How do you calculate total phenytoin levels in patients with hypoalbuminemia?

Calculating Total Phenytoin Levels in Hypoalbuminemia

In patients with hypoalbuminemia, the Sheiner-Tozer equation should be used to calculate the adjusted total phenytoin concentration, but free phenytoin level measurement is preferred when available due to greater accuracy. 1

Understanding Phenytoin Binding and Hypoalbuminemia

Phenytoin is highly protein-bound (>90% to albumin) in the bloodstream, with only the unbound (free) fraction being pharmacologically active and responsible for both therapeutic and toxic effects. When albumin levels decrease:

• The fraction of unbound phenytoin increases
• Total phenytoin levels may appear falsely low while free (active) phenytoin may be in therapeutic or even toxic range
• Standard reference ranges for total phenytoin become unreliable

The Sheiner-Tozer Equation

When free phenytoin levels cannot be directly measured, the Sheiner-Tozer equation can be used to estimate the adjusted phenytoin level:

Adjusted phenytoin = Measured total phenytoin / [(0.2 × albumin) + 0.1]

Where:

• Adjusted phenytoin = corrected total phenytoin concentration (μg/mL)
• Measured total phenytoin = laboratory-measured total phenytoin (μg/mL)
• Albumin = patient's serum albumin (g/dL)

This equation attempts to normalize the total phenytoin concentration to what it would be if the patient had normal albumin levels.

Limitations of the Sheiner-Tozer Equation

Research shows significant limitations with this approach:

• Correlation between calculated and measured free phenytoin is moderate at best (r = 0.817) 2
• Agreement in clinical interpretation between adjusted and measured free levels is only about 77% 2
• The equation tends to overestimate free phenytoin levels, potentially leading to underdosing 2, 3
• Accuracy decreases with more severe hypoalbuminemia 3
• Critically ill patients show even greater discrepancies between calculated and measured free levels 4

Clinical Approach to Phenytoin Dosing in Hypoalbuminemia

1. Measure albumin levels in all patients receiving phenytoin therapy 1

2. Preferentially use free phenytoin concentration measurements when available, especially in:

   • Patients with albumin <3.5 g/dL
   • Critically ill patients
   • Elderly patients
   • Patients with renal or hepatic impairment

3. If free phenytoin levels are unavailable:

   • Use the Sheiner-Tozer equation to estimate adjusted phenytoin levels
   • Interpret results cautiously, recognizing the equation's limitations
   • Monitor clinical response closely for signs of toxicity or therapeutic failure

4. Consider phenytoin dosing adjustments:

   • The FDA label specifically states that "because the fraction of unbound phenytoin is increased in patients with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients" 1
   • Lower initial doses may be appropriate in severe hypoalbuminemia
   • More frequent monitoring may be necessary

Monitoring Recommendations

• Measure both albumin and phenytoin levels simultaneously
• When possible, obtain free phenytoin levels directly rather than calculating them
• Monitor for clinical signs of phenytoin toxicity (nystagmus, ataxia, slurred speech, confusion) even when total levels appear therapeutic
• Consider more frequent monitoring in patients with fluctuating albumin levels

Special Considerations

• In ICU patients, conventional equations show even poorer correlation with measured free phenytoin levels 4, 5
• Older patients may have greater discrepancies between calculated and measured free phenytoin levels 5
• Other factors affecting protein binding (uremia, drug interactions) may further complicate interpretation

By understanding these principles and limitations, clinicians can more appropriately interpret phenytoin levels and make safer dosing decisions in patients with hypoalbuminemia.