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SA: Hello, and welcome to Master the MRCPCH. In this series, we tap into the expertise here at Great Ormond Street Hospital to give you an overview of a topic on the RCPCH exam curriculum. So whether you're revising for an exam or just brushing up on a need to know topic. Hopefully this podcast can give you the information that you need.
I'm Dr. Sarah Ahmed, a paediatric registrar and the current digital learning education fellow here at GOSH.
In today's episode, we are very excited to be welcoming back Dr. James Davison, a consultant in metabolic medicine at Great Ormond Street. Dr. Davison has kindly done a number of episodes for us previously, covering topics such as lysosomal storage disorders and metabolic screening of the neonate. If you haven't already, make sure you check those out.
Today, we're going to be talking about hyperammonaemia. Or how to approach the child with a high ammonia. This topic maps to the metabolic medicine section of the exam curriculum.
Thank you, James, for coming on the show today.
JD: Thank you for inviting me.
SA: So before we delve into more detail, I wanted to start by asking, what would you like people to get out of this podcast today?
JD: I think two main things. I think it's helpful if at the end, we have a good understanding about when to think about testing for ammonia and other metabolic things. So when to think about it and having an understanding about what to do if you're faced with that acute situation with a child or an infant with a high ammonia, just to have some ideas about the first step. So I think those are the two main things.
SA: Yeah. And I think those are really worthwhile learning outcomes as well. So I, I suppose we should start by discussing some biochemistry.
JD: Okay.
SA: So can you tell us a little bit about how ammonia is metabolized in the body?
JD: Yeah. So I think that's an important understanding as we're considering that whole concept of having a high ammonia that we understand where it comes from and what it is and where it's from in the normal biochemistry. So, ammonia is a waste product that comes from protein breakdown. So protein is made up of amino acids, which contain nitrogen and the waste product from breakdown of the proteins and the amino acids is ammonia NH3. That's very neurotoxic, and so the body has a system for rapidly removing ammonia, and that is what the function of the urea cycle is in the liver. So, and you have an ammonia, which is taken through a series of chemical steps, converting it from one amino acid to another and in the end producing urea, which is then a lot less toxic and can be excreted by the kidneys.
And so you have that urea cycle there to, to remove the the ammonia rapidly. And so when we start thinking about any of the conditions where you have a high ammonia, it's because there is some problem with one of those steps in the urea cycle or the overall function of the urea cycle is impaired for some reason. Uh, so yeah, there's a lot more detail in terms of how the urea cycle fits together. But I think the key thing is to take that message that the urea cycle in the liver. As the function of removing the ammonia, rapidly converting it around to urea, which is a lot less toxic and you can excrete in the urine.
SA: I'm getting flashbacks to medical school, but it is all coming back. And I'm guessing that normal ranges for ammonia vary according to age. So do you have a numerical threshold that you like to use to define hyperammonaemia?
JD: yeah. So, different labs will give you a slightly different reference range. But normally a normal ammonia would be less than 40 or 50 micromole per litre. Depending on the lab. Now if you take a sample, as you said, it will vary a little bit by age. So if you have a newborn baby anything up to 100 could be normal and up to 150 in a sick neonate might just be a reflection of the baby being unwell.
In an older child or a teenager you would expect the levels to be lower and so that normal reference range of less than 50 would apply. Certainly you would be more concerned about ammonia of a hundred in a teenager than you would be in a neonate. I think the key thing is if you have an abnormal result is that you don't ignore that, but you think why is that there and potentially get a repeat sample to, to confirm if it is indeed elevated.
SA: Yeah, that makes sense. And actually, maybe we should talk a little bit about sampling now. I was going to mention it later, but it kind of follows on from what we were saying. So, I feel like as paediatricians, we worry a lot about making sure we get a free flowing sample venous in the right bottle. Some places want it on ice, other places don't. What would you suggest for testing for ammonia in terms of the practicalities?
JD: Yeah, I think the gold standard really is having a venous sample that's as free flowing as possible that then gets taken to the lab immediately and processed quickly. And the reason that it needs to be venous rather than capillary is that the tissue levels of ammonia are higher than in the venous blood itself. And so you'll have a higher level just from having a capillary sample. Plus, you're more likely to have more haemolysis from a squeezed capillary sample. So ideally venous and taken to the lab promptly, because if you leave the blood standing around you'll get an artificial elevation of the ammonia as the sample metabolizes.
For that reason, taking it on ice, if you have ice available is useful because it slows the metabolism within the blood sample to stop those higher levels. But if you don't have ice available just get someone to run the sample to the lab. In hospitals that have a pneumatic chute system you don't want to put it in the chute because it will get stuck somewhere. And if a sample is delayed, then you'll get higher levels that are coming out as a spurious one.
So the key thing is venous, to the lab as quickly as possible and tell the lab that you are taking it. So that again, it doesn't then sit in the laboratory reception for a number of hours before it's being processed. Those are, I think, yeah, those are the key things, whether it has to be on ice or not. There's a bit of debate about how useful that is, but yeah, venous and quick.
SA: Yeah, that makes sense. And you mentioned repeating the samples as well. How often should you be repeating samples?
JD: So I think if you've had one first ammonia level and that's elevated, so you want to confirm if it's high having a second sample to confirm if it is genuinely elevated and doing that straight away is important again, you don't want to leave a child having a high ammonia that you're not doing anything about.
So if you've had that first one that's elevated, get a repeat one as soon as you can. If it's still elevated and we're then talking about a child where you are starting to think about management of the ammonia really the repeat frequency will be guided by which treatment you're starting and which pathway we're going down.
But certainly while we're in the acute phase of managing a child with a severe hyperammonaemia, we'll be looking at testing it every four to six hours as we put the treatment in place to, to assess how we're responding to that.
SA: Is it common for children to have a high ammonia? What kind of numbers are we looking at here? Because I feel from experience, we test for it a lot.
JD: It's one of those things where the conditions that we're looking for the various urea cycle disorders or the other metabolic disorders are all individually, very rare conditions. And now it's one of those ones where we are doing a lot more tests to try and pick up. The rare case where the ammonia is high, for example, in our centre as a metabolic tertiary centre, we would probably have one neonate every month or so who comes to our service who has been found to have a severe hyperammonaemia. Now that's across a very wide catchment area. So I think, yes, you're right, we do test for it a lot and we want people to be testing for it a lot. And as we'll talk about the presentation of a child with a high ammonia or neonate, particularly it's very non specific. So we need to have a low threshold to make sure we're testing that as part of the initial workup for your sick baby.
More often than not, it's going to be normal, but what we don't want to do is miss the baby that does have the high ammonia because we know that we need to get on with treatment.
SA: Of course. And that leads us nicely onto presentation. So, what ways do neonates present with a high ammonia?
JD: Yeah, so neonates have a very limited repertoire of how they can present in life. They generally stop feeding. they start vomiting, they might have seizures and they can be drowsy and not waking up properly. And that's that applies to a baby that's got a high ammonia or a baby who's unwell with sepsis or a hypoxic insult.
Essentially, it's a very non specific picture, but a baby who's got a significant metabolic issue with a high ammonia will progressively become more drowsy, more encephalopathic, and they may progress to have erratic breathing to start with. Ammonia is a respiratory stimulant, so they may be tachypnoeic, you might notice a respiratory alkalosis, but as that progresses, breathing can become more affected, and they'll become more profoundly encephalopathic.
So seizures can be a feature of that as well. And again, in the earlier stages, feeding may become less effective. They may have vomiting. So again, those very fairly non specific presentation features.
SA: And is it the same for an old child as well? Can older children present with a high ammonia?
JD: So older children can present. Some of the metabolic disorders and have late onset versions. And so the presentation in older children can be a bit more varied and a bit more chronic, so they can present with an acute encephalopathic episode. So, for example, a teenager who has gone out and been drinking with friends, not been eating well, or maybe has been to a barbecue, had a huge protein load. They can present with an acute encephalopathy and having an ammonia tested in that situation is really important. But you can also have a more chronic presentation of developmental delay. They could have had seizures again intermittently. There can be features in the history as well of unusual dietary preferences. So a child who has a tendency to avoid eating proteins, they might avoid eating meat because they've come to understand that if they eat protein we've already said that ammonia comes from protein breakdown. So if you eat a lot of protein that will push your ammonia up and you start feeling unwell. So they can have that dietary protein aversion and a high ammonia can also present with psychiatric features as well. So there, there can be a whole range of different presentations around the neurology. The ammonia and the other disorders can also have an effect on the liver side. So another possible route into presentation is a child who's got some chronic liver disease as well.
So there's a range of different ways that you may get to that presentation.
SA: I hadn't realized about the psychiatric symptoms but now that we've spoken through it, it makes sense that would happen. And we've kind of, we've spoke about hyperammonaemia as a concept, as a presenting feature. Is it a diagnosis in itself or is it a presenting symptom for other conditions?
JD: So having a high ammonia is a very important finding, but it's not the final diagnosis. There's a common management pathway that we'll talk through, but you, as you said, there is a range of underlying causes and we need to understand what is the cause of that high ammonia.
Within that category, there'll be the primary metabolic disorders. So the conditions that affect the urea cycle function. So the urea cycle disorders, some of the other disorders that affect protein metabolism, like the organic acid disorders, where you get inhibition of the urea cycle and some other metabolic conditions as well. So you've got the primary group of inherited metabolic disorders, and you can also have a high ammonia as a secondary feature. For other conditions, we've talked about spurious or artifactually elevated samples, but you can also see a high ammonia and if you've got significant liver dysfunction for any reason, that would be part of the workup.
If you've got a severe, in a neonate for example, herpes simplex virus disseminated infection that can give a significantly high ammonia, and there can be some drugs as well that can give you a high ammonia. So, I think the bottom line, as you said, is having a high ammonia in itself is not the final diagnosis, and we then need to work through the investigations to work out what is the cause of that high ammonia.
SA: Yeah, and that leads us nicely on to other investigations. So, what other things should we be testing for if we're testing for a high ammonia?
JD: So yeah, that's good. Good question. I think if we're faced with, let me go back to our neonate who's done well presentation um, you have a standard set of tests that you'll be thinking about for any neonate who's unwell, and that would be including screening for sepsis, looking for evidence of hypoxic ischemic insults, and then specifically thinking about the metabolic tests.
Any baby who's unwell would be having a blood gas. It's very important that they have their blood glucose measured. And the lactate alongside the ammonia, and those would be very key primary screening tests from a biochemistry point of view for any unwell neonatal or older child. If you've then identified a child who's got a significantly raised ammonia from those tests, it's useful to think and to interpret that in the light of the other tests. So is there a significant metabolic acidosis? Have they got a very high lactate? Is there hypoglycaemia? Um, and also knowing about the ketones is very helpful, either with a urine dipstick or with a blood ketone monitor, because again, a neonate or an older child who's got very high ketones with a metabolic acidosis and a high ammonia fits together with certain categories of the metabolic disorders.
So you've got those primary tests, some of which are effectively bedside tests that every unwell neonate needs to be having. And then if you have a suspicion from those that there is a metabolic disorder you would then be going on to the second tier of specific diagnostic investigations. And so the tests we would be then advising on would be looking at the plasma amino acids, the urine organic acids, acyl carnitine profile, And it's also really important at an early stage that you get a DNA sample stored so that we can complete all the investigations. That, that's important because some of these neonates, if they're presented with a severe hyperammonaemia and we'll come and talk about the prognosis in a bit, but some of them are so unwell that they sadly don't survive beyond the neonatal period. And so it's really important that we get those key tests taken at an early point so that we can complete investigations.
SA: Absolutely. So let's talk a little bit about treatment then. Let's start with the acute presentation. So if you have an unwell neonate, for example, in A&E, how would you go about initially managing them?
JD: So I think if you've identified the baby's unwell, and you've identified that they've got a very high ammonia level, there needs to be consideration about where does that baby need to be, who needs to be involved, and getting advice and help at an early point is important. So discussing with the relevant neonatal or intensive care retrieval teams and the metabolic team on call to make them aware of the child to start planning already about where they're going to be going to.
SA: In London would that be GOSH or the Evelina?
JD: Yeah, so those are the two main metabolic centres within London. Ideally, with a child with a hyperammonaemia, you need to be planning to retrieve them to a centre that is able to manage them from a metabolic perspective.
Babies, they're often very unwell and they need standard supportive management. So you'd be going through a normal airway breathing circulation approach. And we've already said that sometimes the breathing can become quite erratic and so many of them will require respiratory support, intubation, ventilation, you would be fluid resuscitating as you would for any other child and supporting circulation and so getting those initial steps in place and correcting any hypoglycaemia is very important. And then you move on to think about what are the specific metabolic aspects of the management for this, this child. And so really, the first thing, if you've identified the high ammonia is that we need to stop giving further protein to the baby. By that, what we mean is stopping giving milk feeds. If the baby happens to be on TPN, parenteral nutrition, for any reason, that also contains protein. So we'd be stopping protein, trying to stop loading in protein to the baby that. As a metabolism that can't handle that. So you stop feeds, stop the PN, and instead you need to be putting them down onto intravenous fluids containing dextrose. And what we're aiming to do is to give a glucose infusion rate of between 7 to 10 milligrams per kilo per minute.
And what we're aiming to do there is to make the baby anabolic and by that, what we mean is the opposite of being in a catabolic state. If you're catabolic, you're breaking down protein and making ammonia. If you're anabolic, you're not breaking down protein. And so giving a good glucose delivery, you're aiming to stop further breakdown of endogenous protein to try and stop the further production of more ammonia.
So you've supported ABC, stopped feeds and PN, started them on dextrose and they might become hyperglycaemic. And in that situation, what you would need to do rather than dropping the glucose delivery would be to control that with a standard sliding scale insulin. And insulin itself is pro anabolic, so that's helpful.
If they've got a significant acidosis, but still thereafter you've done any fluid resuscitation then you would need to consider does that need addressing, for example, with a half correction with sodium bicarbonate looking at the electrolytes while you're doing that.
And then how do we go about trying to lower the ammonia. And so we come on to the other metabolic drugs that would be initiated, and there are two drugs that are terms the ammonia scavengers or nitrogen scavengers. So that's the sodium benzoate and sodium phenylbutyrate. Both of those work by providing an alternative pathway for removing ammonia.
And we've said that the ammonia is high because the urea cycle is not working properly. And so those drugs are able to remove nitrogen, remove ammonia via a different route by conjugating onto the ammonia in the form of different amino acids, and then being renally excreted. So we give the ammonia scavengers so they're given as intravenous initial loading doses, followed by further infusions over 24 hours. We also give arginine, which is one of the amino acids that you need for urea cycle function to support that. And we would also, in most situations, also be giving carnitine because that's one of the specific treatments for the, uh, the organic acid disorders.
And at this stage, we don't have the results of those key diagnostic tests. We know the ammonia is high, but we won't get the plasma amino acids and the carnitine profiles back for 24 hours because they take that time to process. So when we start off the management, we're throwing everything in and then would rationalize subsequently. And then the other drug that we'd be often giving is, uh, carglumic acid, which is a an artificial form of the molecule that stimulates urea cycle function at the beginning of the urea cycle. So that's given to try and try to kickstart the urea cycle into working.
So, just to summarize what we've said there, this is a sick baby, you'll be supporting their general management, stopping feeds, giving a good amount of dextrose, plus or minus insulin, correcting the acid base problems, and then giving those drugs to try and start lowering the ammonia down. And going back to your question earlier about when do you repeat the ammonia once done a few hours, you need to then have a repeat ammonia maybe two, two or three hours after you've done that to see what effect have you had in terms of the ammonia coming down.
SA: And talk to your referral centre early.
JD: Exactly.
SA: And if the ammonia isn't coming down or it's really high, do you ever filter these children?
JD: Yeah, so that's the next step, really, that if we are not seeing a good, quick response to that medical management, that really the next step in management is to think about a form of dialysis or hemofiltration to remove the ammonia directly. And certainly, if you have a very high ammonia that's staying above 400 micromole per litre or if you're not seeing a good response to that, that that would certainly be the next step in management.
So you will have initiated those initial steps with the drugs, seeing if there is a response, but in parallel with that, you're also planning to retrieve the baby to one of the centres that's able to then instigate. A form of dialysis to then hopefully get the ammonia down quickly.
SA: Fantastic. And then once the child is stabilized, do they need long term medication to keep the ammonia under control?
JD: Yeah. So really once you've got the baby into that situation or you've rescued them from having a really high ammonia the next steps in our management are cautiously reintroducing some protein because you need protein, you can't survive without it. And so, once the ammonia, once the acid base status is corrected, we would be cautiously introducing protein either as parenteral nutritional or slowly introducing feeds. And really the long term management for any of those metabolic disorders that can cause a high ammonia is to have a protein restricted diet. So we work closely with the metabolic dietetic team to plan a feed that is relatively low in protein and high in carbohydrate and has more energy from the lipid components.
And then also, as you say, the medications are often needed long term to help keep that ammonia under control. So a child who's got a urea cycle disorder will often be on one or other of the ammonia scavenger medications which they'll be taking enterally they would also need to be on arginine supplementation, or if you've got a child who's got one of the organic acid disorders, they would be on long term treatment with carnitine and sometimes long term use of one of the scavengers as well.
So yeah, they. Any child who has a diagnosis of a primary metabolic disorder will have that long term dietetic and medical management put in place. And also having in place plans for what to do for if, and when the baby becomes unwell, when they next pick up an infection or they're unwell, because that's another time where they're at risk of having a high ammonia again. And so they'll have in place emergency plans for what to do. Again, if they're unwell another time, you would be stopping the feeds giving them a good amount of glucose again to try and maintain that. And parents will be trained in what to do if the baby's unwell and having an emergency feed available at home. That is basically a glucose polymer to start while we're then planning next steps in management again.
SA: It's quite an MDT approach, isn't it? So you'll have you guys and then the dietetics and the clinical nurse specialists as well.
JD: Yeah, so it's a big team and also, because these children will be living across quite a broad geographical area, having their local paediatric teams involved, being aware and having open access arrangements with their local teams to help support if and when they're unwell again is very important.
SA: And I suppose the complications of having a high ammonia are the kind of things that we spoke about in terms of presenting features. So encephalopathy and seizures.
JD: The acute presentation really as you said is around the encephalopathy having seizures, but we know that ammonia is neurotoxic. And so one of the concerns from having had an episode of hyperammonaemia is there're going to be long-term neurological damage from that. Um, And so we know that for some children who presented as a neonate with a severe hyperammonaemia episode that can leave them with a significant neurodevelopmental problems as a result of that first severe episode. Quite a high proportion of babies who present with a severe hyperammonaemia may actually not survive that initial presentation because of the severity of the brain insult.
But those who do, we would need to counsel families about the potential risks of neurodevelopmental problems long term. For others, particularly if we've caught the ammonia early treatment has been put in quickly, and there can be a better outcome and really. That just emphasizes the importance of thinking about ammonia early on in the course of a child who's unwell, so that we can recognize and get treatment in place.
The outcome really relates to how high the ammonia is and how long it's been up for, so kind of the area under the curve. And if we can try to minimize that, you can then optimize the outcomes longer term.
SA: Absolutely. And are there any new advances or treatments on the horizon?
JS: So there's always exciting to see what new things that are coming through. And we've talked a bit about the standard management that we would have in place with dietary management and the medications. And those would be lifelong treatment requirements for these families and we have to explain that.
Newer things that are also tried in different situations sometimes liver transplantation is a mode of therapy that's used. So we've said that the urea cycle is based within the liver. And so if you have a urea cycle disorder, actually having a liver transplant will correct that. And so a number of children will go on to have a liver transplant. And that's also used for some of the organic acid disorders. In certain circumstances, so that's another therapy that is certainly routinely used in selected situations, and there are also other things coming through the research pipeline. And so there are some forms of gene therapy that are being evaluated again trying to provide targeting the liver with a corrected form of the gene, and so there are trials for that, and there are also other mRNA based therapies that are in clinical trial as well that we're involved with as well to try and effectively provide a functioning gene or a functioning copy of the MRNA that can be used by the body to make that missing enzyme and improve the outcome. So, so yeah, there are exciting new things on the horizon as well.
SA: Amazing. That's been a really great overview. Thank you so much. Can we end with some quick fire questions? So are there any classic exam questions that might pop up about this subject?
JD: Okay. Yeah, so I think metabolic things do pop up, particularly in the theory parts of the exam often as a data interpretation question. So be prepared to look at some biochemistry results maybe spotting the ammonia, being able to interpret the blood gas. So that's the most likely time that you will see it in the exams.
SA: Yeah. You're unlikely to get an acutely encephalopathic child in the clinical exam. Secondly, are there any useful resources that you'd recommend? And I'll make sure they're all linked in the description.
JD: Yeah, so I think there are a number of resources out there, particularly I'd flag up the British Inherited Metabolic Diseases Group website. So that's www. bimdg. org. uk. that website has a lot of useful information, but including some emergency guidelines for all of the different specific metabolic disorders.
And there are also some guidelines on there for when you're faced with an undiagnosed problem like hyperammonaemia and it talks to a lot of what we've been going through today in terms of the key tests and so on. So, have a good look at that website. Um, There's also links on there to other training opportunities and information as well. So that'll be the best place I would point you to.
SA: Fantastic. And finally, what are your three takeaway learning points?
JD: So yeah, I think number one: I want everyone to be thinking about metabolic in your differential diagnosis whenever you're faced with a, an unwell child and particularly the unwell neonate. So think metabolic in the differential and then you will have your mind open to pick up that rare case when it does present.
I think second learning point is we know that prompt identification and treatment of a child who's got a hyperammonaemia can improve their outcome. So if you think about metabolic, make sure you get the sample, send off the ammonia and chase up the result.
And then I think thirdly, these are rare disorders that are complicated to manage. So if you found a child who's got a high ammonia make sure your seniors are aware and call for specialist help and initiate a timely intervention.
SA: James, thank you so much for what's been actually a really clear and succinct approach to what I know a lot of paediatricians find quite daunting. So thank you very much.
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