So I'm Central Sadai. I'm a part of the surgical pain management team here. Um, so we are fortunate to work with our surgeons. We have, we have extensive experience in managing uh Pus patients. So a lot of patients, especially children and younger adults, um. In our experience, we use a lot of on-cue pumps for our orthopedic procedures. We have thousands of on-cue pumps. We have used thousands of them. And what we have learned, especially with the Pus population, is that nothing is as good as epidural analogiesia for Pus patients. Oncup pumps comes second to epidural in our experience in talking to other hospitals in the country. Including Seattle children who have gone from epidural to acupunct recently, they're having some issues as well. So nothing comes as good as epidural in our experience. We try to optimize our epidural management very aggressively, and what I mean is very aggressively is we start our Pain management is pretty much very similar to yours. We preempt everything and we start with pregabalin before surgery and we use cele coccib before surgery and we add clonidine to the epidural solution along with local anesthetic. We don't have the narcotics. So more than 95% of our patients do not get a PCA along with epidural, which says a lot about how we manage our epidural. We see our patients at least 3 times a day. We tweak the rate or The position to optimize the epidural analgesia. Um So we use OncuPump as a bridge between epidural and oral transition. So, and some of our patients have gone home with Oncuump with good results. We are working on other ways to minimize pain as well, but for us, Epidural works really well, and more than 99% of our patients get epidural analgesia and We select patients who would get on cue pump, and I think I have a slide for that. OK, yeah, so typically older patients, young adults, they have a lot more pain because of rigidity, and we select on cue pump for those patients. And some patients with comorbidity like Ehler-Dunlas syndrome, they have extensive pain and they even have pain before surgery, or those patients we use Oncuump as a bridge between the epidural and oral medications. Patients with psychological problems like depression, excessive anxiety, they benefit from. Something more than narcotics. So for those patients we use on coump, and if there is any history of even family history of substance abuse, those patients would benefit by just minimizing the opioid use, using epidural and Oncuump subsequently. And if a patient has an extensive pectus and we do a more involved surgery, we expect a lot more pain. In that situation, we employ cu pumps subsequent to epidurals. And the recent literature, especially in children, shows that if a child and also their parent They have pain catastrophization if they anticipate negative outcomes. Especially I will have a lot more pain after the surgery. This is called a pain catastrophization. They are more likely to have more pain, and we try to identify these patients before surgery, especially when they come to our preoperative education, and one of our pain nurses will go to the education class and try to identify those patients. In those patients who would do pain catastrophization and with a lot of anxiety, we try to encourage acupunpt use. So, uh, a few, a bunch of questions. Um, I'll start from the end. The, the positioning of the patient, when you have them, when you have an epidural, do you always keep them flat? So when we place epidural, there are two major risks with epidural. So one is the injury with epidural, and most of I think N group, they had the two patients with paraplegia because of epidural placement. So that is a major concern with epidural, but it happens fortunately so rarely, and we can even avoid that problem if you are very careful. So what we do here to minimize the neurological risk of epidural is we try to place our epidurals and the patient is awake with minimal sedation in sitting position, and that minimizes the risk of traumatic epidural placement and we have an experienced dedicated pain team staff, so one day they do the epidural in our hospital to minimize the chance of Injury with multiple attempts by inexperienced people, and the second risk is infection with epidural, especially epidural abscess, if you leave the catheter for too long. So that's why we take our epidural catheters out on the 3rd day after surgery. And another issue, not most of the Neurological risk with epidural is related to trauma in children, especially if you look at the paraplegia or neurological injury from epidural, it's not from traumatic placement, it's from hypoperfusion of spinal cord. So we try to aggressively manage blood pressure to maintain the spinal cord perfusion. And if the child has low blood pressure, we would aggressively manage and reduce the rate and take out clonidine from the solution so that we optimize spinal cord perfusion to avoid neurological injuries. Um, the, uh, Don, regarding the, um, on cue, it's interesting, I think. The data is all over the place with on cue. I mean, some people say there's no difference. Some people have shown a difference. I think it depends on the procedure and maybe, um, you know, specifically for Pus, the on cue pump works. Um, I've had plus minus success with it. Um, and the infection thing was a concern of mine. So it was interesting that you said that, um, that the, the, the group in, in, um. And Don Nuss's group has the issue with infection because I'm concerned about putting a catheter near an implant. Um, so, but you, but it's also interesting that you haven't. Some of the, the questions here regarding all these different things, epidurals and PCAs and, and David, I think I'm going to be answering your, asking your question here is, Don, the stuff you presented mostly with adults, how does this change with adolescents and, and younger children? Do we modify and I guess. You know, after you heard what you just heard, does it, do you think that your management would be different in adolescents versus adults? For me, at least for me. So, um, you know, where I am at Mayo, I can't do children, so I have to do all my kids down at Phoenix Children's Hospital, and they have MOOC catheters not on cue. And I've been working for 5 years to try to get on cue there, but the mood catheters are like 3 ccs or 2 cc's an hour, and they leak like crazy because their introducer is wider than the track, and I feel like they don't help at all. The kids and to be honest, you know, I think it depends on a lot of things. It depends on how much is being delivered. It depends on where it's being delivered to. It depends on the catheter size and length. So the catheters come 5 and 7.5. The 5 is too short to cover the area. The 7.5 is much better, and you know if you have an introducer that dilates the track too wide, you get like this backflow leak, so you don't get the permeation. So I think there's so many factors, and most of the on cue data, if you look at it in thoracic, is all thoracotomy based, and those they actually tunnel subpleural. So I think it's really hard to Extrapolate the data because it's like all these apples and oranges and applications and location and user relativity. Um, you know, in our case, um, all I wanted to know is if they, if they worked as good as epidural, um, and, and it didn't make any difference, and maybe it's because our epidurals with local only don't help that much, but, but overall, you know, the patients are out of here in 2 days and, and they're up walking around the next day and The kids are too, even with the, the mood cat their stays a little bit longer, but even though the catheter probably is not helping as much and we pull it out the second day there because it's leaking all over. So I mean, I, I, I think it's hard to, to, to give an answer. Um, I did not, I have not had a single infection, knock on wood, not with the on cue. And now that I just said that, I'm probably going to have 3 next week, but, it's OK. You knocked on wood, you're good. But yeah, I haven't had any infections and they work good and so they're simple and you know, I've continued to use them. So there was a comment about Experil and the use in kids and I've actually approached them and asked if I could do a prospective trial and they weren't interested. Um. The fear I have, and I'm wondering if anyone, is that if they have a reaction to it, it's there now for 3 days. Is that, have you seen that? So we use Exal, which is lipos in our hospital, but not for Pectus patients. So for adult donor nephrectomy patients, we do a tap block, which is a transverse abdominal plain block. So we have done more than 20 patients now who have had donor nephrectomy. It is very safe. We have not had any problem with allergy, and it is safer than plain local anesthetic, including bupivacaine or ropivacaine. In the sense, the treatment for a local anesthetic toxicity is intralipid. This medication is in the intralipid, so it is safer and it acts for 72 hours. In our experience, the donor nephrectomy experience, our patients go off of PCA one day earlier and they have less opioid related adverse effects and they use less opioids. And unfortunately it is not approved for pediatric use by the FDA yet. And so that's why we don't use for pediatric patients in our hospital. Yeah, I use it on all my adult vats. It's an intercostal block, and I use it for all my bar removals on the adults. And it works extremely well and I like it. I have had a couple of patients that had localized reactions to it that were very impressive. I mean, it's like you drew a big red circle, you know, around the area that's injected. And bad enough that I've had to put one of them on steroids for the reaction because it is going to be 3 days before it goes away. But for the most part, you know, I haven't had issues with it. It works very well. So David, I'm going to try to ask you a question, I guess. So back to the epidural, because we want to address this. He says if you If you have someone for 48 to 72 hours on an epidural during those three days, do they have to lay flat on their back? No, so we allow patients to walk inside the room and so we don't have any narcotic in it, so they can even go outside their room with help. So even if we remove our Foley catheter the next day after surgery, we allow ambulation. So Epidural helps with the ambulation. There's a bunch of questions still, and I guess I would invite. You and Don or whatever to maybe answer some of these because we are running a bit over on time. So maybe now we should take a break and answer some of these narcotic questions through chat. I'm going to talk about our unique CCHMC way of managing pain after PETA surgery and current currently available literature evidence for managing pain after PETA surgery. Then benefits and risks of different modalities of pain management, including say epidural, PCA, on cue wear pumps, and other elastomeric pumps. Then I'll share our protocol, our current protocol, how we manage Pus pain and what are the opportunities to further improve pain control and outcomes following Pus surgery. We are trying to push our limits to just make a big impact on our patients, not only immediate surgical outcome and pain outcomes, how we can leave an impact in their lives. Then I'm going to share some of our ongoing uh pain-related research uh at the end. So the unique aspects of CCHMC way of managing pain, following pectus repair. So unlike other major hospitals, we have a dedicated pain team for surgical pain. We have three different pain services, one for surgical pain, and the surgical pain service manages all surgical patients, including Pus patients. So that service has some faculty and nurse practitioners and evening nurses. So we see a patient, a surgical pain patient, typically a minimum of 3 times in a day, morning rounds, afternoon rounds, and evening rounds. Then we are available 24/7 to take care of minor issues and adjusting medications, taking care of hypertension and other issues related to a patient. And we not only just do everything in the hospital, we start our preparation before surgery, at least 2 or 3 months before surgery, and as soon as surgery is scheduled, even at the time of scheduling, we even encourage a patient to participate in our genetic research with opioids, how we can identify somebody who is at high risk for opioid addiction, respiratory depression, and other side effects, or even persistent pain. I'll talk more about uh research later. Then the preoperative uh uh education visit, uh, we send one of our pain nurses to educate our patients about what to expect about pain management and how we uh manage pain and uh overall family coping. Then in hospital, I have a protocol how we manage our share during that part. Then post discharge, we don't leave our patients hanging after they are discharged. So we schedule an appointment with our outpatient clinic for all patients and ask them to follow up if they need it. So if they don't need our services, then they can cancel that appointment. So preoperatively, Um, uh, we talked about the mandatory pain education by a pain nurse and the optional genetic research, and another part which is recent is mindfulness and meditation. So there are a lot of evidence in medical literature about use of meditation and its benefits to minimize pain and also minimize anxiety and immune function, including after surgery. So this is a relatively new area. So as we are trying to improve outcome beyond the immediate post-op period, so we are going to use meditation techniques, including basic hatha yoga practices to improve the recovery part and coping and anxiety and persistent pain after surgery and In the hospital, even though we are the pain service, we try to minimize opioid use as much as possible by using epidural and Oncu pump as a bridge and other medications, opioid sparing medications. We'll go over that later. Then also we call something called personalized analgesia. We try to identify the right drug for the right patient and the right dose. So that's our research as well. So we'll talk briefly about that at the end. And the follow up we talked about outpatient clinics. We have an outpatient clinic where we see patients who come from home with different problems like difficulty to wean opioid after 1 or 2 weeks and if they have persistent pain after surgery. So we see all those patients in our outpatient clinic. So what is the problem with opioids? We use opioids all the time, and so opioids immediately after surgery, if you use opioids alone, it causes a significant amount of side effects including respiratory depression, nausea, vomiting, constipation, ileus, you can name a lot. So then also we experience a lot of inadequate pain control even with high doses of pain medications. We talked about somebody not breathing and still complaining of pain, so that happens with opioid alone, pain management. Then about 20-30% of PECus patients experience chronic persistent post-operative pain. I call it CPSP, chronic persistent surgical pain. That is defined as if a patient has pain two months after surgery, that is called chronic persistent post-operative pain, and this pain score of 3 or more. Then we have unfortunately a few patients getting dependent and addicted to opioids. So we are trying to limit all those problems associated with opioid by our research, by our practice. So the major problem with opioids is because of their narrow therapeutic indexes. So beyond a certain dose, it will not relieve pain, but it can cause a lot of side effects. And there's a huge interpatient variability as well in how how a patient responds to opioids. It leads to a lot of economic burden and with a lot of side effects and inadequate pain control. So this slide summarizes the epidural versus PCA and the two common modes of pain management. So the benefits of epidural, it provides hands down better pain and better pain relief, and we use almost no opioid in the first few days after the Pus surgery now and with very minimal opioid use and minimal opioid related adverse effects. And so there's strong literature out there in adult literature at least, if you use something to block pain to get to the brain, like any regional analgesia, epidural or oncu pump, so those patients have less persistent post-operative pain, including thoracotomy pain. And if you use epidural, patients have less opioid exposure, and then the risk for opioid dependence is less. If a patient, if a child is on 5 days in a row of oxycodone or any other opioid, the risk of dependence goes up significantly. That's why we try to minimize opioid exposure as much as possible. And with the epidural, patients are intact. They can communicate clearly, and they are not drugged up with PCA opioids. Uh, that's the benefits of, uh, those, those are the benefits, the major benefits of epidural for PECS patients. Uh, we briefly talked about neurological complication with, um, epidural. The major one is paraplegia. We try to minimize that risk by placing epidural before surgery in an awake patient with minimal sedation so they can Collaborate and with the proceduralist. So we have an experienced pain team staff who would be doing the epidural, so that minimizes the risk with multiple attempts. And the other risk is ischemia-related neurological injuries. To avoid that, we aggressively monitor blood pressure and manage blood pressure by taking out clonidine or giving more fluids. And the PCA, the only advantage I see is it is readily available. If nothing works, you can obviously add PCA at any time. So there are a lot of side effects, uh, respiratory depression, there are a lot of deaths associated with opioids at home settings, and sedation is a problem. Constipation is a problem, urinary retention is a problem, and abuse we briefly talked about. And a patient who is getting opioids alone without any local anesthetic is at higher risk for persistent pain after surgery, including PA surgery. So we briefly talk about the recent evidence for managing pain after pectus repair. So in this study, which was published last year, and they looked at all major studies comparing epidural with PCA. There are I think 6 studies, and um and what they found is that compared to PCA, epidural provided better pain control the 1st 2 days. And um, Interestingly, this meta-analysis or systemic review had also included two studies which were from Kansas and which were very supportive of PCA. So in this slide, we can from the same study which was published last year, you can see that the success rate of epidural determines whether uh Patients get good pain control or not. So you can see that most of the studies had good success rate or zero failure rate, except the two studies had a poor epidural placement or success, 22% failure and 35% failure. Probably that's one of the major reasons why in that particular group, epidural didn't help relieve pain as, as good as PCA. And um So, uh, in this slide from the same study which was published last year, we are comparing uh epidural versus PCA, how much time they take in the OR. Uh, epidural obviously takes a little bit of time, 10 to 15 minutes in our experience, uh, to place an epidural, and, um, the calls for anesthesia, it's actually we get a lot less calls because we proactively go see the patients frequently. And with good working epidural, we even see zero pain scores immediately after surgery, the 1st 2 or 3 days after surgery, which is that 10 years ago or 15 years ago it was not heard of zero pain after a major Pal surgery. And we take out our Foley catheters the very next day, the 24 hours after surgery, and so we do a local anesthetic only solution in our epidural, which does not cause any urinary retention. So it's very dermatomal. It blocks only the thoracic dermatomes. The length of stay, the cancer study reported that the patient who had the epidural stayed longer, probably they started off with the epidural, but the epidurals didn't work well. That's why their length of stay was a little bit longer. And in our hospital, most of our patients go home on the 3rd or 4th day after surgery. So briefly compare our experience with cancer experience. This data is from 2013. We are doing better than our 2013 experience now. So one major difference is Dr. Garcia and Dr. Brown, they attract a lot of patients and a lot of more complex patients. As you can see that the Heller index, we attract more severe patients here. And compared to other sites, we take less time to do epidural, maybe 15 minutes, and because we do a lot more complex cases, our surgical time is a little bit longer as well. And our success rate with epidural, um, it's more than 95%, and the number of patients needing PCA on top of epidural, uh, in 2013 it was 14, now it is less than 5%, and, um, So this is our protocol, and um feel free to ask questions. Um, so, preoperatively, uh, we do that education by a pain nurse practitioner, and also we do an EKG. We do EKG just to get a baseline before we start methadone therapy, and we use methadone intraoperatively in the 1st 2 days after surgery. And uh and we use uh pregabalin, which is a gabapentinoid. There's a lot of evidence to show that. If you give pregabalin or gabapentin, Neurontin, one hour before surgery decreases pain after surgery significantly and need for opioid is significantly less. And um We also offer the opioid genetic research to identify those at risk of opioid complications, including opioid dependence and persistent pain. And the meditation, which is relatively new to us and we don't have a lot of experience yet, but we have a good and effective technique we are planning to use that includes transcendent meditation for at least 8 weeks and optionally there will be some additional yogic practices that may improve recovery and minimize pain, persistent pain, and overall the need for opioid in the long term. Intraoperatively, uh, as soon as the patient comes into the hospital in the same day surgery area before surgery, the pain team would go and talk to the patient, explain different modalities of pain management, and the pain team does all our epidurals for PETus patients, and we do it awake to minimize the risk of neurological injuries. And intraoperatively, we use IV form of acetaminophen, very regularly. And IV methadone, we use lower doses. When we used higher doses as used in adults, 15 to 20 mg, we had a lot more sedation problems. That's why in our teenage Picus population, we use 5 mg as max dose. And along with the pregabalin and methadone and anesthesia, most of our patients are too sedated with higher doses of methadone. That's why we cut back on methadone to 5 mg intraoperative dose. We use an IV form of methocarbamol, uh, we, we see a lot of muscle spasms following the PA surgery, and so we use routinely, uh, IV methocarbamol. This cuts back on the use of IV form of uh dippam, so for muscle spasm relief. Post-operative day one, we continue epidural for 3 days and, um, and we remove Foley catheter on post-op day one in the morning and uh. We continue methadone just to make sure, one problem with methadone, uh, besides any other opioid-related problem, is that it can cause prolongation of QT interval. There are reports of ventricular arrhythmias. So to monitor that, we do an EKG just to make sure the QT interval doesn't get prolonged beyond 4080 milliseconds. Then we continue IV form of acetaminophen, methocarbamol. Then we also start IV form of ketorolac, and we do that every 6 hours and alternate with the IV form of acetaminophen just to make sure we minimize opioids. In our experience, the number of patients needing any IV opioid in the 1st 2 or 3 days when they have epidural is less than 5% now, and with the regimen. Then we also continue the preglobulin for 2 days, which has been very effective in minimizing opioid use subsequently on day 4 or day 3. When a patient can eat and tolerate diet, we start oxycodone, typically on post-op day one or post-op day two, and we try to push to post-op day two to minimize opioid exposure as much as possible. Um, if a patient who started with meditation, we would encourage them. Uh, I think that's going to be a future practice, uh, going forward. Uh, on post-op day three, after starting oxycodone, uh, uh, the post-op day tonight, uh, 2 doses or 3 doses, then we stop epidural in the morning around 6:00 a.m. And then we assess the patient how good their pain control is without epidural. If the pain control is good and we continue the same doses of oxycodone, if the pain increases a little bit, then we increase the doses of oxycodone and make the Valium IV or oral Valium at that point of time scheduled every 4 to 6 hours. Uh, for patients, selected patients who are anticipated who have severe pain, as we shared in the last session, we place subcutaneously, Doctor Garcia, Dr. Brown would place catheters, subcutaneous intercostal catheters. We use OncuPump, uh, variable rate. Uh, we start off with 1 mL per hour for each side. Uh, when we have epidural. After we, uh, take the epidural out, we increase the rate to 4 to 6 ml per side. So that has helped us to bridge, um, the gap between the epidural, uh, and the oral medications. Some patients have significant pain the moment we stop epidural. For those patients, uh, uh, the Oncupump has helped a lot. Then we talked about the follow-up, uh, we do a mandatory follow-up, uh 2 weeks after surgery in our pain clinic and we schedule an appointment and patients can uh cancel that appointment if they are doing well, if the opioids are weaned off within a week or so. Any questions about the protocol about when you shut off the, the epidural, do you wean it or do you, yeah, we just shut off. So if, say for example, a 15-year-old, we are running at 8 mL per hour and at 6 a.m. on post day 3 morning, we would stop to zero. We don't wean off, we just stop it. There's been a lot of discussion of Foley catheters that you brought up, but um. Yeah, the one big advantage of not using um Opiates in epidol solution is um In our experience, we don't even use opioids for any epid solution in our hospital, not only for Pectus patients. The advantage of opioids in epid solution is very minimal. It causes a lot more problems, mainly itching, uh, urinary retention, a lot of problems than health. Clonidine can do all those benefits, uh, pain relief without causing itching, without causing, um, urinary retention. And when we do local one epidural, we use high concentration of ropivacaine 0.2%. That provides good pain control, and whenever you use lower concentration 0.12% or 0.15%, it doesn't provide that kind of pain relief. So we use higher concentration. Uh, but it is dermatomal. It doesn't go beyond that level. So we block, uh, just pain here. Yeah. And so, uh, our patients, uh, the Foley is removed on post-op day one. They don't have any problem urinating after Foley comes out on post-op day one. So I guess the question is if it comes out on post-op day one, why put it in? Um, well, what it, it actually we started off with not having the Foley catheter in for the reasons that uh Cento mentioned, but our nurses found that on occasion there were patients who indeed did develop some, some difficulty urinating, uh, and so then we ended up putting it in. So we sort of did a balance because we're, we're, we're, we're, we're very. Uh, compromising surgeons here at Cincinnati Children's, and so we, what we did is said, OK, we'll, we'll just leave it in for a day. So it's not leaving it in the way, you know, 3 or 4 days or. So my question would be to look at your numbers and say of taking it out on post-op day one, how many reinsertions have you had to do. Um, I, I think we have not looked at that data. You don't, I don't. And, uh. Because it might be the same. So, then you're not. The patients get opioids during surgery, and, uh, so probably that can hang around a while, and we are still using methadone, um, and we don't want patients, uh, immediately after anesthesia to get up and use the, um, uh, the pod. So, uh, the, the urinary, uh, catheter helps a lot just to get them through the night, and, uh, so that's why we leave it for safety reasons. Mark, sorry, Mark Saxton said in his data that 1 in 7 subsequently need to be cat. They don't put, he says he doesn't put Foley's in, and 1 in 7 need to be catheterized for retention. So I'm just curious if, if other people, if that's about what you guys saw too, yeah, um, you know, so we haven't looked at that, um, we initially, uh, uh, you know, when we sort of evolved to this protocol said no Foley catheters, but then our nurses who are there dealing with the patients and responding to the parents whose children can't urinate, uh, felt a little uncomfortable with that. So we went ahead and just left it in for, put it in and then just left it in for a day, OK. Last issue that was brought up was about the use of oral versus IV Valium. Yeah, so we try to start with the IV Valium, the very first day, day of surgery, and as soon as the patient can eat and, uh, tolerate food, then we switch to, uh, oral Valium. And another thing I forgot to mention is the naloxicol. So some of our patients get about 50% will get constipation the moment we start oxycodone. And so that's opioid induced constipation. So to relieve that, recently the FDA approved naloxicol use. Naloxicol is a medicine which is very similar to naloxone, but it doesn't cross the blood-brain barrier, so it doesn't. Uh, relieve the analgesic aspect of opioids, but it relieves the constipation side effects. So it works only below the brain. So if a patient has any constipation because of oxycodone or any other opioid, it will relieve the constipation without Say reversing the analgesic aspects. So, uh, we, we, uh, uh, we are approved to use that, uh, here at Children's, even though it is not approved by the FDA for pediatric use yet. And that has been, uh, shown to be effective in relieving opiate-induced constipation. So that's another aspect we can see that we, we are changing, revising our protocol every few months to improve our pain management, uh, in every possible way. So one of the things that we observed for uh for those who there are some of our colleagues who did not believe in epidural and just simply wanted to go ahead with the PCA and one of the things that I found somewhat unsettling is, uh, here we're able to look at respiratory depression, how many episodes of bradycardia and apnea on, on the monitors and. Um, Santo, do you want to comment on that as far as the PCA and respiratory depression? So another patient population, that population is equally painful and so even less painful than Pus, but those patients do not get epidural. They get PCA. We see a lot more respiratory depression in those patients even though they get one day or two days of PCA. And so that's why we try to minimize opioid as much as possible. This is despite giving them IV form of acetaminophen, ketorolac, even despite they got spine surgery, we still use ketorolac and methocarbamol. Still they get into trouble. About 15% of our patients will have low respiratory rate. And all the definition of respiratory depression is less than 8 breaths per minute and saturation less than 90, they will fit that criteria, the 15% of our population. Um, IV tramadol instead of an epidural. IV tramadol, um, it's not effective, and so it is a risk. Recently, there are deaths associated with the tramadol, because tramadol is very similar to codeine. I have a few slides at the end to talk about codeine, tramadol. So if you take the whole population, and most of the population, about 80-85% of them are intermediate or. Extensive metabolizers, so they metabolize tramadol very well and they have good pain control. Um, about, uh, say 10%, 10 to 12% are poor metabolizers. They do not get good pain relief even with IV form of tramadol. About 1 to 2% of Cincinnati population, they are ultra rapid metabolizers. They can have a lot more demethyl tramadol, which is a metabolite of tramadol that causes significant side effects, including respiratory depression. There are reports of deaths in that particular population, ultra rapid metabolizers. If you don't look at their genetic makeup and if you give tramadol, we are taking that risk that in 1 to 2% of the population. So, uh, yeah, so one of the things that we do is, is that we actually do genetic testing, as, uh, Centel just mentioned. Yeah. So before, when they come to the PETus uh clinic, uh, Dr. Garcia's clinic or Dr. Brown's clinic, so we would, uh, take a blood sample or saliva and do the genetic test in the hospital and the patient's, uh, genetic result will be in their electronic medical record. We use EPIC, and when your pain team goes in to write the order, we see whether the patient is ultra rapid metabolizer or not. A poor metabolizer. So, uh, so we have already implemented that particular genetic test. We are in the process of implementing more things, including how to identify those at risk for dependence, how to identify those at risk for persistent pain after surgery. So given the how expansive now the knowledge is as far as pain, uh, how important it is, it sort of begs the question, um, can one person. One specialty, the surgeon, really sort of, is it in their best interest to try to sort of know it all as far as pain management. Uh, I think the day and age where we, um, can for more complex procedures think that we can actually monitor or, you know, um, sort of address the pain management, uh, as well as let's say a pain service, I think is, uh, are short-lived is our, our, our sense. I will tell you it's, is an, uh, it's just an, uh, people have said the comment and I'll say the same thing. It's so impressive. To see, and it's hard to tell. We're, you know, first of all, we're here at a table, everyone's here together, but it, it seems that, that you, you all have really created a, um, a nice model that people are trying to, that people are liking here from the audience and myself that, um, especially if you have enough volume of Pectus patients to create this multidisciplinary team. It's a lot, you know, Cincinnati is a place that has higher volume than most, so at places that may do a couple of practices a year, it may, it may be more difficult, but, uh, having this. Multidisciplinary team between pain and surgery and genetics and everyone for other diseases as well can cross translate, and I think that's what people are getting the most out of today's course. And we, we haven't even delved into meditation. Yeah, so, and there's actually a lot of questions we're not addressing because we don't have time, but so, and so I'll briefly go over why we do what we do. And so methadone, there's a lot of evidence to show that it decreases pain if you do, if you use even one dose of methadone in the OR, it cuts back on the opioid use significantly and it improves pain control in the next two days. And this is for use of gabapentin or pregabalin, Lyrica or Neurontin, and there's good evidence to show that it decreases pain significantly if you even use one dose one hour before surgery. It's all preemptive and um So briefly about persistent post-operative pain, some patients are at higher risk for persistent post-operative pain than others, and thoracic surgery, which is effective surgery, is considered one of the thoracic surgeries, so it's high risk, and even in our population, about 20 to 30% of them go on to have chronic pain. And so pain score of more than 3 at 2 months after surgery. So they looked at not only children but also adults, young adults and children have higher risk of persistent post-operative pain than an elderly patient, and patients with comorbidities like Eller-Dunla syndrome, those with chronic pain, even before surgery, they are at higher risk of having persistent pain after surgery. Patients with psychological problems, depression, anxiety, and poor coping skills and substance abuse, obviously, they have some ongoing. Uh, psychological issues that increases the risk of persistent pain. Um, Whenever we manage pain without any regional anesthesia, and the barrage of noxious stimuli goes to the brain, then it precipitates more pain. The brain remembers that pain immediately after surgery, and it's called a neuroplasticity, so the the brain remembers it even the long term. So 6 months or 12 months after surgery. That's why we try to minimize that stimuli going to the brain by blocking with local anesthetic either epidural or Uh, uh, on Cump, uh, it's a local anesthetic. The higher the amount of opioid we use preoperatively, the higher the risk for persistent pain. And our recent data shows that the moment we use high doses of opioid, it turns down some of the opioid receptor genes, and that that is connected with persistent pain. And that's one of the recent evidences we show the genetic evidences that's why we even why we do the genetic test to identify those at risk for persistent pain. And the recent studies from Seattle, they show that if a child doesn't sleep well before surgery, if they have disturbed sleep and short duration of sleep, if the patient or the patient's parents have pain catastrophization, so if they anticipate negative outcomes, pain or other negative outcomes after surgery, they're at high risk for persistent pain. So for those patients, uh, we, we placed the surgically, uh, the oncu pump and catheters, so that has helped. So briefly about our research and uh so as I mentioned, we already implemented uh preoperative, uh, genetic testing. Uh, we do one particular gene, it's called SIP2D6, which is the major uh liver enzyme which metabolizes most of our opioid, um, oral opioids, including codeine, tramadol, oxycodone, hydrocodone. And so what we do is we get a sample of saliva or blood when they come to the surgical clinic, and so within 2 days, the result will be available in our EPIC. And so this test is covered by most of the insurance companies, so so it's not a problem, it's well approved. And there are a lot of evidence to show that codeine is not safe, tramadol is not safe, and hydrocodone in ultra rapid metabollizers are not safe. That's why we have already implemented this test, but simultaneously for research purposes, we are collecting other genetic associations, other genes associated with outcomes, including respiratory depression, sedation, opioid dependence, addiction, and persistent pain. And so we call this personalized analgesia. We want to give the right amount, probably the lowest amount of opioid possible. The right amount and the right drug. Say not all patients will benefit from oxycodone or tramadol. Some patients may need different medications. So say for example, ultra rapid metabolizers are not good candidates for codeine, tramadol, hydrocodone, but they are OK with morphine and hydromorphone. So this is about not only selecting the right dose, also selecting the right medication or the right opioid. Quite a bright patient. And so we are looking at respiratory depression, as RD, post-operative nausea, vomiting. Opiates often cause nausea and vomiting, which prolongs stay, and sedation is a major problem. And with methadone and some of the sodium channels in the heart, the genetic variants of sodium channel in the heart are associated with prolongation of QT interval and ventricular arrhythmia. We are proactively checking those sodium channel genes. To see whether we can identify those and modify uh methadone dose or even avoid methadone in those patients. And the long term side effects include opioid dependence and chronic pain after surgery. So the first step in personalized analgesia is we have to identify those at risk. And so once we identify them, then we can target. So for example, we already identify ultra rapid metabolizers of sub 2D6 and we target our interventions. Instead of giving tramadol, codeine, we give them hydrocodone and even we cut back on the dose of oxycodone a little bit. Um, So these are the specific aims of our study. If we want to identify all children who come for PETA surgery and whether they are at risk for any immediate side effects, including respiratory depression, sedation, vomiting, and also any long term side effects, persistent pain or opioid dependence. We we have already some good evidence for immediate post-operative problems including inadequate pain control. Some patients, despite getting good doses of oxycodone, still complain of a lot of pain, and we have identified who are at that risk. So by looking at their genotype, we can say this patient is at high risk for respiratory depression even before giving oxycodone. So these are the genetic associations we have already found after surgery in children, and these are different genes, so we can just ignore the names and you can just see so many genes are associated with pain and opioid related outcomes. Mainly we are looking at inadequate pain control, opioid related side effects, so Multiple genes are associated with pain and opiate-related outcomes. We can reliably predict who will have respiratory depression by looking at their genes and their genetic signature behind. So our ultimate goal is we have already implemented SIP 2D6 preoperatively for genotyping, so we want to include other genes so that we can make the overall operative experience very good with the least amount of side effects. So if a patient can have a good surgery without any adverse effects of opioid and pain and the long term, that would be optimal. And so that's why we do the genotyping preoperatively. We are working towards point of care genotyping. Some patients may not come for many things, and if they come at the last moment, and not necessarily PC test patients, other patients, we can still do the genotyping on the day of surgery and get results within an hour or two. So, uh, we want to make everyone a happy camper, uh, with our uh personalized approach. Briefly about the CIP2D6 and the tramadol. So the codeine and tramadol are bad actors. Fortunately, in Cincinnati population we have only 1 to 2% ultra rapid metabolizers. In African American population and especially in Ethiopian population, the ultra rapid metabolizers can be as high as 29%. In those patients, the risk of having major side effects, including respiratory depression, death, and oxic injury, is very high. That's why recently the FDA warned against use of codeine following tonsillectomy. So, uh, and other warnings are coming towards tramadol and hydrocodone. They are under review by the FDA. And so among the currently available opioids, oxycodone seems to be the least affected by the SIP2D6 metabolism. That's why we use it at Cincinnati Children's. Even oxycodone, to some extent is metabolized by sub 2D6. That's why we do the genotyping before surgery. The moment we know the patient is an ultra rapid metabolizer, we avoid oxycodone and use hydromorphone, which is Dilaudid, oral Dilaudid. And this is just the bell curve just to show the whole population it can be put in the bell curve, and these are the two extremes, poor metabolizers. They do not get good pain control with codeine and tramadol, and the other extreme is the ultra rapid metabolizers, which is 1-2% of our Cincinnati population. And um Even extensive metabolizer, which is supposed to be normal population, and if they have any coexisting morbidity like asthma or other sleep apnea related issues, so even they would be at high risk for sedation and respiratory depression. So that's why we avoid. Higher doses of oxycodone in extensive metabolizers as well in addition to ultra rapid metabolizers. So the most important thing is monitoring and Sedation always precedes respiratory depression. In our hospital, uh, every shift, the nurses monitor sedation using Ramsey sedation scale to prevent any respiratory depression, uh, impending respiratory depression, and we also monitor, entitle carbon dioxide continuously in the 1st 24 hours after surgery. This is our hospital's experience. Even though we use maximum amount of opioids, we have the least, uh, incidence of respiratory depression. And, uh, so in the last three years, uh, there's more than three years, we have not used naloxone in, um, uh, for any of our pain patients. For, uh, for the sake of time, there's people that have some questions for you. So I just want to jump to those. Um, first of all, the genotyping, how much, do we know how much that costs? Um, so we, we use a very, there are, uh, the different panels. The panel we use for 50 genes is $50. Uh, so, and the SIP 26 panel, uh, it's less than $1 per gene, and we even looked at the cost saving for a following tonsillectomy study, and uh one particular gene is called the fatty acid amyhylase. I don't know that you can see that. And that particular gene, this one is associated with nausea, vomiting, prolonged stay in PACU, and the cost difference was if a high risk patient, uh, if we know a patient is high risk and uh if we administered doses accordingly, uh, we would be saving more than $100 per patient. So the cost of doing genotyping is significantly less. It's, it's incredible that I mean $50 I think Tylenol costs like a couple 100 bucks, um. Preemptive pain control, uh, the concept of doing intercostal block before the operation. Uh, I've heard that that's not as impressive as we thought. Is it, is it? Where are we at with that now? It is still good and better than nothing, and, but we had to provide good pain control. Intercostal blocks, they, uh, we may miss one or two intercostal nerves and so it may. Not provide as good pain relief as epidural. That's why we use high density epidural block to minimize, uh, pain stimulus as much as much as possible. Higher the dose of local anesthetic, it is better, uh, for preemptive analgesia. That's why we place all our epidurals before surgery, um, before surgical, uh, incision to minimize pain. Uh, the moment you use higher concentration of local anesthetic under anesthesia, the blood pressure drops, so we are taking risk of compromising spinal cord perfusion related injuries. That's why we had to do the balancing act. Great.
