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Episode 7 - It’s All About The Ketamine – Jennifer McEntee MD, MPH, MA.Ed and Daniel Markwalter, MD
24 Plays3 years ago
In this episode Daniel Markwalter guest interviews Jennifer McEntee, a palliative care physician at UNC Chapel Hill about their use of ketamine for inpatient and outpatient palliative care. Dr. McEntee provides a thorough review of patients who may benefit from ketamine treatment as well as strategies employed at UNC for IV and oral ketamine dosing.
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Transcript
Introduction to PallyM Podcast
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This is the PallyM Podcast, a production of palliem.org at the intersection of palliative and emergency medicine.
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I'm your host, Justin Bruton.
Profile on Jennifer McEntee
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Today on the PallyM Podcast, I'm joined by Jennifer McEntee and Daniel Markwalter.
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Jennifer McEntee is an associate professor in the Department of Medicine and Pediatrics and serves as a clinician educator, academic hospitalist, and palliative care and hospice provider.
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Dr. McEntee also serves as the Associate Program Director for the Internal Medicine Residency Program for the inpatient rotations.
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In addition to degrees in education and public health, she completed her residency in internal medicine and pediatrics at the University of North Carolina Chapel Hill and fellowship training in hospice and palliative medicine at Duke University.
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Dr. McEntee is extremely interested in improving medical provider patient communication, medical provider resiliency, international health, public health, quality improvement, resident and medical student education, and in promoting competent, compassionate, patient-oriented care.
Profile on Daniel Markwalter
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Daniel Markwalter received his emergency medicine residency training at the University of North Carolina, where he served as education chief resident and completed fellowship training in palliative care.
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He is currently an assistant professor in the Department of Emergency Medicine and the UNC palliative care program.
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His scholarly interests include ED-based advanced care planning, transitions to hospice from the ED, and palliative care education for emergency medicine physicians.
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Dr. Mark Walter is also a contributor to content at palium.org.
00:01:32
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Thank you both for joining us today.
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Thanks for having us.
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Thank you.
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I appreciate you letting me be a guest interviewer on today's
Ketamine's Role in Medicine
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episode.
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Today, we're talking about a subject that I think is near and dear to both emergency medicine and out of care these days, and that's ketamine.
00:01:47
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Many of us are familiar with the use of ketamine for sedation and agitation in the emergency department and a lot of newer protocols for analgesic dosing.
00:01:57
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There seems to be an explosion of routes of administration these days, intranasal options, looking at topical and nebulized ketamine.
00:02:05
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Recent studies on the use of ketamine for depression.
00:02:08
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It really is a big ketamine world out there.
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So we want to pivot a little bit to the use of ketamine in the overlap between palliative care and emergency department.
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There was some interest in this at the recent 2022 annual assembly.
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And so we're excited to have one of our experts from the University of North Carolina here, Dr. McEntee.
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And she was the palliative care driver behind the ketamine policy at UNC.
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And so we're glad to have you here.
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But I know in particular, you have a story that sort of sparked your interest in the subject.
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Would you mind sharing that with us?
Case Study: Ketamine in Palliative Care
00:02:42
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Thank you so much again for having me to also help spread the word of how ketamine can really help most of our patients, or many of our patients.
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So this patient was a beautiful 40-year-old woman, mother of three,
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who was diagnosed with de novo metastatic breast cancer in 2017.
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And we have seen her numerous times throughout her hospitalizations.
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Many of those times were for pain crisis, secondary to refractory pain.
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The most memorable one related to ketamine was she presented with 10 out of 10 refractory pain.
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At home, she was on methadone, 30 milligrams TID.
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She was also on a Dilaudid PCA, 1.5 milligrams Q15 minutes.
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And she was also on dexamethasone.
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We continued to kind of ramp that pain medicine up through her hospitalization, and we were getting nowhere.
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Her pain still was 10 out of 10.
00:03:29
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At which point, at that point, we decided to transfer her to the ICU because we had to, because that was the ketamine policy at UNC.
00:03:35
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At that point in time, all of our patients had to be treated in the ICU.
00:03:38
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Subsequently, that is no longer the case, which I'm really excited for.
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We can now treat these patients on the floor.
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And we transitioned her to, we started her on a ketamine dose on,
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let's just say June 2nd at 0.1 mg per kg per hour.
00:03:53
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And we were able to slowly titrate that up to 0.25 mg per kg per hour over the next couple of days.
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When I saw her three days later, I approached her and she told me she was in zero out of 10 pain, which I had, I was in utter disbelief.
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I told her I didn't believe her because I'd never seen her without pain, without 10 out of 10 pain.
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For four and a half years, she was unable to climb a flight of stairs.
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She was unable to play and to play with her kids and to do any physical activity with her kids because of the pain.
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And so she said, I'll prove this to you, Doc.
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And she stood up and like danced with me in the room.
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And so she was really adamant that she needed to get out in a couple of days because she needed to go see her daughter graduate.
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And we knew time was limited because of her de novo metastatic breast cancer.
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So we got her out of the hospital on the fifth day of ketamine.
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We quickly transitioned her to PO ketamine.
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And so she was discharged on 20 milligrams of PO ketamine TID.
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She was also transitioned to methadone, 40 milligrams PO TID and a dilated PCA.
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At that day, she was discharged.
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She walked into her daughter's graduation.
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That weekend, she played tennis and she walked up a flight of stairs to be able to sleep with her husband.
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And then seven days after discharge, she was transitioned off of her PCA just to oral dilaudid.
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and continued on the oral ketamine and the oral methadone.
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So quite a remarkable story.
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And when I asked her if I could share her story, she said, oh my gosh, please tell everyone about ketamine and please tell my story.
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So it was a remarkable story for all of us.
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That's awesome.
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It really seems like one of those practice-changing cases and something that I think we all hope with the right patient selection is something we can replicate in other patients as well.
00:05:40
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But taking a step back from that specific example to kind of the larger scope, in your mind, why should emergency medicine and palliative care physicians care about ketamine beyond its use in sedation where it was traditionally been used?
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And then in particular, why is the palliative care world really excited about it right now?
Ketamine as an Adjuvant Therapy
00:05:58
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Well, I think two major things about ketamine that I want to share is, number one, it's relatively safe medicine.
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It's probably a safer medicine than any of the medicines we prescribe.
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It has a safety profile.
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Let me just say, since it was FDA approved in 1970, there was only one lethal case that has ever been administered or has been associated with ketamine.
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And that was, unfortunately, the Elijah McLean incident in 2019 in Aurora, Colorado, where he got a seven, probably, migs per kg dose of ketamine times two.
00:06:25
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And we give just as a reminder what sub anesthetic dosing is so analgesic dosing for ketamine is 0.1 mg per kg and I know we'll talk a little bit more about that but that is a significant difference between seven mg per kg and 0.1 mg per kg so it's a relatively safe medicine and then number two what we don't have anything in our arsenals for opioid refractory pain.
00:06:47
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other than sometimes sedation and other pain adjuvants.
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And so what do we do when we get to the point where we have these patients and many of us see these patients in the emergency room and internal medicine as a hospitalist, I see these patients and in palliative care, I see these patients who have life-limiting illness and have refractory pain to opioids.
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And I think ketamine can be a really good adjuvant therapy.
00:07:09
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Excellent.
00:07:09
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So let's dig into the details a little bit.
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So we're all on the same page.
00:07:13
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Can you provide us an overview of some of the ketamine pharmacology and how it works to provide analgesia?
00:07:18
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Yeah, so ketamine acts on one of my new favorite receptors, the NMDA receptor.
00:07:24
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And so at its resting state, magnesium blocks the NMDA receptor.
00:07:28
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And when the NMDA receptor gets activated, it releases sodium and calcium into the neuronal channel.
00:07:35
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And as you remember going back to your first, second years of medical school, sodium and calcium are very important ions in the pain pathway.
00:07:47
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The NMDA receptor mirrors the opioid receptors in the neural membrane and calcium activates, if I can remember this right, protein kinase C, which diffuses to the neural membrane and then causes hyperalgesia and opioid tolerance.
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And so the hope is, is that if we can decrease the calcium influx, decrease protein kinase C, we can actually decrease opioid tolerance, which thinks we think maybe resets our opioid receptors.
00:08:12
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The other important aspect that many of us kind of forget about is that it also decreases interleukin-6, which is a really important cytokine that causes inflammation.
00:08:21
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And so if we can also decrease inflammation by decreasing interleukin-6, we could also potentially decrease pain.
00:08:26
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So I think ketamine has multi-hits, different receptors and different mechanisms of actions for its pain.
00:08:33
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Lastly, I'll comment that it also hits the muscarinic dopamine, norepinephrine, serotonin receptors, which I'm sure, Daniel, you can talk a lot more about that and how it relates as an antidepressant.
00:08:44
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And I think many of our patients who have been in pain and have severe pain probably have a component of depression, anxiety, and existential suffering, which I think ketamine may...
00:08:53
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help in regards to the kind of euphoria that you get with ketamine.
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And it can help with the depression and the anxiety.
00:09:00
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So I think that should not be forgotten when we talk about the other mechanisms, actions for ketamine.
Ketamine's Broader Therapeutic Benefits
00:09:06
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Yeah, I think you're absolutely right.
00:09:08
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And from an anecdotal standpoint, from patients I've used analgesic ketamine on, you know, frequently it's with conditions with significant overlap with psychiatric disease or even in a setting of chronic life-limiting illness such as cancer or significant overlying components of anxiety or depression.
00:09:28
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And, you know, I agree with your assessment that there's likely benefit from the other receptor actions as well.
00:09:36
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And so thinking about the different routes of administration, you know, we talked a little bit about the IV infusion in the case that you gave us converting over to oral ketamine.
00:09:48
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Talk to us a little bit about how it can be administered and what you know about its use in these different forms.
00:09:55
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And myself and Justin can chime in a little bit about some of the other options that we see in the ED intranasal use or recent trials on nebulized ketamine and even topical or mucosal ketamine.
00:10:06
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That's awesome.
00:10:07
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Great.
00:10:07
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So I'll talk a little bit about the formulation and administration that we use for sub anesthetic or sub anesthetic dosing for pain or analgesic pain or analgesic administration for ketamine.
00:10:17
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So you it's simply just the IV solution that's actually.
00:10:22
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administered in all these different routes.
00:10:23
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And so it's the IV solution through the IV, through the subcutaneous route.
00:10:26
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If you give ketamine IV or subcutaneous, in IV it's active within seconds, we think.
00:10:32
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Subcutaneously, it maybe takes 15 to 20 minutes.
00:10:36
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The oral bioavailability of ketamine is tricky.
00:10:40
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We think it's probably anywhere between 1 to 17% of the bioavailability for oral ketamine.
00:10:45
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The important thing to remember is that it's
00:10:49
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metabolized by C3A4 to norketamine and norketamine is bioavailable.
00:10:55
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It is bioactive in our system.
00:10:57
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And so we think norketamine does play a significant role in the oral version of ketamine in its actions.
00:11:04
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And so I think the administration is nice with ketamine because it can be administered IV subcutaneous.
00:11:09
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There's topical preparations you talked about intranasal.
00:11:11
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It can also be supplied through a suppository rectally.
00:11:15
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So I think there's lots of different variations on how we can administer ketamine if you can find the pharmacy to compound it or to actually provide the patient with the medication.
00:11:26
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Yeah, and frequently I've seen that be a barrier to some patients in the palliative care world when we're talking about outpatient use, but finding the appropriate pharmacy for the preparation, certainly.
00:11:39
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In the emergency department, I think probably outside of IV dosing or intramuscular dosing in a setting of agitation, I think intranasal use would be the one that ED providers are next most familiar with.
00:11:53
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Often had dosing around probably like one mg per kg.
00:11:57
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Of interest, there was a trial published in the Annals of Emergency Medicine in December of last year that looked at three different dosing regimens of nebulized ketamine for pain in the ER.
00:12:07
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They looked at 0.75 mg per kg, 1 mg per kg, and 1.5 mg per kg in nebulized forms and saw a reduction in pain scores for all three dosing regimens of a similar magnitude.
00:12:20
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And then there are options available for topical ketamine, looking at use in complex regional pain syndromes or neuropathic pain, reducing allodynia, and then even use for oral solution for mucositis pain.
00:12:36
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I'm going to flip it over to Justin.
00:12:38
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I know he's had some experience with this as well.
00:12:40
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Justin, what's your experience been?
00:12:43
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Well, it's interesting.
00:12:44
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Actually, recently I've had several trauma patients who have been hemodynamically unstable and were needing to start chest tubes and do other things.
00:12:52
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So that's been really helpful to have something in the arsenal that you can give when you really don't want to give them opiates and you're trying to resuscitate them.
00:12:59
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Kind of very different from the palliative care world.
00:13:02
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Certainly burns.
00:13:03
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We have a burn center.
00:13:03
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So many times I've used it for burns to as an adjuvant along with with when we're having escalating doses of opiates.
00:13:10
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And then in the palliative care, in addition, I haven't actually used it as much in palliative care in the in the IV form.
00:13:16
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I've had some experience with that with needing with patients are.
00:13:21
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Our current protocols have it limited to our inpatient pain service.
00:13:24
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So we use it a lot in the ED, but our inpatient pain service has access to that.
00:13:30
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Where I've personally used it some in palliative medicine, fortunately, we do have local compounding pharmacies.
00:13:35
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It's actually for refractory neuropathic pain.
00:13:38
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So topical preparations I found to be helpful.
00:13:41
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I've had patients really get some benefit from that.
00:13:43
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Yeah, excellent.
00:13:45
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Yeah, that's great.
00:13:46
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And so I think we got a couple examples just then of maybe some patient populations where this could be helpful.
00:13:53
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But let's maybe be a little more specific so that our listeners can get a sense of who they might identify as great candidates for ketamine.
00:14:02
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So...
00:14:03
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You know, the two broad categories might be patients requiring palliation in the ED for some acute incident or maybe acute on chronic pain.
00:14:11
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And then there's sort of the broader palliative care population.
00:14:15
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And so in your opinion, Dr. McAtee, what patients should we be thinking of and considering for analgesic ketamine?
00:14:22
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So I think as you, Daniel and Justin commented, really refractory neuropathic pain is something that we don't have a lot of tools in our arsenal for.
00:14:30
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And so I think that is something that we should think about ketamine.
00:14:33
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So refractory neuropathic pain, again, pain that's refractory to opioids that we are just not touching it with opioids and we're escalating rather quickly.
00:14:41
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I think the other patient population that we need to talk about is our patients with sickle cell disease.
00:14:48
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There have been many, many case reports about the benefit of using ketamine in our patients with sickle cell disease by decreasing their opioid tolerance and maybe resetting their opioid receptors and decreasing the amount of opioids that these patients experience throughout their lifetime.
00:15:03
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And I think that is something that I would love to see us start using more at UNC and at other tertiary quaternary care academic centers.
00:15:11
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And then lastly, patients who cannot tolerate the side effects of opioids.
00:15:15
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So if they have severe constipation, if they have severe nausea, vomiting, and sedation, or like you said, Justin, are hypotensive and their clinical status is tenuous, ketamine generally doesn't have
00:15:28
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a hypotensive side effect, right?
00:15:30
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The side effects of ketamine generally are the opposite and will cause hypertension or tachycardia.
00:15:35
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And so I think probably those four patient populations, again, refractory neuropathic pain, opioid refractory pain, patients with sickle cell disease, and then patients who are really having a hard time tolerating the side effects of opioids.
00:15:48
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Excellent.
00:15:49
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And I think Justin mentioned a few populations that we may think of specifically in the ED.
00:15:53
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And yes, there's some overlap, those who are on chronic opioids and we may be looking for opioid sparing options or ways to dose reduce.
00:16:01
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But in the acute setting, point control pain in the setting of burns is very common.
00:16:06
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Trauma is a great one, especially for a short acting agent where you need to do some procedures such as chest tubes, even conditions leading to depression.
00:16:17
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some of your respiratory distress in which you can provide some analgesia.
00:16:20
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But in the ED, if it's consistent with patients' goals of care, it can also allow you a chance to then provide maybe some dissociative dose ketamine to then provide some respiratory support.
00:16:31
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And so it's a very flexible agent in that regard in the ED.
00:16:34
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And can I add something, Danny?
00:16:36
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I think the other, as I think about this more, I think another patient population that would benefit is those patients who have
00:16:43
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somatic pain, so physical nociceptive neuropathic pain, and also have this component of existential suffering, anxiety, depression, where we know ketamine has an important role, specifically with depression.
00:16:56
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I think if those, all three of four or five of those things coexist in the same patient, which happens in many of our palliative care patients, specifically our young palliative care patients, I think ketamine may also play an important role there.
00:17:07
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For sure.
00:17:09
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Excellent.
00:17:09
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So we've identified different routes of administration, some patients that may benefit from ketamine, but we also need to be thinking about who it's not
Considerations and Side Effects of Ketamine
00:17:18
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appropriate for.
00:17:18
Speaker
So Dr. McAtee, tell us a little bit about the contraindications to ketamine use and are there any studies or things we need to look at before trying ketamine in a patient?
00:17:29
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Yeah, so there's, you know, I'll talk about the second first, the latter.
00:17:34
Speaker
There are no great randomized control studies in regards to ketamine.
00:17:37
Speaker
There are no randomized control trials in regards to sickle cell patients, which I would really love, our patients, excuse me, with sickle cell disease, which I would really love to get off the ground and use a multi-center, have a multi-center study for that specific patient population.
00:17:50
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Yeah.
00:17:53
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And let me, the caveat of everything that I'm about to say is that all of the side effects and contraindications regarding ketamine have been all based on anesthetic dosing, which again is 10 times higher than the dosing we use for analgesic dosing.
00:18:07
Speaker
So the side effects that we see predominantly for ketamine again, are the psychomimetic effects.
00:18:12
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So those emergence phenomenon of having some hallucinations, auditory visual hallucinations, some cognitive effects that are all go away once ketamine is stopped.
00:18:21
Speaker
The cardiovascular side effects we also see are like increased heart rate, increased systolic blood pressure.
00:18:27
Speaker
From a GI perspective, we see nausea.
00:18:29
Speaker
We can see nausea.
00:18:30
Speaker
We can see anorexia and some hypersalivation.
00:18:34
Speaker
There are relatively...
00:18:37
Speaker
No contraindications to ketamine.
00:18:39
Speaker
We at UNC have a policy that says there's a grade B, so moderate contraindication regarding psychosis.
00:18:47
Speaker
So we generally, who are patients who are psychotic, we don't give ketamine to because that will...
00:18:53
Speaker
again, increase the risk of ongoing psychosis and pregnancy.
00:18:57
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The other relative kind of moderate contraindications are severe cardiovascular disease, increased intracranial pressure, increased intraocular pressure, cirrhosis, and moderate liver disease.
00:19:08
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Again, those contraindications are all based on 10 times dosing at the anesthetic dosing versus the one-tenth of that dosing, which is analgesic dosing.
00:19:18
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Excellent.
00:19:19
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I think many listeners will be interested in how the policy developed here at UNC.
00:19:27
Speaker
At many places, the anesthesia pain service is sort of in charge or traditionally been in charge of ketamine infusions.
00:19:35
Speaker
Certainly in the ED, we are equipped and comfortable and capable of using ketamine infusions.
00:19:42
Speaker
But once a patient maybe is admitted, how does the palliative care service take over that?
00:19:46
Speaker
Or specifically at UNC, how did that policy come about and to give the palliative care team and the consult service the opportunity to manage that medication?
00:19:56
Speaker
So that's all really relatively exciting new news.
00:19:59
Speaker
When I first joined faculty back to UNC in 2016, it was a really barren landscape of ketamine.
00:20:05
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In fact, we lost a patient early on that probably would have benefited from ketamine and may have prevented her death, which was then highlighted to me is the need that I need to do something about ketamine at UNC.
00:20:14
Speaker
And so I did some research and found as a new faculty member that there's another faculty member who actually did residency with Dr. Andrew LeBlanc, who was in anesthesia, who was help leading and spearheading the ketamine policy at UNC.
00:20:27
Speaker
And so then the two of us joined forces and did grand rounds once we got the ketamine policy approved for internal medicine grand rounds and anesthesia grand rounds and continue to kind of do ongoing work.
00:20:40
Speaker
And we continued to push for palliative care providers to be able to write for ketamine.
00:20:47
Speaker
And Dr. LeBlanc really wanted the ketamine policy just to be successful at UNC.
00:20:51
Speaker
And so we were very conservative at the very beginning and only letting anesthesia pain write for ketamine.
00:20:57
Speaker
And when we saw the success and how safe this medicine really is, we continued to train our palliative care faculty and fellows.
00:21:07
Speaker
and advanced practice providers on the use of ketamine and how to write for ketamine and look at the order set and reevaluate the order set.
00:21:16
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And in January of 2022, for six years after I joined faculty, we were able to finally have our palliative care providers write for ketamine, which is a huge step in the landscape of ketamine at UNC.
00:21:30
Speaker
It really broadens our scope as providers as well as providing, I would argue, better patient care.
00:21:37
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at UNC.
00:21:38
Speaker
Yeah, that's great.
00:21:40
Speaker
And so I think it might be helpful to even hear a little bit about what the policy at UNC looks like so that others can think about maybe an appropriate dosing regimen or how to create a protocol at their institution.
00:21:54
Speaker
So based on what's been developed at UNC, what are your recommendations for dosing and initiation?
00:22:00
Speaker
Yeah, so at UNC, because of the conservative nature of our policy, we don't do any bolus dosing or a trial dose of ketamine.
00:22:07
Speaker
So for a patient who comes in and needs ketamine for refractory pain, and we want to use it in the IV form
00:22:15
Speaker
We generally start patients off on a 0.1 mg per kg per hour infusion of ketamine.
00:22:21
Speaker
And we will go to a max dose of 0.5 mg per kg per hour.
00:22:25
Speaker
In the literature, you'll see a max dose of 1 mg per kg per hour for, again, at sub-anesthetic dosing, analgesia dosing.
00:22:32
Speaker
But we maxed ours out at 0.5, which, again, is very conservative.
00:22:36
Speaker
We realized that, but we wanted to prove that this is a safe, kind of a successful medication.
00:22:40
Speaker
We've had success with that max dosing.
00:22:42
Speaker
And we will tightrate that up maybe every eight to 12 hours.
00:22:46
Speaker
So maybe twice a day and double it to like 0.1 and we'll only go by 0.05 microgram per gig per hour increments.
00:22:55
Speaker
And we'll use it over five to seven days is kind of the length of the IV infusion that we'll use.
00:23:00
Speaker
At that point, we think we'll see the benefit and hopefully the open receptors have reset.
00:23:04
Speaker
If we decide to stop the infusion, palliative care will recommend maybe transitioning to oral ketamine if we've seen some benefit.
00:23:12
Speaker
Oral ketamine, generally I would start off, despite what your dose was from an IV infusion, 10 to 25 milligrams Q8 hours.
00:23:20
Speaker
And you can titrate that up over every 48 hours by about 25%.
00:23:25
Speaker
And you can titrate that up to the max dose, which is 200 milligrams Q6 hours, which I have never seen.
00:23:31
Speaker
Mm-hmm.
00:23:33
Speaker
are 0.5 mg per kg, which would be your max dose.
00:23:39
Speaker
The oral ketamine is tricky because we don't think there's any randomized control trials for
00:23:46
Speaker
large randomized controlled trials for
Monitoring Ketamine's Effects
00:23:48
Speaker
IV ketamine.
00:23:48
Speaker
There's hardly anything for oral ketamine.
00:23:51
Speaker
And so I would say probably the length of duration for oral ketamine would be maybe one month, three to four weeks.
00:23:59
Speaker
At that point, the major side effect that you're looking out for for oral ketamine is ulcerative cystitis.
00:24:05
Speaker
So maybe getting weekly urine dipsticks just to make sure that you're not developing ulcerative cystitis is something that I would be concerned about from a long-term side effect of ketamine.
00:24:14
Speaker
This is what we see in patients who have substance use disorder or abuse ketamine on the streets.
00:24:20
Speaker
So generally, again, start at 0.1 and titrate up to 0.5 mix per kg over five to seven days for IV ketamine infusion.
00:24:28
Speaker
And for PO, I would generally start 10 to 25 milligrams Q8 hours and increase by 25% every 48 hours, if that makes sense.
00:24:34
Speaker
It absolutely does.
00:24:35
Speaker
And you call that conservative, but I think for ED physicians who have been using bolus dosing for pain in the ER, it's going to sound very familiar.
00:24:47
Speaker
So
00:24:48
Speaker
the ER here, typical dosing will be 0.1 to 0.3 mg per kg if you're just gonna do a bolus for pain, having done that for chest tubes or orthopedic injuries.
00:24:58
Speaker
No, I actually think that aligns really nicely probably with what a lot of people's experience is.
00:25:02
Speaker
And so certainly then hearing about how that gets translated into an infusion
00:25:06
Speaker
And then kind of what that transition to oral ketamine is like that, as you said, is it kind of a data-free zone?
00:25:13
Speaker
There's much to be desired with understanding exactly probably what the best dosing regimen is, but it sounds like you've had success with that.
00:25:19
Speaker
We've had success with numerous patients in regards to oral ketamine.
00:25:23
Speaker
And some even patients where IV ketamine didn't work, oral ketamine has worked.
00:25:27
Speaker
I can't explain that, but that has been our patient's experience.
00:25:31
Speaker
And then I think the other thing that I should probably mention is
00:25:35
Speaker
Because of the hypersalivation that you can get with IV ketamine, generally we provide right for an order for glycopyrolate, just PRN for the side effect prophylaxis.
00:25:45
Speaker
Then if they do have hallucinations and they can tolerate the hallucination and they're not super bothered by it, sometimes we just let that continue to happen.
00:25:52
Speaker
For example, my patient that I mentioned at the very beginning of this podcast, she was definitely having syphilis.
00:25:57
Speaker
some auditory hallucinations where she was hearing that the nurses were talking about sex on the beach.
00:26:02
Speaker
And she said that was, she said that was fine.
00:26:03
Speaker
She really appreciated.
00:26:04
Speaker
She knew that it wasn't real and she kind of appreciated having that experience.
00:26:09
Speaker
And so if it does bother the patients, but they, we think we're having benefit from the ketamine, we will try benzodiazepines, low dose benzodiazepines or low dose Haldol to kind of help with that.
00:26:19
Speaker
No inside effect of the medication.
00:26:20
Speaker
Yeah.
00:26:21
Speaker
Yeah.
00:26:22
Speaker
I think you touched on this briefly before, but just to kind of drive home the point, what sort of ongoing monitoring or you mentioned side effects already, but what sort of ongoing monitoring do you need for these folks?
00:26:36
Speaker
Are they always on a monitor?
00:26:38
Speaker
Are you getting daily lab draws?
00:26:40
Speaker
What sort of monitoring do these folks get?
00:26:42
Speaker
Yeah, so that is, again, our policy at UNC highlights that they want a baseline EKG.
00:26:48
Speaker
There's no indication for that, but that is what our policy says.
00:26:51
Speaker
A baseline EKG, a basic metabolic panel, making sure they're not pregnant, so a urine pregnancy test, and then ongoing monitoring while they're on ketamine because of the tachycardia that it can definitely cause.
00:27:02
Speaker
And so those patients generally are on a telemetry monitoring.
00:27:06
Speaker
They don't have to be in a telemetry monitored unit, just a unit that can have, they can have,
00:27:12
Speaker
a remote tele is fine.
00:27:14
Speaker
And then as we start the infusion, we get vital signs more frequently, like Q4 hours for the first, maybe for the first 24 hours.
00:27:21
Speaker
But then after that, if their vital signs are stable, we just continue to have regular vital signs, vital sign checks.
00:27:28
Speaker
The other thing that I didn't mention before is that as we titrate up the ketamine, we generally decrease the opioids by half.
00:27:34
Speaker
So as we start ketamine, we cut their opioids in half.
00:27:36
Speaker
And then we continue, we're seeing good pain relief.
00:27:40
Speaker
We will continue to kind of cut the opioids and decrease the opioids as we're seeing increased benefit from the ketamine.
00:27:45
Speaker
Yeah.
00:27:46
Speaker
And I think that's a really important point to drive home that for many of these patients, it does not only necessitate a reduction in their opioid dosing, but, you know, while they're on the infusion, but hopefully for maintenance afterwards.
00:27:58
Speaker
And so, you know, the question there is sort of, you said, you know, five to seven days is kind of typical max length.
00:28:04
Speaker
What endpoint are you looking for therapy?
00:28:06
Speaker
You started somebody on infusion.
00:28:08
Speaker
What's sort of your endpoint where you say, all right, I think we're where we need to be.
00:28:11
Speaker
You know, let's work on getting off of the infusion.
00:28:14
Speaker
Yeah.
00:28:15
Speaker
Definitely what I look for is decreasing their pain, whatever that is, a pain where they can function, hopefully, or at least function better than they were functioning before.
00:28:23
Speaker
And if we reach that pain, then if we reach that threshold, I keep them on the infusion for maybe 24, 48 hours to kind of make sure we maintain that effect.
00:28:31
Speaker
And then we'll slowly transition them off and...
00:28:35
Speaker
onto oral ketamine if we've seen the effect.
00:28:37
Speaker
And if we don't see the effect within three to five days, then ketamine may not be the drug of choice for them.
00:28:43
Speaker
It may not be a drug that works for them.
00:28:44
Speaker
And then we can just stop the ketamine infusion and continue the opioids and think about novel therapies.
00:28:50
Speaker
our interventional procedures.
00:28:51
Speaker
So I think we're looking for the effect that we want on their pain and on their daily life and their function.
00:28:57
Speaker
And if we can get that, then we can stop the ketamine infusion, transition to oral ketamine and continue their opioids and hopefully follow up with their palliative care provider as an outpatient so we can continue to titrate down their opioids.
00:29:08
Speaker
Perfect.
00:29:09
Speaker
And I think for our listeners, it's really interesting because, you know, we have some, you know, palliative care providers, maybe some are more in the ED world, some who are straddling both.
00:29:19
Speaker
And obviously, the protocol that you've described is for an inpatient infusion.
00:29:24
Speaker
But maybe in the future, we'll have enough data to back up or tell us more about...
00:29:31
Speaker
converting people from maybe they got some IV ketamine in the ER and getting them on oral ketamine and getting them discharged, maybe some options for even a more abbreviated regimen.
00:29:39
Speaker
So I think you mentioned this before, but just to sort of drive home the point and get people thinking about it, it's not like there are ketamine pills sitting around.
00:29:46
Speaker
So when you're getting somebody on oral ketamine, how do you prescribe it?
00:29:50
Speaker
I think the best piece of advice is check with your pharmacy to make sure they have it before you even think about prescribing it because they don't have it.
00:29:57
Speaker
And if they can't get it, it's a moot point.
00:29:59
Speaker
It is relatively cheap.
00:30:01
Speaker
It's a World Health Organization essential drug.
00:30:03
Speaker
So it's a who list of essential drugs.
00:30:05
Speaker
And so at UNC, for example, I think it's $17 to get it filled for a two week supply.
00:30:10
Speaker
And the important thing to remember about oral ketamine is that it only will last for two weeks.
00:30:16
Speaker
After two weeks, it's no longer in an acceptable form.
00:30:21
Speaker
I don't know if it biodegrades at that point in time, it's no longer effective, are safe to administer.
00:30:26
Speaker
So after two weeks, we can only use the oral ketamine for two weeks.
00:30:29
Speaker
So after two weeks, we have to discard it.
00:30:32
Speaker
And so you have to, number one, have a pharmacy who can prescribe or who can fill it, have an insurance or a patient be able to afford the copay or afford the $17.
00:30:42
Speaker
And then be able to have a provider who's going to be willing to kind of on prescribe it ongoingly.
00:30:49
Speaker
And so generally the dose that I would start out again, is just, it's just the IV form in the liquid solution that people drink.
00:30:56
Speaker
And you can find compounding pharmacy that will make it into a pill and you're
00:31:00
Speaker
in certain areas of North Carolina, at least.
00:31:03
Speaker
And we generally start off at 10 to 25 milligrams Q8 hours is generally the starting dose.
00:31:07
Speaker
If they've gotten an IV dose in the emergency room and they tolerated that well and you want to transition to oral ketamine, you could probably do 20, 25 Q8 hours and be safe.
00:31:16
Speaker
and then have an ongoing provider continue to monitor them.
00:31:20
Speaker
Does that answer your question?
00:31:21
Speaker
Yeah, absolutely.
00:31:22
Speaker
And some of this is obviously going to be dependent on, as you said, the local pharmacies.
00:31:27
Speaker
And so that's the importance of checking with pharmacies.
00:31:29
Speaker
But also when it comes to follow-up, that's going to depend on the structure and network and what your local resources are.
00:31:38
Speaker
And so give us a sense of who's following up these patients for the product care team at UNC.
00:31:45
Speaker
Yeah.
00:31:45
Speaker
Yeah, so many times our UNC palliative care outpatient providers will follow these patients up.
00:31:50
Speaker
Whether it is a palliative care provider that's embedded in our cancer clinic with UNC or embedded in our internal medicine clinic.
00:31:57
Speaker
And so if the patient doesn't have cancer, the patient can go to our palliative care provider in our general internal medicine clinic.
00:32:03
Speaker
And so generally, they're palliative care providers who are following them up.
00:32:06
Speaker
If the patient's going home on hospice, hospice will also follow them up and hopefully continue to provide ketamine if it's on their formulary.
00:32:13
Speaker
And then I think my hope is, is that as we get more and more and more of our residents and internal medicine physicians comfortable with this drug, again, I would like to highlight that it's safer than many of the drugs that we prescribe them, that they will be able to and feel comfortable helping meet this need for our patients if this is showing to be really beneficial.
00:32:33
Speaker
Yeah, and I'm really glad you brought up the piece about hospice as well, because for many hospice agencies, this is on their formulary, and many inpatient hospice units will and do use ketamine as an adjunct or as an independent analgesic outside of opioids.
00:32:51
Speaker
And so...
00:32:52
Speaker
Knowing that, especially from an ED standpoint, if you have a patient who is dying and you're having trouble with pain control, but you feel like they are stable enough and it's in line with their goals to get them to an inpatient hospice unit, you may actually find inpatient hospice units who are okay with you starting them on ketamine and getting them to the inpatient unit where they will continue the ketamine.
00:33:15
Speaker
And so it's not just for folks who were thinking about plugging into a clinics scenario and maybe someone you see in the ED who ultimately will go to hospice.
00:33:24
Speaker
Right.
00:33:27
Speaker
Much about ketamine is either a data-free zone or a data-limited zone.
00:33:34
Speaker
Whether it's oral ketamine, topical, nebulized ketamine, we're just looking for more data.
00:33:38
Speaker
We aren't great at identifying which patients will benefit exactly, what the optimal protocols are.
00:33:44
Speaker
Where do you see ketamine going in the future, and what are your hopes for research and its
Future Directions for Ketamine Use
00:33:49
Speaker
use?
00:33:49
Speaker
Yeah, so I really would love to partner with anybody who's out there who wants to do a multi-centered trial in regards to ketamine with our patients with sickle cell disease, as well as with our palliative care patients who have opioid refractory pain.
00:34:01
Speaker
I think that's where the data needs to come from.
00:34:04
Speaker
It's really hard, and why I'm focusing on patients with sickle cell disease is because it's really hard to get patients in our palliative care population to
00:34:14
Speaker
to conduct research.
00:34:15
Speaker
It's really hard for me to deny a medicine that I think could help them if they're randomized to a medicine that may not be helpful to them as like a placebo in regards to opioid refractory pain.
00:34:28
Speaker
I would give them ketamine if that was my
00:34:31
Speaker
And so it's really hard for me to deny them ketamine if they only have days to live and they're in refractory pain.
00:34:37
Speaker
It's really hard to conduct research on that patient population.
00:34:40
Speaker
And it's really hard for them to come in for research.
00:34:42
Speaker
And so that's why I really would like to focus on the patients with sickle cell disease, because I think that is a much more readily studied patient population and could really benefit from the use of ketamine in their lives.
00:34:54
Speaker
Mm hmm.
00:34:55
Speaker
I think the hope is, is that we can, when we can't get randomized control trials, you have to go to the Cochrane Review.
00:35:02
Speaker
There's the Cochrane Review said there's not enough evidence.
00:35:04
Speaker
And then where do you go?
00:35:05
Speaker
You go to the guidelines.
00:35:06
Speaker
And I think this is where palliative care needs to kind of step up to the plate in my mind and really start developing palliative care guidelines in the reuse, in the use of ketamine, around the use of ketamine.
00:35:16
Speaker
Anesthesia, as we were writing our policy for UNC, anesthesia had just come out with their own guidelines about the use of ketamine, oral, and IV for chronic and acute pain.
00:35:27
Speaker
And so I think we as maybe departments of medicine, departments of emergency medicine, palliative care, anesthesia need to come together to form kind of universal guidelines if we can't get randomized control trials started and initiated.
00:35:40
Speaker
So that's where I'd really love to see kind of these uniform guidelines for this patient population specifically.
00:35:48
Speaker
And then again, like I said, I would love to partner with anybody who's interested in our patients with sickle cell disease because I think they would really benefit.
00:35:55
Speaker
And then I'd love to see kind of how ketamine can also be used for patients with existential suffering or
00:36:03
Speaker
this deep sense of anxiety and depression around their pain and around their suffering, because I think there is use of maybe potential use for ketamine in that specific patient population.
00:36:12
Speaker
Cause I think that is why many, some of my patients have had benefit from ketamine.
00:36:17
Speaker
And so I think there's a lot of hope around ketamine.
00:36:20
Speaker
I am not,
00:36:22
Speaker
naive enough to think that it's going to be the end-all be-all drug for everybody.
00:36:25
Speaker
It definitely isn't.
00:36:26
Speaker
And it's definitely not for many patients, but if it does work for some patients, it's really nice to find out those patients that it works for, um, and to give them some pain-free days are some pain less days, um, for sure.
00:36:39
Speaker
Yeah.
00:36:40
Speaker
And kind of to bring it home, is there anything we haven't touched on that you think our listeners should hear?
Conclusion on Ketamine's Potential
00:36:46
Speaker
I think the goal of all physicians, specifically palliative care physicians, is to make every day as good as we can for our patients and to help them live as well as they can.
00:36:56
Speaker
And I think if ketamine can help that and can provide well-being for our patients and help them live the best life that they can live with whatever time they may have left, I think it needs to be in our arsenal.
00:37:10
Speaker
And so I think in our arsenal of tools to kind of help treat these patients.
00:37:15
Speaker
And I'd love to be an advocate for that and also help other institutions, other providers in regards to the use of ketamine.
00:37:25
Speaker
And I think we just need to think outside the box at times for many of our patients when the traditional therapies don't work.
00:37:31
Speaker
And I think this may be one of those times that we can think outside the box.
00:37:36
Speaker
Absolutely.
00:37:37
Speaker
And we're real excited to see kind of what the future of ketamine is.
00:37:39
Speaker
Yeah, I hope to be on this podcast again in a year or so so that we can recap what the advances of ketamine have been.
00:37:46
Speaker
I love it.
00:37:46
Speaker
Thank you very much.
00:37:47
Speaker
Thanks so much for having me.
00:37:48
Speaker
You bet.
00:37:49
Speaker
Thank you so much, Dr. McAtee.
00:37:51
Speaker
That was extremely informative.
00:37:53
Speaker
And as somebody who appreciates having this tool in my arsenal in practice, you've given me some more ideas about how it can be utilized.
00:38:00
Speaker
And Dr. Mark Walter, thank you for being our guest interviewer for this episode and also for your contributions to our content on palium.org.
00:38:09
Speaker
Thank you.
00:38:11
Speaker
Happy to be part of it.
00:38:13
Speaker
For more information on current topics in the fields of palliative and emergency medicine, please visit pallium.org.