00:14:58,340 --> 00:14:59,860 trial, we're doing this every 397 00:15:00,660 --> 00:15:02,179 maybe not every day, but every week or 398 00:15:02,179 --> 00:15:03,860 month in the hospital for patients to have 399 00:15:03,860 --> 00:15:05,700 this. And based on this trial, we should 400 00:15:05,700 --> 00:15:08,360 really be looking for reasons to give patients 401 00:15:08,774 --> 00:15:12,214 combination enzymatic therapy, as opposed for reasons for 402 00:15:12,214 --> 00:15:13,414 them not to get it. Cause we think 403 00:15:13,414 --> 00:15:15,975 this is a positive intervention that will have 404 00:15:15,975 --> 00:15:19,254 good outcomes for their future lung health, their 405 00:15:19,254 --> 00:15:21,334 lung expansion, and for not needing surgery to 406 00:15:21,334 --> 00:15:21,990 get there. 407 00:15:22,309 --> 00:15:24,230 All right. Thanks everybody for listening. Thank you, 408 00:15:24,230 --> 00:15:26,309 Luke, for again, an excellent study in walking 409 00:15:26,309 --> 00:15:28,409 us through so efficiently and succinctly. 410 00:15:28,789 --> 00:15:30,389 And we'll see you all next time when 411 00:15:30,389 --> 00:15:31,690 you tune in for Palm Beach.