Work-Up and Initial Management of Common Metabolic Emergencies in the Inpatient Setting

Work-Up and Initial Management of Common Metabolic Emergencies in the Inpatient Setting Kristin Lindstrom, MD Division of Genetics and Metabolism Phoenix Children s Hospital AzAAP Pediatrics in the Red Rocks

I have no disclosures for this presentation. I do not plan to discuss unapproved or off label use of products

Learning Objectives Focus on 2 main types of metabolic emergencies: Hyperammonemia Metabolic Acidosis For each type of emergency, you should be able to: Identify combinations of clinical scenarios and laboratory findings that would suggest a metabolic emergency Determine the initial management steps for various metabolic emergencies

What is a Metabolic Emergency? A situation that, if not recognized, and/or not acted upon in a timely fashion can be rapidly lethal Some cases can be so severe that they may not be salvageable despite early recognition and prompt initiation of treatment However, in many cases, with the right initial management you can save a life and improve the ultimate clinical outcome A metabolic emergency can be the first presentation of an inborn error of metabolism (IEM), or an episode of decompensation in a patient with a known diagnosis, often triggered by intercurrent illness or other stressors (fasting, medications )

Two Major Types of Metabolic Emergencies Hyperammonemia Urea Cycle Disorders Organic Acidemias Fatty Acid Oxidation Disorders Metabolic Acidosis Organic Acidemias Primary Lactic Acidosis Fatty Acid Oxidation Disorders (Hypoglycemia, while a component of many IEMs, is often not the most striking finding and typically corrects with treatment of the underlying condition. Endocrine disorders, including glycogen storage diseases, should be the top differential of severe/relentless hypoglycemia until proven otherwise)

Food Energy

Carbohydrate Fat Protein ATP

Protein AA Proteolysis Glycogen synthesis OA Gluconeogenesis Glycogen Glycogenolysis Glucose Fructose Galactose Fat Glycerol Lipolysis Glycolysis Lactate NH 3 Urea Cycle Urea Pyruvate Acetyl CoA Krebs Cycle ketogenesis ketolysis NADH β-oxidation ketones Oxidative Phosphorylation FFA ATP

Hyperammonemia Definition: In children and adults, >50 umol/l (or ULN at your lab) In newborns, >100 umol/l When we really worry >100 umol/l in an older child/adult >150 umol/l in a newborn First thing to do if you get an elevated level repeat it! Drawn from a free flowing vessel (no heelsticks!) Put immediately on ice Sent to the lab as STAT Consider an arterial stick

Hyperammonemia Why is it so bad? Causes cerebral edema Exactly why unclear, but thought to affect the aquaporin system and water/potassium homeostasis in brain Common progression of symptoms if unrecognized/untreated: lethargy, anorexia, hyperventilation, hypothermia, seizures, neurologic posturing, hypoventilation, coma, death

Causes of Hyperammonemia Liver failure Hypovolemic shock Heart failure Infection (hepatitis, HSV, urease positive bacteria) Medications (asparaginase, valproic acid) Inborn errors of metabolism

Pathogenesis Urea Cycle Defects Direct inability to dispose of toxic nitrogen generated from breakdown of all amino acids in the form of non-toxic urea Organic Acidemias Inhibition of the urea cycle at the most proximal part of the cycle

What should prompt you to check an ammonia? Any infant with lethargy, poor feeding, tachypnea and hypothermia who starts seizing Therefore potentially in any infant who is ill enough appearing that you order a blood gas A respiratory alkalosis that cannot otherwise be explained The high ammonia causes brain irritation and hyperventilation, even though there is no CO2/acid they need to breath off Unexplained mental status changes

Management of Hyperammonemia Always repeat the initial level On ice, free flowing, run STAT, arterial stick if necessary Are there potential causes other than an IEM? If IEM suspected and child does not yet have a diagnosis, send plasma amino acids, urine organic acids, plasma acylcarnitines, urine orotic acid Urea cycle disorders often present by 2-4 days of age (before the NBS comes back) OTC deficiency is not on most state NBS

Treatment Strategies: Stop Catabolism of Protein Stop dietary protein intake for 24-48 hours Will need to restart at lower amount, depending on diagnosis Establish more than 1 line of IV access, may need central line Start dextrose containing IVF Mild = D10-1/2 normal saline at 1.5-2x maintenance Severe = high GIR (~15) with addition of insulin to keep blood glucose between about 100-200 IV intralipids, ~2-3 g/kg (NOT in fatty acid oxidation disorders)

Treatment Strategies: Scavenge Nitrogen IV Ammonul (sodium benzoate and sodium phenylbutyrate) bolus with 250 mg/kg (or 5.5g/m2 for >20kg) over 90 minutes and then the same dose given as a 24 hour infusion IV Arginine (urea cycle intermediate) bolus with 200 mg/kg (or 4g/m2 for >20kg) over 90 minutes and then the same dose given as a 24 hour infusion Give together in the same (central) line; extravasation caustic! Recheck ammonia after bolus completed, and then hourly until clearly trending down

Treatment Strategies: Dialysis If ammonia is >500 umol/l or no response after 4 hours of IV scavengers, consider dialysis This will take hours from the decision to initiate to actually dialyzing, and the clinical picture may change significantly (for better or worse) in that time Keep checking ammonia! For infants, CVVH is safer than hemodialysis Goal is to get ammonia under 100 umol/l and start IV scavengers once dialysis discontinued Peritoneal dialysis is not very effective Cooling in addition to dialysis for protection of CNS can be considered (~ 3 day commitment, including re-warming)

Rules of Thumb The higher the initial level, and the faster the rate of rise, the more aggressive you need to be with treatment Sometimes IV fluids and protein restriction does the trick Don t be afraid of too much sodium administration mild/moderate hypernatremia is neuroprotective Many of these treatments are expensive and you are going to get a lot of flak for trying to order them order them anyway

Additional thoughts Families should be told early about the likely long-term sequelae of hyperammonemia (the higher the ammonia and the longer it s elevated, the worse the prognosis) Valproic acid should be avoided for treatment of seizures due to worsening hyperammonemia Withdrawal of care as an option Liver transplantation as an ultimate cure would be necessary down the road

Metabolic Acidosis

Metabolic Acidosis Pathogenesis is more straight forward Cells can t function in an overly acidic an environment Diagnosis, long-term treatment strategy and prognosis can be much trickier than with hyperammonemia

The first big determination Lactic Acidosis vs Other Acidosis = Organic Acids

Protein AA Proteolysis Glycogen synthesis OA Gluconeogenesis Glycogen Glycogenolysis Glucose Fructose Galactose Fat Glycerol Lipolysis Glycolysis Lactate NH 3 Urea Cycle Urea Pyruvate Acetyl CoA Krebs Cycle ketogenesis ketolysis NADH β-oxidation ketones Oxidative Phosphorylation FFA ATP

When to suspect metabolic acidosis? In any infant with lethargy, poor feeding, tachypnea and hypothermia If there is poor perfusion/mottling on exam In a child with abdominal pain and escalating emesis The chicken or the egg?

Main Differential Diagnoses* Lactic Acidosis Sepsis Congenital Heart Disease Hypoperfusion Dehydration Organic Acidemias Diabetic Ketoacidosis Methylmalonic Acidemia (MMA) Propionic Acidemia (PA) Isovaleric Acidemia (IVA) Pyruvate Dehydrogenase Deficiency Pyruvate Carboxylase Deficiency Mitochondrial/ETC dysfunction *Lactic acidosis can co-exist with organic acidemia

How to tell which acid is the primary one causing the acidosis? In the setting of a metabolic acidosis ( ph, bicarb, anion gap): Check a blood lactate level Normal <2 mmol/l, false elevations common, may need to repeat Mild elevations are between 3-5 mmol/l Check urine for ketones Elevated ketones can be any organic acid Ideally, run a STAT urine organic acid analysis if ketones are present to identify the organic acid(s) Ask: is this lactate high enough to be responsible for the entire anion gap?

Approximate Calculation* Lactate is measured in mmol/l Because lactate is monovalent, 1 mmol/l is roughly = 1 meq/l Anion gap is measured in meq/l Therefore, a lactate of 8, which is essentially 6 units above normal, could be expected to raise the anion gap about 6 units above normal So for a lactate of 8, an anion gap in the low 20s could make sense, but if the gap was 35, there s probably another acid present in an abnormally high amount * very approximate

Treating metabolic acidosis caused by organic acidemia: Stop Protein Catabolism Stop all sources of dietary protein for 24-48 hours (but not more) Stop catabolism by providing ample, safe calories: Dextrose + insulin administration Intralipids ~2g/kg High dose IV levo-carnitine administration 100 mg/kg/day divided Q6H (200 mg/kg may be needed for propionic acidemia) Provide base buffer with bicarb administration (1-2 meq/kg given over 30-60 minutes, repeat as needed or add to IV fluids) stop once plasma bicarbonate level is in the low-teens or if ph is nearing normal

Treating metabolic acidosis caused by an organic acidemia Treat concomittant hyperammonemia which may require any/all therapies previously discussed including dialysis, but also may improve significantly with hydration and calories so trend frequently at first May benefit from addition of other cofactors associated with the patient s specific disease: hydroxycobalamin injections (Cobalamin disorders, MMA) glycine (IVA) biotin (PA)

Treating lactic acidosis Need to do a lot of intervention in a short period of time to determine the cause of the lactic acidosis and therefore the treatment strategy and prognosis Primary lactic acidosis is essentially a diagnosis of exclusion, and is often unrelenting and difficult/impossible to effectively manage

Treating lactic acidosis R/O sepsis work up and empiric antibiotics Cardiac echo Assessment for possible bowel necrosis Intravascular repletion in case of dehydration Good IV access with an arterial line if possible to monitor blood gases and lactate frequently The lactate on an ABG is often lower than a plasma lactate

Primary Lactic Acidosis Pyruvate Dehydrogenase, Pyruvate Carboxylase Deficiency, Mitochondrial Disease Often unrelenting lactate production despite all interventions, lactate levels often > 8 Too much glucose may cause increase in lactate production closely watch what happens to lactate when you increase GIR Anapleurotic compounds like C7 (triheptanoin) may be useful in pyruvate carboxylase deficiency Bicarbonate treatment is key in both the acute and chronic state, but bicarb can only do so much if acidosis is unrelenting

If you only remember 3 things In an ill appearing child, a respiratory alkalosis is NOT reassuring check an ammonia! If a child is sick enough appearing that you re concerned about sepsis and you think about checking a blood gas, check an ammonia! If you have metabolic acidosis of unclear etiology, check both a lactate and a urinalysis (for ketones) and consider STAT urine organic acid analysis if possible to figure out which acid is wreaking havoc