CASE:

A 6-year-old female presents with emesis and fatigue. The patient’s mother reports her daughter has a history of Maple Syrup Urine Disease. The day before presentation, on routine urine check, the patient had 2+ ketones in her urine. The patient consumed a protein restricted diet, which initially cleared the ketones. However, on the morning of presentation, the patient began vomiting, appeared more lethargic and had 4+ ketones in her urine. On arrival, she was tachycardic and tachypneic. Her exam was significant for a tired appearing female with dry mucous membranes and poor skin turgor.

DIAGNOSIS:

Maple Syrup Urine Disease

DISCUSSION:

When I think of inborn errors of metabolism, I immediately begin to hyperventilate and feel as though I am back in the library in medical school frantically trying to study for Step 1. But then I remember: “I’m an emergency medicine doctor, and it’s less important that I remember that the enzyme branched-chain alpha blah blah blah is deficient in the autosomal something maple syrup urine disease, and more important that I remember how to recognize and subsequently stabilize these patients when they come into my department in metabolic crisis.” And even luckier for me, it’s actually pretty straightforward so long as you know what labs to order and how to respond to them.

When to Suspect:

As with our patient above, pediatric patients are often diagnosed with metabolic disorders well before they walk through our emergency department doors. Sometimes however, patients will present with their first metabolic crisis and no formal diagnosis. It is not as important for us to diagnose these disorders in the emergency department, but rather to recognize the patient that may have one and to know how to stabilize them.

In general, one should suspect metabolic disorders in any sick neonate.[1] Presenting symptoms are varied and can overlap with those of sepsis and congenital heart disease including poor feeding, irritability, lethargy, seizures, hypoglycemia, jaundice and shock.[2] Sometimes the history in regard to the timing of these symptoms or relation to certain foods may point more specifically to a certain metabolic disorder, such as poor feeding in the morning, an aversion to protein or carbohydrates, or diarrhea after eating a carbohydrate filled meal. Failure to thrive should also raise suspicion. Physical exam is commonly non-specific. Vital signs are usually significant for tachycardia and tachypnea without increased work of breathing secondary to metabolic acidosis.[2] They frequently have signs and symptoms of dehydration, including depressed fontanelle, poor skin turgor, and they may have low overall tone.[3]

How To Evaluate:

For the purpose of this discussion, we’ll assume this is the patient’s first presentation and you are concerned about a possible metabolic disorder. For testing, the provider should consider a full septic workup (CBC, BMP, VBG, Lactate, UA, blood and urine cultures, CSF) in addition to POC glucose, serum and urine ketones, LFTs, lactate, ammonia.[1] Additional testing can be done to help diagnose the specific disorder, but the above will help guide you in the direction of how to best stabilize these patients and further point you toward or away from a metabolic disorder. Hypoglycemia, hyperammonemia (should be < 100), acidemia, elevated ketones (serum or urine) are all indicators of inborn errors in metabolism.[2] Specific associations include:

• Hypoglycemia- glycogen storage disease

• Hyperammonemia- urea cycle defect

• Hyperammonemia + acidosis- organic acid disorder

• Acidosis + normal ammonia + ketones- aminoacidopathies

• Acidosis + neg urine ketones- fatty acid oxidation defect [1]

How To Treat:

Ok, so you already know this person has a metabolic disorder OR you’ve just diagnosed it. Well done. Now, on to the making-them-better part. First and foremost, like with all of our patients, ABCDs are essential. Keep in mind, however, that if you have to intubate, try to match their pre-intubation respiratory rate, which is likely driven by their metabolic acidosis, so as to not worsen the acidemia. [1] Address circulation as you usually would, treating hypovolemia/dehydration with a crystalloid bolus. DO NOT GIVE HYPOTONIC FLUIDS. This may increase the risk of cerebral edema. [1]

Once the ABCDs have been addressed, the remainder of therapies are geared toward eliminating toxic metabolites and treating dehydration. First step is make the patient NPO. This eliminates the addition of any the offending agents (formula, breast milk) that will add to the toxic metabolite load. [2] Next is fluid hydration. As mentioned for circulation, give a crystalloid bolus, and then transition to D10 at 1.5-2 times maintenance. [2] This serves to both treat dehydration and increase metabolite excretion by increasing urine output. [3] Be sure to evaluate respiratory status frequently, however, as cardiac disease is not uncommon in this population. And really, that’s it. For those who are not fully differentiated, or if there is concern for concomitant infection, broad spectrum antibiotics such as ceftazidime could be considered. If you are lucky enough to know the specific disorder, additional medications can be added and started in the emergency department. Often the patient’s family members will have a specific sick plan that they follow, or be able to refer you to their child's specialist for further help.

Important Additional Considerations:

Inborn errors of metabolism can also cause bone marrow suppression resulting in an immunocompromised state and making patients increasingly susceptible to sepsis secondary to unusual organisms. As such, initiating broad spectrum antibiotics in this population is not unreasonable. [1] Cerebral edema is another symptom to be on the lookout for, especially in patients with urea cycle or organic acid disorders, as they will have elevated levels of ammonia. [1] Suspect cerebral edema in the patient whose metabolic abnormalities are improving, but whose mental status remains altered. Treat with mannitol 0.5 mg/kg (assuming not hypotensive) and avoid steroids, as this will worsen the hyperammonemia. [1]

TAKE-AWAYS:

• SUSPECT metabolic crisis in the sick/septic appearing neonate from out of town/without access to genetic testing who is tachycardic and tachypneic without any increased WOB, OR in the patient with known metabolic disorder who appears septic with tachycardia and tachypnea

• TREAT WITH

  • ABCDs

    • If intubating, make sure you maintain a high RR to help with the metabolic acidosis

    • Avoid hypotonic fluids

  • Make the patient NPO

  • Initiate D10 at 1.5-2 times maintenance

  • Consider broad spectrum antibiotics

  • Monitor for signs of cerebral edema secondary to hyperammonemia and treat with mannitol 0.5 mg/kg

    • Avoid steroids as this worsens hyperammonemia

• TRUST THE PARENT. They are likely the most knowledgeable when it comes to how to treat their child’s disease. Ask them if they have a sick plan and execute it.

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Author: Megan Perry, MD is a third year emergency medicine resident at Brown University/Rhode Island Hospital.

Faculty Reviewer: Lynne Palmisciano, MD is an emergency medicine attending at Hasbro Children’s Hospital.

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REFERENCES:

1. Qureshi N, Oriaifo IA. Metabolic Emergencies in Infants and Children. In: Tintinalli JE, Ma O, Yealy DM, Meckler GD, Stapczynski J, Cline DM, Thomas SH. eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw-Hill

2. Danner DJ. Maple Syrup Urine Disease. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:468-9.

3. Saudubray JM, Nassogne MC, de Lonlay P, et al. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatal. 2002;7:3-15