Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children

Pediatr Crit Care Med. 2006 Sep;7(5):434-9; quiz 440. doi: 10.1097/01.PCC.0000235252.43921.DE.


Objective: To determine the relationship between estimated free, measured free, and measured total phenytoin levels in critically ill pediatric patients, assess the utility of the Sheiner-Tozer equation in predicting free phenytoin levels, and identify comedications that may influence phenytoin binding or confound attempts to maintain therapeutic concentrations.

Design: Retrospective chart review.

Setting: Twenty-four-bed medical-surgical pediatric intensive care unit.

Patients: Sixty critically ill pediatric patients receiving phenytoin for treatment of seizures in a large multidisciplinary intensive care unit.

Interventions and main results: The linear correlation between free and total phenytoin concentrations was moderate (r = .795), but the mean difference between actual free concentrations and those estimated from total concentrations using the Sheiner-Tozer equation was -0.31 +/- 0.5 microg/mL (95% confidence interval, -1.3 to 0.7). This difference was of concern, as 10% of patients had toxic free levels (>2 microg/mL) when simultaneously measured total levels were therapeutic (<20 microg/mL). The mean free/total phenytoin ratio was 0.13 +/- 0.07 (range, 0.06-0.42) and varied considerably among patients. Free fractions were particularly elevated in children whose serum albumin concentrations were <2.5 g/dL (0.22, p < .001). However, the relationship between free phenytoin and serum albumin concentration appeared to be nonlinear. Coadministration of valproic acid and cefazolin also increased free fraction (p < .001).

Conclusions: Measured total phenytoin concentrations are unreliable for directing therapy in critically ill children. In part, this is because phenytoin binding shows greater variability in this population than has been reported in adults. This phenomenon is exacerbated by coadministration of other highly protein-bound drugs. Instead, free phenytoin concentrations should be routinely measured in critically ill children to prevent possible intoxications and ensure therapeutic dosing. Corrections using the Sheiner-Tozer equation were unreliable.

MeSH terms

  • Adolescent
  • Adult
  • Anti-Bacterial Agents / pharmacokinetics
  • Anticonvulsants / blood*
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / therapeutic use*
  • Blood Chemical Analysis
  • Cefazolin / pharmacokinetics
  • Child
  • Child, Preschool
  • Critical Illness*
  • Humans
  • Hypoalbuminemia / metabolism
  • Infant
  • Infant, Newborn
  • Intensive Care Units, Pediatric
  • Phenytoin / blood*
  • Phenytoin / pharmacokinetics
  • Phenytoin / therapeutic use*
  • Protein Binding
  • Retrospective Studies
  • Seizures / drug therapy
  • Sensitivity and Specificity
  • Valproic Acid / pharmacokinetics


  • Anti-Bacterial Agents
  • Anticonvulsants
  • Valproic Acid
  • Phenytoin
  • Cefazolin