A 68-year-old man is evaluated in the intensive care unit for altered mental status and un… — USMLE Step 3

A $68$ -year-old man is evaluated in the intensive care unit for altered mental status and uncoordinated movements. He was admitted $5$ days ago for severe community-acquired pneumonia complicated by septic shock. He was intubated for $3$ days and was successfully extubated yesterday. His past medical history is significant for focal impaired awareness seizures, for which he has taken oral phenytoin for the last $4$ years. His current medications include intravenous ceftriaxone, subcutaneous enoxaparin, and his home dose of phenytoin, which is administered via a nasogastric tube.

On physical examination, temperature is $37.2^{\circ}$ C ( $99.0^{\circ}$ F), blood pressure is $110/70$ mmHg, and pulse is $88$ /min. The patient is lethargic but arousable. Neurologic examination reveals prominent bilateral horizontal nystagmus, dysarthria, and severe dysmetria on finger-to-nose testing.

Serial laboratory studies over the course of his admission are shown below:

Parameter	Day 1	Day 3	Day 5 (Today)	Reference Range
Serum albumin	$3.5$ g/dL	$2.6$ g/dL	$1.9$ g/dL	$3.5-5.0$ g/dL
Blood urea nitrogen	$22$ mg/dL	$45$ mg/dL	$68$ mg/dL	$8-20$ mg/dL
Serum creatinine	$1.1$ mg/dL	$1.9$ mg/dL	$2.8$ mg/dL	$0.7-1.3$ mg/dL
Total serum phenytoin	$11$ mcg/mL	$13$ mcg/mL	$15$ mcg/mL	$10-20$ mcg/mL

Which of the following is the most appropriate next step in the evaluation or management of this patient's neurologic findings?

Obtain a serum free phenytoin concentrationAnswer
B
Order a non-contrast head computed tomography
C
Increase the phenytoin dose to target a total concentration of $18$ mcg/mL
D
Administer intravenous lorazepam
E
Add enteral valproic acid to the antiepileptic regimen

Answer

Obtain a serum free phenytoin concentration to accurately assess for medication toxicity in the setting of hypoalbuminemia and acute kidney injury.

The correct answer identifies the need to measure a free phenytoin level. Phenytoin exhibits nonlinear (Michaelis-Menten) kinetics and is highly protein-bound (approximately

90\%

). When a patient develops severe hypoalbuminemia, the number of binding sites decreases, causing the unbound, pharmacologically active fraction to rise. Furthermore, this patient has acute kidney injury; uremia alters the structural conformation of albumin, further reducing its affinity for phenytoin. Consequently, a total phenytoin level of

15

mcg/mL in this patient masks a severely elevated free fraction that is causing his classic toxicity symptoms (nystagmus, dysmetria, lethargy). The definitive next step in monitoring is to obtain a free phenytoin concentration.

Step-by-Step Solution

Evaluate the clinical presentation.

The patient has new-onset lethargy, bilateral horizontal nystagmus, dysarthria, and dysmetria.

These are classic, dose-dependent signs of central nervous system toxicity from phenytoin.

Analyze the laboratory trends in the context of the medication.

Total phenytoin is

15

mcg/mL (therapeutic range

10-20

mcg/mL). However, albumin has dropped significantly to

1.9

g/dL, and the patient has developed acute kidney injury with uremia (BUN

68

mg/dL).

Phenytoin is normally

90\%

bound to albumin. Hypoalbuminemia means there are fewer binding sites, and uremia alters the affinity of existing albumin, both leading to an increased free (unbound, active) fraction of the drug.

Determine the appropriate management step.

Order a serum free phenytoin concentration.

Because the total level is misleadingly 'normal', evaluating the free fraction (target

1-2

mcg/mL) will confirm the suspected toxicity and guide dosage adjustments.

Key Concept

In patients with severe hypoalbuminemia or uremia, total serum phenytoin levels are an inaccurate measure of pharmacologic activity because the unbound (free) fraction of the drug increases significantly, necessitating the measurement of free phenytoin levels to diagnose toxicity.

Alternative Method

Instead of waiting for a free phenytoin lab result (which is a send-out test at many institutions), clinicians can mathematically estimate the adjusted total phenytoin level using the Winter-Tozer equation. For patients with renal failure, the formula is: Adjusted Total Phenytoin = Measured Total / ((0.1 * Albumin) + 0.1). For this patient, the estimated adjusted total level would be

15 / ((0.1 * 1.9) + 0.1) = 15 / 0.29 \approx 51.7

mcg/mL, which massively exceeds the therapeutic upper limit of

20

mcg/mL.

Estimated Time:1m 30s

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Answer

Step-by-Step Solution

Key Concept

Common Mistakes

Alternative Method

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