PEM Adventures Chapter 2

Are you ready for another PEM adventure? This time, the stakes are a little higher. Join us on another journey (with an inbuilt time travel machine) as we manage Grace…

Meet Grace. Grace is a 15-year-old vegetarian environmental activist. She’s thrilled because she recently hit 10,000 followers on TikTok—social media is SO the way to spread the word.

She spent yesterday at an illegal climate strike rally outside parliament. Buoyed up on the adrenaline of a thrilling protest, she and some buddies returned to her friend Zak’s house, where they celebrated in style with vodka pops. But this morning, horrified by the fact Grace was impossible to wake, Zak called the emergency services.

Meanwhile, you’ve just fished a pea out of a child’s ear when the red phone rings. Hearing the pre-alert, you mobilise the team and prep a bay in resus. Minutes later, Grace is wheeled in with Zak in tow, and she’s transferred to a trolley.

Your SHO, Lucy, does a primary survey:

• A: Tolerating an oropharyngeal airway. No stridor or stertor.
• B: Self-ventilating in 15L O2 via a non-rebreathe mask. Her respiratory rate is slightly raised, but her chest is clear, and she has no other signs of respiratory distress.
• C: Warm and well perfused, heart rate 68 with normal heart sounds and normal pulse volume. Blood pressure is 115/70, and capillary refill time is less than 2 seconds.
• D: GCS 7, made up of M4, V2, and E1. Pupils are size 3 bilaterally and normally reactive to light. Tone is generally low, but reflexes are normal, and plantars are down going.
• E: No rashes, no bruises and Grace is currently afebrile.

Lucy gets Grace’s mum’s number from Zak and phones her to get a bit more information. Grace is a healthy adolescent with no significant past medical history. She’s not on any medications, is not allergic to anything and is fully vaccinated. She’s been completely well with no fever, cough, coryza, or any other symptoms. She did have a cold sore a few months ago – could that be relevant?

Grace’s parents, who had gone away for the first time since covid-lockdown lifted, are running to the train station to make their way back home.

Back in resus, you put in a cannula, and send off some bloods: FBC, U&E, LFT, CRP, blood culture and an alcohol level.

Her venous gas shows a pH of 7.47, pCO2 of 2.7, bicarb 14, lactate of 2.7 and normal glucose.

That’s odd, you think to yourself, a respiratory alkalosis with some metabolic compensation. You pause for a second and work through your list of possible causes.

1. Could this be a central cause of hyperventilation? A bleed? A tumour? A meningoencephalitis? You put up a request for CT brain. 
2. Could this be a respiratory cause? Asthma? Pneumonia? Pneumothorax? Better get a chest x-ray too.
3. Could this be sepsis? You prescribe ceftriaxone and add acyclovir. There was that coldsore after all…
4. Pregnancy?
5. Endocrine or hypermetabolic cause? Maybe DKA? No… her blood sugar’s normal. Or thyrotoxicosis?
6. Maybe it’s something toxicological? You remember, from your undergraduate days, learning that salicylates cause a respiratory alkalosis.

You add a salicylate level, and paracetamol for good measure, add thyroid function and ask for a catheter urine for beta HCG and a tox screen.  

But her catheter urine doesn’t give you any extra clues. Grace’s urine beta-HCG is negative, her tox screen is negative and her dip is negative.

The resus nurse gently touches your elbow and quietly says, “Do you want to call the anaesthetist?”

Good question, you think to yourself. Her GCS is 7 and she’s tolerating the oropharyngeal airway, but she’s breathing well for herself at the moment. What do you want to do?

With fortuitous timing, CT ring down to say they’re ready for Grace.

Satisfied that A, B and C are all stable, you turn to take the brake off the trolley when Lucy, your SHO, asks, “But do we only want a plain non-contrast CT?”

That’s a good question, you think to yourself. Is that all I want? What neuroimaging will you choose?

You haven’t ruled out infection. So, when you’re back down in resus, you ask Lucy if she’d like to do the LP.

“Really? Is that safe with her low GCS?” she questions. 

What do you think? Should you LP?

You’re still not sure what’s causing Grace’s low GCS though. Maybe the bloods will help. So you log in to the computer to check Grace’s results.

Huh, you think to yourself. Grace’s FBC and CRP are normal; it’s sounding less and less like infection.

Her urea is low and her liver enzymes are raised, with a slightly prolonged INR.

Her salicylate and alcohol levels are undetectable. This isn’t feeling so toxicological anymore.

You mull this over with Lucy. Maybe this is a viral picture. There was that cold sore…

Just then Maureen, the ED cleaner, pops her head into the office. “Might this be of any use?” she asks. She’s holding the RCPCH Decreased Conscious level guideline.

You quickly flick through. Bloods… imaging… you’ve done pretty much everything it suggests. But then you take a closer look at the list of bloods it suggests. And there, in black and white, it says ammonia.

“Of course!” you say out loud. “That would explain the respiratory alkalosis!”

You draw off an ammonia sample, get it on ice and ask Raymond, the dashing porter, to run it down to the lab. You give the lab a ring so they can get the machine primed.

While you’re waiting for the result to come back, Zak comes running over. He’s just been looking in Grace’s backpack for her mobile and found a high protein Diet book. Apparently she’s been trying to lose weight for TikTok. Could it be relevant?

The cogs begin to whir… Hang on a minute… A high protein diet in a vegetarian environmental activist?

The lab phones with Grace’s ammonia level.

It’s over 500! And normal is less than 40.

It all falls into place. Selective vegetarian… Recent protein load… Raised transaminases… High ammonia… This is all beginning to sound a bit metabolic.

But what should you do about that ammonia? As far as you can see, the DeCon guidance only tells you to take it, not what you do when it comes back at over 10 times the upper limit of normal.

“Just a sec,” says Lucy scrolling through her mobile phone, “The British Inherited Metabolic Disease Group have got this covered. They’ve produced a whole range of easy access emergency guidelines, including this one, for the management of an undiagnosed hyperammonaemia.”

“It says, turn off protein catabolism by giving a 10% dextrose bolus followed by a dextrose infusion to provide an alternative energy source. If her glucose climbs, add insulin but don’t reduce the dextrose – otherwise, she’ll just start breaking down more protein. And, finally, mop up that ammonia with scavengers like phenylbutyrate and sodium benzoate.”

The words ‘ammonia scavengers’ remind you of another post you read on Don’t Forget The Bubbles, about the different types of metabolic conditions, how they present and the various treatment strategies. You make a mental note to read it again later to remind yourself of the differences between an amino acid and organic acid.

Meanwhile, you hastily prescribe…

•       A 2ml/kg bolus of 10% dextrose
•       a dextrose infusion
•       And those ammonia scavengers, sodium benzoate and sodium phenylacetate

Grace is subsequently diagnosed as having a urea cycle disorder. You’re amazed to discover that although most diagnoses are made in neonates, diagnoses are sometimes made in adolescents and adults presenting encephalopathic after a big protein load or when catabolic, such as after trauma, childbirth, major surgery, major haemorrhage, critical illness, rapid weight loss or simply after switching to a high protein diet. This is particularly true for ornithine transcarbamylase (OTC) deficiency, which although is X-linked, can present in symptomatic female OTC carriers. Little diagnostic clues include autoselective vegetarianism (that protein makes them feel a bit ‘ugh’) and subtle or behavioural difficulties from chronic low-level hyperammonaemia.

You bookmark a fantastic review article to read later and flick back through your undergraduate biochemistry textbook to remind yourself about urea cycle defects… and hastily close it again when you remember how little you knew even then, at the prime of your undergrad years.

Wow, what a shift. You pack up your stethoscope and head home, reflecting on your day as you walk to the bus stop.

Grace has taught you the importance of…

But what happened to Grace? Let’s jump in the time travel machine and find out…

Your epic diagnosis of a late presenting metabolic disorder was the talk of the ED. The RCPCH DeCon poster was put up in the ED staff room and from that point onwards, everyone remembered to check an ammonia in a patient presenting with an unexplained low GCS. 

Lucy was nominated as employee of the month. This shift was a pivotal moment in her career as she decided PEM was her vocation.

The ammonia scavengers did the trick and Grace made a full recovery.

Grace focussed her efforts on reducing plastic waste in hospital and successfully petitioned for the introduction of plastic-free PPE, reducing plastic waste during the COVID-19 pandemic by an incredible 275%.

She hit 3 million TikTok followers (and you’re one of them).

This PEM adventure wouldn’t have been possible without some help from some amazing people. Thank you to Roshni Vara, Consultant in Paediatric Inherited Metabolic Disease at the Evelina London, Costas Kanaris, PICU and retrieval consultant at the Royal Manchester Children’s Hospital and Jon Lillie, PICU and retrieval consultant at the Evelina London Children’s Hospital.

Here are some of their wise words of advice…

As Costas says in The N of 1 matters, we’ve outlined our take on Grace’s case and how we’d manage her in our own resus bays. Medicine’s not always so clear cut and there are often different approaches to the same problem, but this is our consensus on minimising risk using, as Costas says, a rational, evidence-based and pharmacologically prudent approach (I love that phrase Costas!)

Should we intubate Grace?

Grace is self-ventilating but the fact that she is tolerating an oropharyngeal airway means some of her airway reflexes have gone. Scanning a child with a GCS of 8 or less, without securing the airway, puts them at risk. If they vomit, they aspirate. If they stop breathing and arrest in the scanner, the CT room is one of the least fun places to run an arrest, perhaps second only to an elevator. Are there any counter-arguments? Yes, and they’re soft.  One is “this patient is encephalopathic/obtunded and may have seizures; if the child starts fitting we won’t be able to tell as they’ll be paralysed”.  Costas says he usually stands his ground and says that if someone is worried about seizures then the child can be given a long-acting antiepileptic. Levetiracetam is his preference, although phenytoin would work just as well unless there’s suspicion of an overdose of an arrhythmogenic agent. The last thing you need is to tip this child into an arrhythmia.

When should a lumbar puncture be performed in a child with a decreased conscious level?

CT is a useful tool for ruling out raised intracranial pressure before proceeding to lumbar puncture. And we’d agree. But Grace has a low GCS and this changes the picture.

If we take a look at the full RCPCH DeCon guideline it dedicates a whole section to answering the question about LP in decreased conscious level. So, let’s start there.

The DeCon guideline advises a lumbar puncture if your differentials are viral encephalitis or tuberculous meningitis and advises that we consider lumbar puncture when our differentials are bacterial meningitis, sepsis, or the cause of the low GCS is not known. This is cloaked with the phrase “when no acute contraindications exist” and this is key. So what are those contraindications?

What’s the evidence? Well, it’s mostly been derived by expert opinion, and there aren’t many people who’d dispute them.

But what about when you have a normal CT? The radiologists can look for midline shift and for signs of impending herniation by assessing the position of the cerebellar tonsils. So, surely that can rule out raised ICP, allowing an LP to be done?

The DeCon guideline quotes a study published in 2000 that showed that in 124 CT scans from 65 children with traumatic brain injury, CT had an excellent sensitivity of detecting raised ICP of 99.1%, with a specificity of 78.1%. But, a 2019 revision to the guideline says that no further evidence about the sensitivity or specificity of CT in detecting raised ICP in children has been found. None. Although the sensitivity in the one quoted study was very high, it was felt that one study, in children with traumatic brain injury, could not be extrapolated to all children with a decreased conscious level. And so the guideline states that a normal CT scan does not exclude raised ICP. If other contraindications are present, don’t use a normal CT to justify LP.

What does this mean in practice? Well, in a child with a GCS of 8 or less, like Grace, there’s no rush to do an LP. It’s unlikely to change your management acutely in the ED. Her infection can be treated empirically and once she’s more stable, and you have more information including, potentially, an MRI, she can then have an LP for PCR.

What neuroimaging should we do?

That’s a good question, answered beautifully by an article by Hayes et al, published in 2018. Although this article focuses on neuroimaging for headaches, it has a great section on when you might choose each type of scan.

We’d all agree that the ideal imaging to look for a brain tumour is an MRI. It gives excellent detail about the brain tissue as well as other intracranial soft tissues and the extra-axial CSF spaces.

But, if you want a quick answer, or your access to MR is difficult, a non-contrast CT can be performed easily from the ED. If there’s no possibility of a later MR, then contrast-enhanced CT might be better as it gives more detail, but it’s more radiation – this is one for discussion with the radiologist.

CT is very sensitive in detecting blood, and it can be done quickly, in an emergent setting from the ED. So, in children with thunderclap headache, when you want to exclude subarachnoid hemorrhage, a non-contrast CT will be your first choice scan. If blood is detected, then add in arterial imaging: CT or MR angiography (CTA or MRA). Contrast is injected and images taken in the arterial phase.

CTA or MRA are also useful in the investigation of suspected stroke. In practice, you need an answer fast, particularly if the child’s within the thrombolysis window and could be a candidate if there’s evidence of ischaemic stroke, so a CTA is a more practical scan. The CT component looks for blood or large areas of parenchymal infarct, while the angiography looks for filling defects in the arteries that could indicate a thrombus.

If you’re looking for intracranial extension of infection, such as from an orbital cellulitis, mastoiditis or a brain abscess, then a contrast-enhanced CT will highlight suppurative collections.

And if you suspect a venous sinus thrombosis, such as in children with coagulopathies, sickle cell disease, infective spread from meningitis / mastoiditis / sinusitis, or secondary to dehydration or renal failure? Then you need to look at the venous spaces. CT or MR venography (CTV or MRV), when contrast is injected and images obtained in the venous phase, will give you the answers you need.

And what ARE the causes of a respiratory alkalosis?

There are a few! Here are the main ones:

• Central: brain tumours, meningoencephalitis; stroke
• Respiratory: asthma, pneumonia, pneumothorax, PE
• Sepsis
• Pregnancy
• Endocrine and hypermetabolic cause: DKA, thyrotoxicosis
• Toxicology: salicylates 
• Hyperammonemia: liver and metabolic disorders 

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Select references

The management of children and young people with an acute decrease in conscious level. A nationally developed evidence-based guideline for practitioners. RCPCH. 2015 update, with 2019 revisions. Management of children and young people with an acute decrease in conscious level – Clinical guideline | RCPCH

Undiagnosed Hyperammonaemia. Diagnosis and Immediate Management. British Inherited Metabolic Disease Group. Last reviewed 2017. The major causes are as follows (bimdg.org.uk)

Hirsch, W., Beck, R., Behrmann, C. et al. Reliability of cranial CT versus intracerebral pressure measurement for the evaluation of generalised cerebral oedema in children. Pediatric Radiology 30, 439–443 (2000). https://doi.org/10.1007/s002470000255

Expert Panel on Pediatric Imaging:, Hayes LL, Palasis S, Bartel TB, Booth TN, Iyer RS, Jones JY, Kadom N, Milla SS, Myseros JS, Pakalnis A, Partap S, Robertson RL, Ryan ME, Saigal G, Soares BP, Tekes A, Karmazyn BK. ACR Appropriateness Criteria^® Headache-Child. J Am Coll Radiol. 2018 May;15(5S):S78-S90. doi: 10.1016/j.jacr.2018.03.017. PMID: 29724429.

Mitani H, Mochizuki T, Otani N, Tanaka H, Ishimatsu S. Ornithine transcarbamylase deficiency that developed at the age of 19 years with acute brain edema. Acute Med Surg. 2016;3(4):419-423. doi:10.1002/ams2.214

Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, Rhead WJ, Sniderman King L, Christman BW. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin. 2005 Oct;21(4 Suppl):S1-8. doi: 10.1016/j.ccc.2005.05.002. PMID: 16227111.

Kanaris C, Ghosh A, Partington CG389(P) A case for early ammonia testing in all encephalopathic patients: female patients with x-linked ornithine transcarbamylase deficiency. Archives of Disease in Childhood 2015;100:A158-A159. http://dx.doi.org/10.1136/archdischild-2015-308599.343

Summar, Marshall. (2005). Presentation and management of urea cycle disorders outside the newborn period. Critical Care Clinics. 21. IX-IX. 10.1016/j.jccc.2005.08.004.