Dr. Harry Cridge, veterinary internal medicine specialist, joins Dr. Andy Roark to talk about why we shouldn’t be SO afraid of pancreatitis. They discuss common pitfalls in the treatment of this condition, how to effectively work these cases up, and finally how the new drug PANOQUELL-CA1 works in these cases.
This episode is brought to you ad-free by Ceva Animal Health!
PANOQUELL-CA1 IMPORTANT SAFETY INFORMATION: The safe use of PANOQUELL®-CA1 has not been evaluated in dogs with cardiac disease, hepatic failure, renal impairment, dogs that are pregnant, lactating, intended for breeding or puppies under 6 months of age. PANOQUELL®-CA1 should not be used in dogs with a known hypersensitivity to fuzapladib sodium. PANOQUELL®-CA1 is a highly protein bound drug and its use with other highly protein bound medications have not been studied. The most common side effects in the pilot field study were anorexia, digestive tract disorders, respiratory tract disorders and jaundice. PANOQUELL®-CA1 is not for use in humans. Limited data is available on the potential teratogenic effects of fuzapladib sodium. Therefore, anyone who is pregnant, breast feeding, or planning to become pregnant should avoid direct contact with PANOQUELL®-CA1.
Conditionally approved by FDA pending a full demonstration of effectiveness under application number 141-567.
It is a violation of Federal law to use this product other than as directed in the labeling.
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LINKS
REVIEW: Advances in the diagnosis of acute pancreatitis in dogs
Dr. Andy Roark Exam Room Communication Tool Box Team Training Course
Dr. Andy Roark Charming the Angry Client Team Training Course
All Links: linktr.ee/DrAndyRoark
ABOUT OUR GUEST
Dr. Harry Cridge, MVB, MS, PG Cert Vet Ed, DACVIM (SAIM), DECVIM-CA, FHEA, MRCVS
American & European Specialist in Small Animal Internal Medicine
RCVS Specialist in Small Animal Medicine (Gastroenterology)
Harry qualified from the University College Dublin, Ireland in 2016 and went on to perform a Small Animal Internship at Mississippi State University, USA followed by a Small Animal Internal Medicine Residency and a master’s in veterinary sciences at the same institution. He became a Diplomate of the American and European College of Veterinary Internal Medicine in 2021. Following his residency, he moved to Michigan State University where he currently serves as an Assistant Professor of Small Animal Internal Medicine, in addition to an administrative role with oversight of the internship and residency programs within the college. Harry has published several research articles in peer-reviewed veterinary journals and lectures regularly at national and international courses/conferences.
EPISODE TRANSCRIPT
Dr. Andy Roark:
Welcome everybody to the Cone of Shame Veterinary podcast. I am your host, Dr. Andy Roark. Guys, I got a Halloween episode for you. Dr. Harry Cridge is here. He is a veterinary internal medicine specialist and he’s joining me today to talk about maybe why we shouldn’t be so afraid of pancreatitis. We’re talking about pancreatitis panics today. We’re talking about the horror stories of how pancreatitis cases go wrong and what’s real and what’s not. We are talking about common pitfalls and the treatment of the condition, how to effectively work these cases up. And finally how the new drug PANOQUELL CA-1 works in these cases. Guys, quick to the point, super useful and one less thing to be terrified of. Guys, let’s get into this episode, but before we do, I just got to stop real quick and say thank you. Thank you to Ceva Animal Health for making this episode possible ad free. Guys, let’s get into it.
Kelsey Beth Carpenter:
(singing) This is your show. We’re glad you’re here. We want to help you in your veterinary career. Welcome to the Cone of Shame with Dr. Andy Roark.
Dr. Andy Roark:
Welcome to the podcast, Dr. Henry Cridge. Thanks for being here.
Dr. Harry Cridge:
Yeah, thank you for having me.
Dr. Andy Roark:
Oh, it is my pleasure. So for those who do not know you, you are on the faculty at the College of Veterinary Medicine at Michigan State. You are a boarded veterinary internist and you are a researcher and your research focus is in disorders of the pancreas. And so I wanted to have you on today to talk with me a little bit about the scariest part of the abdomen in my mind, which is the pancreas, which is where when you make it mad, bad things happen. And I want to ask you, here’s what I’m looking for for you. I want a little bit of comfort in my treatment of pancreatic disease and illness, and it’s in my mind the pancreas is kind of this glowing red button that I really don’t want to press. And so I want to talk to you in realistic terms. I just want to start a high view about pancreatic disease and illness, and I wanted to ask you about what are the most common pitfalls that we make in treating pancreatic disease? And let’s just start there. So again, it is a sort of a scary thing for me. And so let’s just start at how much is a risk and what are the most common risks?
Dr. Harry Cridge:
Yeah, so I think in order to effectively talk about treatment of pancreatitis, we really have to think about how we diagnose the disorder and what our goals are. And that may vary dependent on the clinical situation you’re in. Historically, people used to use pancreatic biopsies, but we all know that they have significant limitations. They’re invasive, they’re costly, they’re
Dr. Andy Roark:
Terrifying. They’re terrifying.
Dr. Harry Cridge:
Yes, they’re not good anesthetic candidates. So we’ve fortunately largely moved away from that for that very terrifying reason. But it does put us in a position where we’re now reliant on an overall assessment of the clinical data that we have. That may be the patient history, may be the signal, and it may be the results of imaging and pancreatic lipase assays. We ourselves then become the gold standard. And while that’s fantastic for us and fantastic for job security, we do need to be very aware of some of the limitations of some of these diagnostics so that we can accurately interpret them and do the best by the patient.
Dr. Andy Roark:
Okay. Let’s drill into this a little bit. So I am intrigued here. So I like your idea. The pancreatic biopsy is generally I’m not doing those and so it makes me feel good that that’s not accepted standard and we’ve got to move past that. Talk to me about the limitations in the standard tools. So my impression with pancreatitis is I kind do some voodoo. I think most veterinarians sort of do. I look at the patient, I’m feeling the abdomen, I’m looking for clinical signs. I’m looking for obvious pain or discomfort. I’m looking for the general dumpiness. I think that that’s a clinical turn is dumpiness looking at the general dumpiness that I’m looking at the blood work and I’m kind of squinting at the lipase. And that’s probably, I don’t know how much that means exactly. Again, I kind of take it with a grain of salt, but I’m definitely looking at amylase, lipase, things like that. I’m going and then my pancreatic lipase, snap tests, things like that. But even then I still know that there’s a big range of what is clinical and maybe what is diagnostic. And so anyway, can you sort of flesh out in more specific terms what you mean when you say “We have to be careful in making diagnostic here and there are shortcomings in how we do this?”
Dr. Harry Cridge:
So I think as veterinarians we have to think ultimately what is the purpose of the test that we perform. And in a case where we have a patient that’s clinically unwell, has cranial abdominal pain and we’re suspicious for pancreatitis, then the question becomes what do we have to rule out in order to not change how we treat this patient?
Dr. Andy Roark:
Okay, I like this.
Dr. Harry Cridge:
We may get away with limited blood work, some level of pancreatic lipase assessment and a radiograph to rule out the foreign body that we don’t want to miss. So practically that may be what we need in a first time offender with no other complications, but that patient that’s not getting better or that patient that keeps coming back, that’s probably a case we need to be a little bit more solid in our diagnosis to make sure we’re treating the right thing. And I suppose that’s where we have to look a little bit more closely at the limitations of each of the diagnostic tests we have.
And you mentioned a few of those diagnostics predominantly blood work, biomarkers, lipase, amylase, and pancreatic lipase. And what I like to encourage people to think about with those particular assays is lipase and amylase. They can come from multiple different tissues. And why that matters to us as clinicians is if they’re elevated, we can’t say for sure that it’s coming from the pancreas. It could be coming from another organ system or it could be not getting excreted properly, the problem with the kidneys or something else. So we try to find an assay that is the most specific to lipase from the pancreas. And the hope there is if that’s elevated, the pancreas is inflamed, the pancreas is annoyed. So we try and pick a more specific test out of those tests. The pancreatic specific lipase or the quantitative test that often gets sent out to the lab is going to be the most specific one, the one that we can put most strength in our diagnosis behind.
But we do also have to be aware that there are other diseases outside of the pancreas that can also irritate the pancreas. We know for a fact that if the abdomen is angry, the pancreas is also angry. So just having the elevated lipase on its own is not going to be enough. We need to still do imaging and look at all that data together. And that’s why we went into some challenges is we can’t rely on a single test. So it can be challenging to get all those diagnostics and convince our owners to do those, but the cases that probably need that the most are those cases that keep coming back or those cases that aren’t responding to standard of care therapy.
Dr. Andy Roark:
Talk to me a little bit about your perspective on ultrasound as a diagnostic tool in pancreatitis. How much value is that over radiography just to rule out foreign bodies? Just wade in a little bit on that because you haven’t mentioned it as a diagnostic tool.
Dr. Harry Cridge:
So I think those lipase assays have to be combined with some level of imaging. Ultrasound is the one that’s most classically used, and ultrasound is very valuable in the fact that we can really see if there are any changes to pancreas consistent with pancreatitis, but also we can help rule out other abdominal disorders that could cause similar clinical signs. One of the times that we run into some challenges with ultrasound is there’s been a few studies recently that have looked at those cases that you may have seen in practice where you finally convinced the owner to do the lipase test, the ultrasound, and you think you’re doing a great job and then all of a sudden all your test results disagree with each other and you’re like, well, what do I do now? And that patient population certainly does exist. We’re getting more data out now to try and explain why those discrepancies are occurring.
And I think one of the things we have to think about is these are biomarkers of disease and each biomarker of disease or each imaging finding takes a certain amount of time to develop and a certain amount of time to disappear. And the preliminary data that we have is that any of the biomarkers of inflammation, so pancreatic lipase or C-reactive protein, any of those inflammatory type of biomarkers have relatively short half lives. So they’re going to go up relatively quickly after an injury to the pancreas, but they’re also going to fall off relatively quickly with most data out now saying that within two days of diagnosis of pancreatitis that pancreatic lipase is going to return to within the reference interval, whereas ultrasound changes may persist for longer. So when we’re taking a single time point in these cases, we don’t know where exactly on the upswing or the downswing of those lipase markers or the ultrasound we’re going to be, and that’s when discrepancies can occur.
So the way that we are trying to work on that in practice is thinking about these tests is more dynamic than we originally did. I think we used to say, okay, we’ve got my diagnosis, we’re good to go. But those cases where there are discrepancies, they’re probably cases where we need to do either repeat imaging or repeat lipase or repeat snap test to see how things are changing over time. And that can help further solidify that diagnosis. So thinking about the half-life of some of these tests and thinking about, okay, if they disagree, let’s get another time point and see which direction are we moving and are we moving towards agreement and that it was a relatively recent injury or are we getting further apart and it was probably a past pancreatic injury.
Dr. Andy Roark:
When you think about gastroenteritis, pancreatitis, do you see levels of disease? Is there a mild pancreatitis in your mind or are they always to be worked up the same way? Talk to me about severity in the disease as you see it.
Dr. Harry Cridge:
Yeah, so there’s certainly fairly substantial variations in the degree that an animal is, whether they’re clinically affected by pancreatitis or not at the referral level, we get a lot of the severe pancreatitis cases, the one that causes the most stress but also the most fun. But there were a lot of cases in practice where you can make the diagnosis and sometimes treat them on an outpatient basis. And we’ll touch on that a little bit later when we talk about treatment options. But yeah, there’s certainly a big, big spread and I think there’s probably the fact that some animals have chronic disease that we under recognize and they have acute on chronic flare and typically are a little bit more mild, at least in my opinion, versus the first time really severe acute disease.
Dr. Andy Roark:
What do those acute on chronic cases look like to you? I mean, how do I not look at this and go, well, this is acute pancreatitis, what should I be looking for if I’m trying to catch on to that? Is it just that I’ve seen this patient before or Yeah.
Dr. Harry Cridge:
I think it’s twofold. One is if that patient keeps coming back and keeps getting diagnosed with pancreatitis, I think the likelihood of these being independent events specifically if they’re in short succession is probably lower. And it’s probably had some level of chronic perhaps subclinical inflammation going in the pancreas between flare-ups. And then the other thing is ultimately a lot of these patients come in on an emergent basis, so we’re all focused on stabilizing these patients and getting them to where they need to be. But when we take a step back and think about asking more detailed questions, often these animals will have more substantial GI histories than they were initially reported. And we actually found that in a study we did relatively recently. I think last year we took several hundred dogs that had elevated pancreatic lipase concentrations and we surveyed and looked at clinical presentation of these dogs, what risk factors for disease they had, and also how many of them had past episodes of GI disease, and it was a significant number of them that had these chronic GI histories that perhaps go under recognized on first glance.
Dr. Andy Roark:
Yeah, that makes sense. It’s funny, I love that you called out sort of emergency cases where they show up and you’re the emergency doctor and you have no idea what the rest of their file looks like. And I think about cases I’ve seen when you look at this patient, especially if it’s a 10, 12 year old dog that’s had GI upset diarrhea, things like that throughout its year, it’s easy to just gloss over that and not really say, Hey, is this something that’s related to what we’re dealing with today? And so anyway, that’s a arrow I’m going to put in my quiver. I need to start looking for the chronicity of that. So anyway, I love that you say that. How do, let me just ask you this again. I said this is sort of a fear episode for me. What mistakes do you see as people start to address these and decide how they’re going to treat these cases? Do you see, I don’t know, do people tend to be less aggressive than they need to be or are there tricks that you say, oh man, I don’t know why doctors consistently don’t do this, or Talk to me a little bit about how people struggle to treat these cases.
Dr. Harry Cridge:
And I think this sort of touches on both diagnosis and treatment in terms of diagnosis, there was some common pitfalls, and again, I don’t always think that these are the fault of the veterinarian. It’s often the situation you’re in and the finances that you have available to you. But there are a lot of cases where clinical signs and abnormal SNAP test, it’s not a guarantee of a diagnosis of pancreatitis. There’s a lot of all the diseases where it’s either a false positive test, which is proposed in the literature, or this animal has some level of pancreatitis, but it’s secondary to whatever else is going on. So relying on just the SNAP test is probably not great, particularly in cases that are recurrent. Other things that we sometimes see is those patients that keep coming back, we’re all really, really good at managing those acute pancreatitis cases.
We get ’em on fluids when we can. We treat them for pain medications as we can and we get them better. But I think one of the things we sometimes don’t put as much time into is thinking about are there any identifiable risk factors to prevent this animal to keep coming back? So in those patients measuring a triglyceride concentration, looking to see if they’ve been on drugs that have been associated with pancreatitis in the past and whether they need to be on those drugs. Some of those common ones is anti-seizure medications, and some of those you of course can’t come off, but it’s worth looking at and thinking about, and especially screening for lipid disorders or endocrine diseases. They’re the cases that when we identify those and treat those, my opinion is they’ve got a reduced chance of recurrence and reduced chance of coming back in with a severe disease again.
Dr. Andy Roark:
I like it. That makes sense. One of the new things this year that I’ve really seen a lot of discussion of is the PANOQUELL -CA1 medication that just sort of just came out is conditionally improved by the FDA. Can you talk a little bit about the role that you see PANOQUELL- CA1 playing in treatment of these patients?
Dr. Harry Cridge:
Yeah, so as you mentioned, PANOQUELL- CA1 is a new drug on the block and there’s a lot of excitement about it. I think there’s a lot of excitement because for many, many years we’ve been restricted to just supportive and symptomatic care in these patients. And we all know from our own experiences or from the literature that as hard as we try, there’s often a significant morbidity and mortality, especially with the severe cases. So having a new option is really exciting. I think it has got conditional approval over time they’ll need to work full approval, but it’s really exciting to have a novel treatment on the block for these tough cases. The way that the drug works is it’s a drug that acts on neutrophilic inflammation. So the way that inflammation is obviously strongly associated with pancreatitis. So the theory behind this drug is if we reduce the amount of neutrophils that come out of the blood vessels into the tissues, we’re going to reduce the amount of inflammation and therefore help this patient.
The way that it does that is it focuses on how neutrophils come out of the vessels. So we think all the way back to vetco, we think about the rolling, the activation, the adhesion and migration of neutrophils from the vessels into the tissues, and that PANOQUELL- CA1, the fuzapladib acts on one of the key players in that. So the key player acts on is something called leukocyte function associated antigen one or LFA1, and that is a specific molecule that allows that neutrophil to subsequently extravasate. So that fuzapladib blocks the activation of LFA1, which then prevents it from being able to go into the tissues so it stops that neutrophil extravasation.
Dr. Andy Roark:
What’s the impact if I catch this late, so I understand the slowing down, reducing neutrophils coming out of the vessel, that makes sense to me, but it feels like if I inherit a pancreatitis case and everything has already flared up, am I still getting benefit from this medication?
Dr. Harry Cridge:
So I think certainly what we know so far based on the studies that are out there is that it has been shown to improve the clinical signs associated with the acute onset of pancreatitis. And that was a fairly broad patient population that was used in those studies. We do over time, I think we’re going to work out when is going to be best to use this medication, but when we really think about it, there’s a lot of these cases where the degree of inflammation is what’s causing the challenge. If you get in nice and early and prevent that severe neutrophilic inflammation, in theory, that would strongly benefit the case. And there’s a lot of utility in using this early in the course of disease later in the course of disease. Of course, helping with any level of inflammation is going to be of benefit is just working out how beneficial it may be in those particular cases.
Dr. Andy Roark:
Yeah, that makes sense. Getting back to our horror theme, what are the side effects? Are there contraindications that we’re looking at, things like that?
Dr. Harry Cridge:
The only labeled contraindication is don’t give this drug to a dog that is allergic to the drug, which it’s a classic and one that’s always on the label. So that’s the only label contraindication. As with any new drug that comes out, there’s certain ways that we can look for adverse effects. One of those is to look at the safety studies, and one of that is to look at any adverse event that was reported in the efficacy studies. So when we look at the data, and that is available to anybody on the FDA website, the freedom of information summary for the particular drug, you can look and see what adverse events occurred in the patients that received the drug and what adverse events occurred in those that didn’t receive the drug or those that received the placebo. A lot of the adverse events that were reported are GI upset, some elevations in liver enzymes and various other adverse effects, and any of those could be either from the underlying disease or from the drug administration. So that’s why we try and look at what happened in those that got the drug and what happened in those that didn’t get the drug. And the other place we look is the target species safety data, again, which is publicly available to any veterinarian out there that wants to look at this data firsthand. And in those type of studies, what they do is they give the new drug and they give it at higher doses and for longer periods of time than is on the label, and they look to see what happens.
So fuzapladib, PANOQUELL – CA1, it’s like a five times overdose, and they get it for nine days instead of three days, and they look to see what happened in those populations. A higher blood pressure was noted in those dogs on significantly high doses of the medication, and there was some injection sites swelling it in one dog, I believe, among some other adverse effects. So right now it’s hard to be 100 percent sure what’s the drug and what’s not, because a lot of the clinical signs that were reported are things that we see in pancreatitis. The dog that’s vomiting, that has nausea. So we can’t definitively associate those with the drug. But as more and more people use the drug and more and more data comes out, I think we’re going to have a much stronger idea of the specific nature of that drug.
Dr. Andy Roark:
Tell me about the route of administration and the time to affect. I mean, how do we get this on board? How long does it take before we start to see benefits?
Dr. Harry Cridge:
Yeah, so that’s a great question. So the drug is given once daily for three days, and it’s given intravenously in terms of what data has been used for the drug approval was the clinical improvement, the clinical score system by day three, the end of the drug administration. But the next of question is it’s an injection. So how do I store that and what can I use it for? So it’s a medication that comes as a powder LIA drug, and it’s mixed with a sterile diluent, and it’s then stored in the fridge for up to 28 days. So once you have this drug in practice, you can store it for up to 28 days, and it’s a multi-dose vial, so it’s really, really useful for multiple patients.
Dr. Andy Roark:
Is there anything that says I have to give this intravenous injection to a hospitalized patient? I mean, sometimes I’m trying to help patients. They may have money constraints. Sometimes we treat complicated cases on an outpatient basis. Anything that says I have to have the patient in hospital, does it need 24 hour monitoring? Anything like that?
Dr. Harry Cridge:
No, absolutely not. So the medication is, it’s a once a day medication and it’s intravenously, but there’s nothing specific about the drug that would mean that they would’ve to be hospitalized between those injections. I know there’s a lot of cases in practice where we treating these outpatient, whether it’s a milder case or financial limitations or frankly, the staffing available in the hospital to manage these as an inpatient. So I think it certainly has utility in outpatient management as well as inpatient management.
Dr. Andy Roark:
Awesome, Dr. Henry Cridge, thank you so much for being here. Thanks for making me feel safe about pancreatitis. I appreciate that. Are there any resources that you really like anywhere that you would point people if they want to learn more?
Dr. Harry Cridge:
Yeah, so the Ceva Connect website is really, really useful. They’re putting a lot of really clinically relevant information about the drug on that website. They also have a dehydration wheel, which is designed for those veterinarians in practice where you may not always have the amount of time to fully calculate fluids or you perhaps just want somebody to double check you. You can enter the patient’s weight, the level of dehydration. It’ll tell you what fluid rates might be appropriate for that particular patient. It’s a lot of really useful things just for the general management of pancreatitis on there. We at Michigan State have put out a review article on pancreatitis in both the general veterinary internal medicine and JAVMA and the Clinicians Briefs. There’s a lot of publicly accessible data on how we treat these patients, and at the end of the day, we’d love to hear how other people treat these patients. The more we talk about pancreatitis and the more we learn from each other, the better chance we have of improving the outcome in these patients that don’t always have the same outcome that we would hope for.
Dr. Andy Roark:
No, that’s amazing. I’ll put links to all these resources down in the show notes. Everybody can check ’em out. Guys, I hope you’ll take a look. Gang, thanks for being here and listening to everybody take care of yourselves.
Dr. Harry Cridge:
Listen, thank you.
Dr. Andy Roark:
And that’s it. That’s what I got for you guys. I hope you’d enjoyed it. Thanks so much to Dr. Cridge for being here. Thanks to Ceva Animal Health for making this episode possible. I hope you learned something. I hope you’re going to be able to put this to work so that maybe it makes your pancreatitis cases a little bit less scary. I know it will for me anyway. Take care everybody. Talk to you soon.
