Pediatric PuzzlerOctober 2007

CC: “I keep vomiting”

HPI: 9 yo male presents with one week history of intermittent vomiting. He was punched in the head one week prior but had no outward signs of injury, though he did have emesis on the day of the injury.

Since then he has vomited on and off. The emesis was NB NB.

HPI

Three days prior to this visit he stayed home from school because of decreased appetite and malaise.

He went to school the next day but was sent home because of nausea.

That evening he was well until after dinner when he had multiple episodes of emesis.

Of note… no headaches and no visual changes

More history…

Mom finally called the pediatrician and was sent to the ER.

The patient had a head CT done and was given IVF. The CT was read as normal.

He was discharged home.

The first visit

Any questions?

During your shift in the CHER, the patient is brought in by his mom for lethargy.

She said he was watching cartoons and was slow to answer questions.

He became listless and lethargic. He required lots of stimulation to answer questions.

He was noted to have one (small) episode of bilious emesis as well.

The Return

PMH: mild intermittent asthma. No recent illnesses

Meds: Albuterol PRN, last use 1 month ago Imm: UTD Dev: Normal, does well in school Fam Hx: noncontributory Social: Lives with mom, dad and brother in

Metairie. Travel Hx: none, occasionally goes camping

with sibling.

Background

Ht: 143 cm (95%) Wt: 27 kg (50%) T 98.9 HR 86 RR 22 BP 100/70 Gen: pale, thin, does not open his eyes when

you ask him to but follows other motor commands “raise your leg”

HEENT: no nuchal rigidity or meningeal signs CV: rrr no murmur Chest: CTAB Abd: benign Skin: no rash, icterus, track marks, petechiae,

etc

Physical Exam

Neuro: ◦ MS: responds to painful stimuli, nonverbal,

follows some commands◦ CN: PERRL, no photophobia, EOMi, symmetrical

face, tongue midline◦ Tone: normal◦ Motor: 5/5 in all extremities when pt would

cooperate◦ Sensory: Appeared intact◦ DTR: 2+ everywhere except 3+ patellar B and

4-5 beats of ankle clonus B

Physical Exam (con’t)

What is going on with this patient???

Top 3 Differentials &Top 3 Tests

Problem DefinitionIntermittent Vomiting x 1 wkAcute Mental Status ChangesIn an otherwise well child

Encephalopathy◦ Hypoxic ischemia◦ Hypoglycemia◦ Cerebral Edema◦ Increased ICP◦ Toxins

Acute CNS infection◦ Bacterial◦ Viral

Postinfectious◦ Mycoplasma◦ Varicella◦ Etc

Toxins◦ Exogenous◦ Endogenous

Renal failure? Liver failure?

IEM◦ Urea metabolism◦ Inherited Organic

acidemias Reye Syndrome Complex migraine Temporal lobe

epilepsy

Differential Diagnosis

Labs are Back!

Bolus given. Sent Home Bolus given. Admitted.

ER visit day prior:◦ BUN 17, Cr 0.7◦ HCO3 20

◦ Other electrolytes, LFTs, Amylase, Lipase, CBC was normal

◦ UA: SG 1.030,1+ ketones

◦ KUB: wnl◦ Head CT: wnl

Today:◦ All the same labs were

repeated Results were the same!

◦ Utox: negative◦ LP:

CSF was normal

Patient becomes more alert after bolus. He asks for food and is loving the Children’s

Hospital TV channels. Speech is dysarthric

◦ Mom says that this is NOT his normal speech◦ BUT she is happy that he is acting more like

himself

Response to Intervention

You’re called because the patient becomes agitated.

He is kicking, screaming, and pulling at his IV.

Why this acute decompensation???

Later that night…

You’re the HOI on call.

What do you do?Any further tests?Has anything entered into your index of suspicion?

CMP◦ normal

Ammonia◦ 220 umol/L (nl <30)◦ This level was repeated and confirmed

More labs sent

Problem Redefined9 yo male with acute mental status changes, vomiting and hyperammonemia.

Ammonia released from catabolism of amino acids◦ Cell breakdown◦ Excess dietary protein

Excreted as urea (kidney) via urea cycle as conversion of glutamate to glutamine (liver)

Increased ammonia almost exclusively toxic to the brain

Ammonia

NH3 must be measured in every sick child who is encephalopathic for an apparently unknown cause

Otherwise hyperammonemia may be missed and the child deprived of treatment.

Signs and Symptoms (>100-200 umol/L)◦ Lethargy◦ Confusion◦ Vomiting◦ Acute ataxia◦ Hyperactivity◦ Coma (>300)

Ammonia

In healthy neonates, NH3 is <100◦ If sick can be up to 180umol/L◦Suspect IEM in neonates if >200umol/L

In older children, NH3 is <80umol/L (nl=<35)◦Think IEM if >100umol/L

What’s Hyperammonemia?

Blood sample must be taken as uncuffed venous or arterial, kept on ice, and analyzed immediately.

It’s put in a green or purple top tube False elevations are common

◦ Hemolysis◦ Delay in processing◦ Exposure to room temp

How to draw ammonia level

Why is the ammonia so high?

Any guesses?

Inadequate function of urea cycle◦ Hepatocellular dysfunction◦ Deficient urea cycle enzymes

Acquired Reye Drugs (valproate, chemotherapy)

Inherited Urea cycle enzyme deficiency Organic acidemia Fatty acid oxidation defects

UTI from urease-producing organisms Increased muscle activity

◦ Respiratory distress and seizures (not >180umol/L)

Reasons

Blood gas◦ Respiratory alkalosis as NH3 stimulates resp center◦ Metabolic acidosis think organic acidemia vs FAO d/o

Urine ◦ Ketones- organic acidemia

BMP◦ Anion gap

Liver function tests Plasma and urinary amino acids Urine organic acids Acylcarnitine profile

◦ Fatty acid oxidation defects Plasma carnitine level

What tests should I order?

Back to Our Patient

Urine OA came backElevated orotic acid

Plasma AAElevated glutamine levelLow/Absent citrulline

Most common urea cycle disorder

The ammonia that is not detoxified by the urea cycle is converted to glutamine and glutamate.

Increased glutamine in astrocytes osmotic shift of fluid into astrocytes swelling/cerebral edema

A word on OTC deficiency

The goal of the urea cycle is to breakdown ammonia into urea.

This process takes place in the hepatocytes.

It’s that simple!

In other words…

Is an x-linked disorder (1/30,000)◦ The other urea cycle defects are AR◦ Does rarely occur in girls! 10% of female carriers

become symptomatic Typical presentation

◦ Males in first week of life with lethargy, vomiting, hypothermia (looks like sepsis)

◦ Respiratory Alkalosis Late Onset Disease

◦ Typically females with vomiting, lethargy and behavioral changes

OTC deficiency

Symptoms can occur following viral illness, childbirth and use of VPA.

Onset of symptoms frequent at the time of weaning from breast milk

CT/MRI can show evidence of acute ischemia. Generalized high intensity in white matter, brainstem, basal ganglia and bilateral frontal lobes.

EEG- slowing, can show triphasic waves

Features of OTC Deficiency

Triad of encephalopathy, respiratory alkalosis and hyperammonemia.

NH3 levels (> 500 uM hemizygotes), > 100 uM heterozygotes.

Normal anion gap respiratory alkalosis

Serum amino acids: low citrulline, arginine, increased glutamine. Urine: high orotic acid.

DNA diagnosis available

Diagnostic Considerations

Stop protein intake! Provide adequate calories to prevent

catabolism (10% dextrose) Only use lipids if fatty acid oxidation ruled

out Generous amounts of fluids to promote

ammonia excretion

Treatment…

Sodium benzoate and sodium phenylacetate to promote ammonia excretion

If NH3 >400 or no improvement in 8hrs- hemodialysis or hemofiltration

NO exchange transfusion, blood product transfusion or drugs that impair liver function

Call genetics

More Treatment…

Plasma glutamine is useful marker for effective therapy (<1000umol/L)

Decrease protein intake acutely during infection

Ibuprofen instead of Tylenol

Diet- low protein. Most patients can receive less than the RDA of protein and maintain good growth

Ensure essential amino acids and vitamins/minerals

Long Term Management

What triggered his presentation?◦ Intermittent vomiting associated with increased

protein intake◦ He was well in the mornings because of overnight

fast.◦ Vomiting occurred later in the day because of

eating Overall trigger was mild viral illness

◦ Not from the school bully!

Back to Our Patient

June 2007… AG a 7yo female was transferred to the PICU with a 3 day history of lethargy progressing to coma.

Dialysis was started for hyperammonemia She was diagnosed with OTC deficiency

◦ Confirmed heterozygote by DNA◦ Apparently, she lived on a vegan commune with

her mom and spent the weekend with dad chowing down on burgers.

◦ She was also on valproic acid for epilepsy.◦ Both factors contributed to the presentation!

In Our Own Backyard

•HYPERCHLOREMIA

•METABOLIC ACIDOSIS

•HYPERBILIRUBINEMIA

•REDUCING SUBTANCE IN URINE

Inborn Errors of MetabolismDiagnostic Approach

INFANT/CHILD WITH SUSPECTED

METABOLIC DISEASE•KETONES NEGATIVE ENCEPHALOPATY < 24 HRS

METABOLIC ACIDOSIS

•HYPOGLYCEMIA

•LOW KETONES

•METABOLIC ACIDOSIS

•KETONURIA

•+/- HYPERAMMONEMIA

•RESPIRATORY ALKALOSIS

•HYPERAMMONEMIA

•NEGATIVE KETONES

FATTY ACID OXIDATION

DEFECT

ORGANIC ACIDEMIA UREA CYCLE

DISEASE

GALACTOSEMIANON KETOTIC HYPERGLYCINEMIA

•HEPATOSMEGALY•HYPOGLYCEMIA

GLYCOGENSTORAGEDISEASE

Have a super duper day!

Thank you to Dr. Allison Conravey and Dr. Marble for their expertise!

Thanks for participating in

the pediatric puzzler!