Document Type : Original Article


1 Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Clinical Pharmacy, Islamic Azad University, Tehran, Iran

3 Department of Anesthesia and Intensive Care, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Clinical Pharmacy and Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

5 Department of Anesthesia and Intensive Care, Imam‑Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

6 Department of Anesthesia and Intensive Care, Tabriz University of Medical Sciences, Tabriz, Iran

7 Department of Biopharmaceutics and Pharmacokinetics, Tehran University of Medical Sciences, Tehran, Iran

8 Students’ Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

9 Department of Clinical Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

10 Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Department of Anesthesia and Intensive Care, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran


Objective: Phenytoin is an antiepileptic drug used widely for prophylaxis and treatment of 
seizure after neurotrauma. Phenytoin has a complex pharmacokinetics and monitoring of its 
serum concentrations is recommended during treatment. Total phenytoin concentration 
is routinely measured for monitoring of therapy. In this study, we evaluated the correlation 
between phenytoin total and free concentrations in neurotrauma critically-ill patients to 
determine whether the phenytoin total concentration is a reliable predictor of free drug, 
which is responsible for the therapeutic effects.
Methods: A total of 40 adult head trauma patients evaluated for free (unbound) and total 
serum phenytoin concentrations. Patients were divided into two groups. GroupA consists of
20 unconscious patients with severe head injury under mechanical ventilation and Group B 
consists of 20 conscious self-ventilated patients. Correlation and agreement between total 
and free phenytoin plasma concentrations were analyzed.
Findings: Pearson correlation analysis and Bland-Altman test showed weak to moderate 
correlation (r = 0.528) and poor agreement between free and total phenytoin concentrations 
in patients with severe trauma and higher Acute Physiology And Chronic Health Evaluation 
II (APACHE II) scores (GroupA) and good correlation (r = 0.817) and moderate agreement 
in patients with mild to moderate trauma and lower APACHE II scores (Group B).
Conclusion: Our results indicated that total phenytoin serum concentration is not a 
reliable therapeutic goal for drug monitoring in severely-ill head trauma patients even in 
the absence of hypoalbuminemia, renal and hepatic failure. It seems justifiable to measure 
free phenytoin concentration in all severely ill neurotrauma patients.


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