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Untreated hyperammonemia can cause irreversible neurologic damage, coma, or death. A high level of clinical suspicion is necessary to quickly recognize and implement emergency interventions for hyperammonemia in the acute presentation of urea cycle disorders (UCDs). Pamela M. Peeke, MD, MPH, FACP, FACSM, is joined by Anna-Kaisa Niemi, MD, PhD, and a patient who was hospitalized for hyperammonemia at age 8 years to discuss the importance of improved recognition of hyperammonemia and awareness of the underlying causes, such as UCDs. Dr. Niemi is a neonatologist and associate professor at Rady Children’s Hospital in San Diego, California, USA. This podcast is sponsored by Horizon Therapeutics.
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This podcast is sponsored by Horizon Therapeutics. Hyperammonemia caused by an underlying metabolic defect, such as a urea cycle disorder, requires a high degree of clinical suspicion. Untreated hyperammonemia can lead to permanent neurologic injury, coma, or death. Consider plasma ammonia testing for any patient with signs or symptoms of hyperammonemia. To learn more, visit ucdincommon.com.
Dr. Peeke: Hello and welcome to the Society of Critical Care Medicine Podcast. I’m your host, Dr. Pamela Peeke. Today, we’ll be talking about hyperammonemia and underlying causes of elevated ammonia, such as urea cycle disorders, or UCDs, in the critical care setting. I’m joined by Dr. Anna-Kaisa Niemi, MD, PhD, who is a neonatologist and associate professor at Brady Children’s Hospital in San Diego, California. I’m also joined by Isaac, who will be discussing his experiences as a patient. Welcome, everyone. Before we start, Dr. Niemi, do you have any disclosures to report?
Dr. Niemi: I do not have any disclosures.
Dr. Peeke: Thank you very much. I want to start with an overview of the podcast. What are the learning objectives? The listener will have an improved understanding about the risks of unrecognized hyperammonemia involving patients with undiagnosed metabolic disorders. This podcast is needed because untreated hyperammonemia can cause irreversible neurologic damage, coma, or death. Therefore, a high level of clinical suspicion is necessary to quickly recognize and implement emergency interventions for hyperammonemia in the acute presentation of UCDs. Learners need improved recognition of hyperammonemia and awareness about the diagnosis of underlying causes of elevated ammonia, such as urea cycle disorders, in the critical care setting to optimize early management and improve patient prognosis and outcomes.
What are the knowledge gaps that the podcast will address? Learners are unaware about the risks of unrecognized hyperammonemia, which include irreversible neurologic damage, coma, or death. Further, critical care listeners may misattribute the signs and symptoms of hyperammonemia to more common causes, such as sepsis and intoxication, and infrequently test for ammonia in admitted patients. All right. Now with that said, we have two panelists, Dr. Niemi and Isaac. Isaac, I’d like to go to you first, and I’d like you to share with everyone how old you are.
Isaac: Hi. I’m 27 years old.
Dr. Peeke: Okay. And what do you enjoy doing? What are you doing right now with your life?
Isaac: Currently, I’m trying to get through my basic college right now and I’m trying to go for hopefully AAA that I can eventually go into videogame design so that I can be a head of my own design company. I’m trying to study the basics, like basic programming, basic team management, basic lead and all that and hopefully find a program that can fit that sort of thing.
Dr. Peeke: Oh, my gosh. I’m just exhausted listening to you. All right. Let’s go to the UCD. What type of urea cycle disorder do you have?
Isaac: OTC, which is ornithine transcarbamylase deficiency.
Dr. Peeke: How old were you when you were first diagnosed?
Isaac: Around eight.
Dr. Peeke: Ah, eight years old. We’re going to be getting into your experience with this. Dr. Niemi, tell us why you have this professional interest in hyperammonemia and UCDs.
Dr. Niemi: It started from medical school. When we learned about the urea cycle and how it works, that it detoxifies ammonia to urea, for me, I like pathways in general, metabolic pathways. That was something fascinating and the fact that you can actually treat those conditions, and there’s step by step, it’s like a detective diagnosis. So for me, as soon as I heard of those in medical school, that was, “Okay, that’s what I want to do in my life,” focus on hyperammonemia in metabolic disorders. That guided my career pathway, I went to pediatrics and then specialized in clinical genetics and then metabolic genetics to focus on hyperammonemia and other metabolic disorders.
But as I was going through residency, I realized that I really liked the ICU setting, working at the bedside with critically ill babies or children. So, at some point in metabolic genetics, I decided that I would switch to neonatology. I did a neonatal fellowship and then I’m working in the neonatal ICU. In addition to other critically ill newborns, I can take care of babies with hyperammonemia at the bedside. So it’s kind of guided my whole career choices.
Dr. Peeke: Good heavens, that was one heck of a lecture on that cycle, on that pathway. It really affected you in such a wonderful and positive way, and we’re all benefiting from that. Would you please provide a high-level introduction of the urea cycle disorders and the impacts due to elevated ammonia? This really includes patients of all ages.
Dr. Niemi: Urea cycle disorders, there’s a defect in the urea cycle. There are a few different urea cycle disorders. They almost all lead to a similar outcome with hyperammonemia if untreated. The role of the urea cycle in our body is to detoxify ammonia, ultimately through various steps, to urea or, as we know in the ICU setting, in the laboratory results, to BUN, which is then excreted in the urine as a nontoxic form. This ammonia in our body comes from bacterial gut metabolism. It comes from muscle breakdown and turnover. It comes from the food that we eat, high-protein food. It’s important to detoxify the ammonia that’s a side product of our metabolism. If there’s a block in the urea cycle, then ammonia level rises and the ammonia itself causes the symptoms.
In babies, the impacts are, overall, they become lethargic because it affects the brain. That’s the main symptom. They become tired, lethargic, vomiting. If it’s elevated for too long, it can cause permanent brain damage and developmental delays in babies and children. In adults, some urea cycle disorders do not present until adulthood or are not diagnosed until adulthood. Prolonged level of ammonia can cause differences in mental status changes. But overall, the impact in the long term could be psychiatric conditions or issues in executive function or mental function overall if it’s untreated for a long time. There’s a big impact on the mental ability of children and adults, so that’s why it’s important to diagnose and treat early.
Dr. Peeke: Excellent. We’ll be getting into that in more detail in a moment. Now I’m going to pivot over to Isaac again. I know, Dr. Niemi, you’re listening in on this whole history. I’m really curious about your thoughts about what happened with Isaac and his experience. We’ll circle back with that in a minute. Isaac, I’m really looking at the when and how you were diagnosed with your UCD. What do you remember about going to the emergency room? What was going on? What were the symptoms that led you to be taken to the emergency room? You were only eight years old.
Isaac: I’m just going to tell you here and now, I have no memory whatsoever of that trip to the hospital because my memory got wiped from eight before. So all this is going to be secondhand accounts I gathered from my family.
Dr. Peeke: All right. That’s totally fair. We love that. What do you remember, whatever feedback you got?
Isaac: The one last thing I do remember before slipping into the coma was that I felt very tired and that my head was just in this internal fog sort of thing. I just didn’t know what was happening. Apparently, my mom and dad said, on the way over, it was around December of 2003, after my grandma, love her, bless her, but she had us basically go on an extensive hike as a family outing, and then eventually had this huge feast for Christmas and all that. After that, on top of stress, heat, and all that protein made it so that all this happened and one after the other, and I kind of just passed out because of that. From what I could tell, when I was being airlifted to a hospital, apparently I was not only incoherent but I also said at one point, apparently, I was blind, but I don’t remember anything about that.
Dr. Peeke: All right. Wow, that sounds like an extraordinary experience. Do you remember anything about going to the emergency room? You were airlifted, so you’re obviously in a very critical care setting. What do you remember about any of that?
Isaac: Sorry, but none at all. Like I said, all of this is going to come from secondhand accounts. Basically, ever since the coma, anything earlier than eight or eight itself has been basically reset in my head.
Dr. Peeke: Okay, that’s not a problem. So, you don’t really have any memory yourself of what happened in critical care and the physicians who were surrounding you?
Isaac: I do have notes about how the doctors handled it.
Dr. Peeke: Okay. Let’s go to that place, to where the doctors handled it.
Isaac: Apparently, when we got to the ER, some medication that they gave me to try to stabilize me or all that apparently made the situation worse and made me get even iller as a result. So I had to go to another ER that had better care and better doctors because my situation was just getting worse and worse because people were apparently misdiagnosing as a result of all this, because I was apparently entering what they called hyperammonemia.
Dr. Peeke: Do you remember what the original diagnosis physicians think you had?
Isaac: Some guessed that it was probably Reye syndrome or meningitis, and they tried to treat for that. That, again, made it worse.
Dr. Peeke: So they thought it was Reye syndrome and some problem with your brain like meningitis, maybe, an infection. How did you finally get diagnosed?
Isaac: It took a pediatric neurologist to randomly guess it from one class he took in college because he thought that the symptoms looked familiar from one random thing he studied back in his college days. And thank God he did because he guessed correctly and he managed to help before all that. We still didn’t know what it was, so it wasn’t diagnosed. But because of his guess, I think I managed to live for that.
Dr. Peeke: I see. Very good. How long were you in the hospital? Do you remember?
Isaac: I think about a week, maybe a week and a half.
Dr. Peeke: When you said you don’t remember much and you were pretty comatose and out of it and back and forth, when did you actually regain consciousness?
Isaac: I regained consciousness, unfortunately, I don’t have a specific date, but I think it was maybe a week or so after I fell into a coma, because I know the coma was at least a week.
Dr. Peeke: That is an extraordinary journey for you, Isaac. Needless to say, you were quite fortunate to get that diagnosis. I’m going to pivot now to Dr. Niemi. What do you think of this story that Isaac just said?
Dr. Niemi: It’s unfortunate that hyperammonemia is something that is often initially missed because there are a lot of other conditions that may mimic the symptoms, like mental status changes, coma, lethargy, tiredness, brain fog. He said he felt foggy in his brain before he passed out. Those are the kind of symptoms that want to make you think about elevated ammonia. Similar symptoms can happen in other conditions like meningitis or liver failure or a brain bleed or seizures or intoxications from medications. A lot of the times, the other reasons are more common. That’s where emergency room or ICU physicians often first check, even though just thinking about hyperammonemia, checking an ammonia level is something that can be done.
It’s an interesting story that you had, Isaac. It’s sort of typical, it takes a little while to get a diagnosis, especially if a physician has never seen hyperammonemia, and it is often that way because it’s pretty rare. But once you’ve seen it once and you’ve diagnosed it once, you never forget it. So I bet that neurologist will probably never forget that and always remember to check ammonia with mental status changes. So it is often misdiagnosed initially and there’s a delayed diagnosis.
Dr. Peeke: That’s extremely helpful. Interestingly, is there a difference between admitted children and adults? Is there a different manifestation when they first are admitted?
Dr. Niemi: Yes, there’s a siding scale from neonatal to toddlerhood to childhood, to adolescence and adulthood. But overall, if you take both ends, like neonates and newborns and young adults or adults, the neonates’ symptoms can be very specific. Newborns can’t really tell they have a headache or they feel tired or, as the ammonia level rises, their ability to feed becomes less, they become more lethargic or tired, they may start vomiting. The ammonia causes brain swelling, so it’s very nonspecific symptoms. The vomiting, tiredness, lethargy, that could be a lot of things in a neonate, sepsis or infection, brain bleed, seizures, so many different things. Adults may often complain of headaches, especially after high-protein meals such as Thanksgiving, Christmas, or some pizza outing; headaches or foggy brain or present with mental status changes after some feast. Some psychiatric symptoms, some present with psychiatric symptoms, chronic mild hyperammonemia after high-protein meals, and it affects behavior. But the symptoms can be very nonspecific, again, in adults. Many other more common reasons that can cause these symptoms, but it’s more of we just need to think about hyperammonemia to be able to check it.
Dr. Peeke: What is the window where a person like Isaac is in coma? How long did they have before they begin to manifest more permanent damage? He was fairly much out of it for about a week, according to his history. Does that also change between children and adults?
Dr. Niemi: That’s hard to say, but every patient’s vulnerability is individual. I’ve seen babies that have had very high ammonia level of 3000 and they are thriving school-aged kids or toddlers. The important thing is duration of hyperammonemia in newborns. It’s generally several hours or days of very high ammonia. And then, adults also, it’s chronically happening, these similar episodes. Again, I don’t really have a good timeline for adults. But the longer the duration, the more effects. But every person is an individual. If you have a complete deficiency of some urea cycle enzyme, typically the elevation of ammonia is higher and it’s more severe. If you have a partial deficiency, the elevations may be milder and then it is less severe. I’m glad Isaac is thriving right now, going to school and studying to do videogames and things. I think everybody is an individual person. But generally, and especially in infants, the higher it is, the longer it is, and the length of it seems to be the most important thing.
Dr. Peeke: Excellent. And for our critical care peers, what lab assessments might you have ordered to verify your suspicion if you see someone like Isaac, say for instance, enter the critical care arena?
Dr. Niemi: The first thing is to think about hyperammonemia. If someone has mental status changes, neurologic changes, lethargy, sleepiness, just thinking about hyperammonemia and ordering ammonia levels, that’ll give you the diagnosis of hyperammonemia. When you order ammonia, it should always be sent stat, meaning rapidly on ice, so there’s no false elevations. If the ammonia blood sample tube sits in room temperature for an hour, it’ll be for sure elevated, but it could be falsely elevated, so it should be always sent stat on ice. It’s an easy, quick, rapid test. It’s not a complicated genetic test. It’s available in every single hospital, so any emergency room doctor, ICU doctor, can easily order it as long as you think about it.
Once you have the hyperammonemia diagnosis or, you know you have hyperammonemia, then you just have to figure out the cause and evaluate the severity of other derangements. Then, the other tests that you would order are basic tests such as blood gas to see if there’s acidosis or alkalosis. Alkalosis could tell you it’s a urea cycle. Severe acidosis could tell you that it’s organic acidemia. Chemistry panel to look at electrolytes, hydration level, anion gap. Then, urine ketones are helpful. You should also screen for something that has triggered the hyperammonemia, screen for infections, like CBC, CRP, procalcitonin. Those are basic tests to evaluate the state of the patient at the time, so you can manage acutely. Then, once you have hyperammonemia and you’re figuring out the actual diagnosis, you send special tests that a metabolic specialist may guide you to send, such as urine organic acids.
Dr. Peeke: Which specialists do you really need to get involved to be able to confirm that diagnosis of this rare disease?
Dr. Niemi: There are several specialists that will be involved in the care of these patients in the long term, but in the acute phase, to help with the diagnosis, management, evaluation, metabolic geneticists or some clinical geneticists who are not necessarily specialized in metabolic but have enough experience. Metabolic geneticist is the key and then also neurologists, especially if you’re thinking about mental status changes. You may need to assess neurologic status, EEG for seizures, those things. So metabolic geneticists and neurologists, those are the two important ones. But to help with the diagnosis and management of the condition, that would be a metabolic geneticist.
Dr. Peeke: Excellent. That is incredibly helpful. All right. Isaac, it’s your turn again. So here you now have this urea cycle disorder, you now know all about it. What is your emergency plan? Obviously you need to have something in place so that if you run into a problem you may need to go to an emergency room or hospital, how do you know when you need to go? What are the signs and symptoms? Tell us what your plan is in general, like who’s going to be going with you? Who have you shared this plan with?
Isaac: One of the most important things is that you always have to have a letter of emergency sort of thing, where basically you have to have a letter stating what the genetic disorder is, what it does, the specifics of it, what not to give because there are common medicines that hospitals and emergency rooms give out that are supposed to help regular people, but unfortunately, for people with UCD, we have to specify in a letter or anywhere on our body, like a band or something, a medical band, that we are allergic to certain types of medications.
Dr. Peeke: Do you have a medical alert bracelet on you or something?
Isaac: Yeah, a medical alert bracelet. A metal one that has the information on the back is usually what you’re supposed to wear all the time so that doctors can understand you’re not passed out because you’re drunk or anything but it’s actually because of ammonia emergency.
Dr. Peeke: Have you shared all this with your family or roommates or however that works?
Isaac: it’s definitely something that my family knows because my mother has it, because obviously this is hereditary. So, we have this plan for the whole family. My dad fortunately doesn’t have it, but my dad knows exactly what do if either my mom or me gets into this situation. He’s more than ready to get down to the ER with either of us if something were to happen. But fortunately, we haven’t actually had a situation like that. But we do have the plan in place so that the instant we show a sign of being too lethargic, being distant, having high ammonia signs and all that, we immediately just get ready, grab the letter, and get down to the hospital and just be prepared to tell them what needs to happen.
Dr. Peeke: You’re saying that you really haven’t had to go to the emergency room. You’ve been watching yourself very carefully, following the lifestyle habits that you need to do to be able to stay out of trouble?
Isaac: Basically. Surprisingly and fortunately, very prudent when it comes to actually following all of this. I was a very odd kid, so I didn’t mind changing my diet all that much. Fortunately, we haven’t had any situation where we needed to enact the emergency plan, but we do have it set up just in case.
Dr. Peeke: All right. What’s the basis of your diet right now?
Isaac: The basis is that, so long as I stick to around a prescribed 45 to 50 grams of protein per day, which, just to put in perspective, a typical meal from McDonald’s is around 30, that’s just for their smallest burger. it’s not as much as you may think, but as long as I’m careful and I take my prescribed medication when I need to along with anything else, and along with a few vitamin supplements, I’m pretty much set for the day as long as I don’t go crazy and I don’t overextend myself. Sometimes I can go a few grams over but I usually try to avoid that so that my body doesn’t get stressed out. Mostly I try to stick to around maybe 40 to 50, usually lowballing around 40 grams per day.
Dr. Peeke: Very good, and good for you for sticking to that and knowing all about it and having that emergency plan in place. Dr. Niemi, what are some of the biggest knowledge misconceptions and barriers preventing the timely identification of elevated ammonia in the critical care setting? One can imagine that, depending on where you are, if you’re not in a big university setting and, I’m making an assumption there that there’s somebody there who might be able to be more helpful than if you are out in an area where maybe you don’t have enough specialists who can identify this. What are some of the biggest knowledge misconceptions about this?
Dr. Niemi: Three things. One of them is that, once you haven’t seen it for a while, let’s say you learned about it in medical school or read an article once, but it’s so rare that there may be physicians who will never see it. There may be physicians who treat it all the time in a major tertiary care center, and they think about it all the time. But sometimes if you haven’t seen it or thought about it for years, you just don’t think about it. So that’s the first barrier, preventing timely identification that it’s not in your mind.
The second thing is related to the third thing, that the symptoms are very nonspecific, lethargy, tiredness, the mental state is not good, they may be saying funny things or a foggy brain, and the symptoms are nonspecific. The third thing is that the other causes of those symptoms are much more common, like infection, meningitis, liver failure, and I think Isaac gave a perfect example, being drunk. Especially in adolescents, young adults, and adults, if you’re drunk, you could look similar to when you have hyperammonemia. So it often could be misjudged that this is a young adult or adolescent who is just drunk and the possibility of hyperammonemia is not even thought of. Just to think about the possibility of hyperammonemia in someone and just order an ammonia level stat on ice.
Dr. Peeke: That’s incredibly important to acknowledge. Isaac, what do you want clinicians who work in critical care to remember or learn from your situation?
Isaac: The main thing I want is that rare disease happens because, the amount of times I have to explain what this disease is, what the symptoms are to a lot of people, I know in lower positions, it’s not something you’re going to encounter every single time, but there are going to be times where you’re going to encounter a rare disease. They’re rare, but they’re not impossible or mythical. I think the most important thing is that doctors need to be aware of rare diseases and be aware that they might have to change the usual everyday treatment plan so that they don’t end up messing something up. It would be nice if we just had to mention the name of what it is that they would know what not to give and what to do and all that.
Dr. Peeke: That’s so terribly important, Isaac. I think Dr. Niemi and I both agree that it’s wonderful that you had the random luck to be able to be diagnosed as you were at that time. I think that we’re taking your words to heart and that we hope that this podcast is going to be heightening the awareness of critical care physicians and teams out there to keep this in mind because one never knows. Just as you said, it may be rare, but it happens, and so we have to be there for you. I can’t thank you enough, Isaac, for your insights here. Dr. Niemi, if our listeners would like to learn more about hyperammonemia or any of the urea cycle disorders, where would you recommend that they look?
Dr. Niemi: There are several websites where one can learn about hyperammonemia diagnosis for professionals and families. Some of these are governmental, some of them are nongovernmental. One of them is National Urea Cycle Disorders Foundation, nucdf.org, there’s information about urea cycle disorders. Then there are sites for medical professionals that include a link to urea cycle consortium treatment, what guidelines, for example. Another one is checkammonia.com, there’s also about how to recognize hyperammonemia, how to test for it. Obviously, if you don’t think of hyperammonemia, you don’t find these websites. But once you think of it, there’s a lot of information. For example, checkammonia.com has a “find a metabolic geneticist” search. You just put your state there and search and it’ll give you a list of hospitals or centers where there’s metabolic geneticists and their names.
Then there are patient-related or family-related sites where even professionals can find interesting information about low-protein recipes to see what families are going through and what they have to follow. One is ucdincommon.com. The other one is ucdfamily.org. The final thing is obviously medical articles. I would like to mention one article and then one medical resource. One good article for adults or older intensivists, like a pediatric ICU intensivist, is in the Annals of Intensive Care, “Management of Late Onset Urea Cycle Disorders: A Remaining Challenge for the Intensivist?” It was published in 2021. It’s a nice review article. In general, a free public website is GeneReviews. If you google GeneReviews and then type “urea cycles,” there’s a whole review about how to diagnose what the disorders are, different disorders. I would mention those couple of websites as excellent resources.
Dr. Peeke: Fantastic. That’s just a wealth of knowledge and resources. We so appreciate that. I just want to thank both of you, Isaac and Dr. Niemi, for being copanelists on this podcast. This has just been a wealth of knowledge and insight in, quite frankly, personal experience from both of you as a provider, as well as a patient. Thank you so very much. This concludes another edition of the Society Critical Care Medicine Podcast. For the Society of Critical Care Medicine podcast, I’m Dr. Pamela Peeke.
This podcast is sponsored by Horizon Therapeutics. Hyperammonemia caused by an underlying metabolic defect, such as a urea cycle disorder, requires a high degree of clinical suspicion. Untreated hyperammonemia can lead to permanent neurologic injury, coma or death. Consider plasma ammonia testing for any patient with signs or symptoms of hyperammonemia. To learn more, visit ucdincommon.com.
Pamela M. Peeke, MD, MPH, FSCP, FACSM, is a nationally renowned physician, scientist, expert, and thought leader in the field of medicine. She is a Pew Foundation Scholar in nutrition and metabolism, assistant professor of medicine at the University of Maryland, holds dual master’s degrees in public health and policy, and is a fellow of both the American College of Physicians and the American College of Sports Medicine. Dr. Peeke has been named one of America’s top physicians by the Consumers Research Council of America. She is a regular in-studio medical commentator for the national networks and an acclaimed TEDx presenter and national keynote speaker. Dr. Peeke is a three-time New York Times best-selling author and is a science and health advisor for Apple.
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