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Published on: August 30, 2018
Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children
Gerhard K Wolf1, Craig D McClain, David Zurakowski
1Children's Hospital, Boston, MA, USA.
Insights
Total phenytoin levels are unreliable for guiding treatment in critically ill children. Free phenytoin levels should be monitored to prevent toxicity and ensure effective dosing, as standard calculations are inaccurate.
Area of Science:
- Pediatric Critical Care Medicine
- Clinical Pharmacology
- Neuropharmacology
Background:
- Phenytoin is a crucial antiepileptic drug used in pediatric intensive care units.
- Accurate therapeutic drug monitoring is essential for optimizing phenytoin efficacy and minimizing toxicity.
- Variability in protein binding can significantly impact phenytoin pharmacokinetics, especially in critically ill populations.
Purpose of the Study:
- To evaluate the correlation between measured free and total phenytoin levels in critically ill pediatric patients.
- To assess the accuracy of the Sheiner-Tozer equation for estimating free phenytoin concentrations in this population.
- To identify factors, including comedications, that influence phenytoin binding and therapeutic management.
Main Methods:
- Retrospective chart review of 60 critically ill pediatric patients.
- Analysis of phenytoin levels (total and free) and serum albumin concentrations.
- Evaluation of the Sheiner-Tozer equation's predictive performance.
- Identification of concurrent medications impacting phenytoin levels.
Main Results:
- A moderate linear correlation (r = .795) was observed between free and total phenytoin concentrations.
- The Sheiner-Tozer equation showed a significant mean difference (-0.31 ± 0.5 μg/mL) between estimated and measured free phenytoin levels.
- Ten percent of patients exhibited toxic free phenytoin levels despite therapeutic total levels.
- Elevated free fractions were noted in patients with low serum albumin (<2.5 g/dL) and those receiving valproic acid or cefazolin.
Conclusions:
- Measured total phenytoin concentrations are unreliable for therapeutic drug monitoring in critically ill children.
- Phenytoin binding exhibits greater variability in pediatric intensive care patients compared to adults, influenced by factors like hypoalbuminemia and comedications.
- Routine measurement of free phenytoin concentrations is recommended for safe and effective dosing in this vulnerable population.
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.
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