Journal of Research in Pharmacy Practice

Total Phenytoin concentration is not well correlated with active free drug in critically-ill head trauma patients

Document Type : Original Article

Authors

. Kourosh Sadeghi 1
. Farin Hadi 2
. Arezoo Ahmadi 3
. Hadi Hamishehkar 4
. Mohammad‑Taghi Beigmohammadi5 5
. Ata Mahmoodpoor 6
. Mohammad Reza Rouini 7
. Shirin Farhudi 8
. Narjes Hendoui 9
. Atabak Najafi 3
. Mojtaba Mojtahedzadeh 10

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

Abstract
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.

Keywords

Critically-ill patients
free drug concentration
head trauma
hypoalbuminemia
  Phenytoin

1. Annegers JF, Hauser WA, Coan SP, Rocca WA. A populationbased study of seizures after traumatic brain injuries. N Engl 
J Med 1998;338:20‑4.
2. KhanAA, BanerjeeA. The role of prophylactic anticonvulsants 
in moderate to severe head injury. Int J Emerg Med 
2010;3:187‑91.
3. von Winckelmann SL, Spriet I, Willems L. Therapeutic 
drug monitoring of phenytoin in critically ill patients. 
Pharmacotherapy 2008;28:1391‑400.
4. Richens A. Clinical pharmacokinetics of phenytoin. Clin
Pharmacokinet 1979;4:153‑69.
5. Zielmann S, Mielck F, Kahl R, Kazmaier S, Sydow M, Kolk J, 
et al. A rational basis for the measurement of free phenytoin 
concentration in critically ill trauma patients. Ther Drug Monit 
1994;16:139‑44.
6. Hong JM, ChoiYC, KimWJ. Differences between the measured 
and calculated free serum phenytoin concentrations in 
epileptic patients. Yonsei Med J 2009;50:517‑20.
7. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE 
II: A severity of disease classification system. Crit Care Med 
1985;13:818‑29.
8. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, 
Bruining H, et al. The SOFA (sepsis‑related organ failure 
assessment) score to describe organ dysfunction/failure. On 
behalf of the working group on sepsis‑related problems of the 
European society of intensive care medicine. Intensive Care 
Med 1996;22:707‑10.
9. Friel PN, Ojemann GA, Rapport RL, Levy RH, Van Belle G. 
Human brain phenytoin: Correlation with unbound and total 
serum concentrations. Epilepsy Res 1989;3:82‑5.
10. Johno I, Kuzuya T, Suzuki K, Hasegawa M, Nakamura T, 
Kitazawa S, et al. Is free fraction measurement of phenytoin 
always necessary in pediatric epileptic patients? Ther Drug 
Monit 1988;10:39‑44.
11. Rimmer EM, Buss DC, Routledge PA, Richens A. Should we 
routinely measure free plasma phenytoin concentration? Br J 
Clin Pharmacol 1984;17:99‑102.
12. WolfGK, McClainCD, ZurakowskiD, DodsonB, McManusML. 
Total phenytoin concentrations do not accurately predict free 
phenytoin concentrations in critically ill children. Pediatr Crit 
Care Med 2006;7:434‑9.
13. Lindow J, Wijdicks EF. Phenytoin toxicity associated 
with hypoalbuminemia in critically ill patients. Chest 
1994;105:602‑4.
14. Fedler C, Stewart MJ. Plasma total phenytoin: A possibly 
misleading test in developing countries. Ther Drug Monit 
1999;21:155‑60.
15. Shohrati M, Mojtahedzadeh M, Rouini M, Gholami Kh, 
Eftekhar B, Sadidi A, et al. Correlation of free fraction of 
phenytoin and plasma albumin level in head trauma patients. 
Daru 2002;10:1‑5.
16. Krasowski MD, Penrod LE. Clinical decision support of 
therapeutic drug monitoring of phenytoin: Measured versus 
adjusted phenytoin plasma concentrations. BMC Med Inform 
Decis Mak 2012;12:7.
17. Boucher BA, Rodman JH, Fabian TC, Cupit GC, Ludden TM, 
West ME, et al. Disposition of phenytoin in critically ill trauma 
patients. Clin Pharm 1987;6:881‑7.
18. Shohrati M, Rouini M, Mojtahedzadeh M, Firouzabadi M. 
Evaluation of phenytoin pharmacokinetics in neurotrauma 
patients. Daru 2007;15:34‑40.
19. BoucherBA, WoodGC, Swanson JM. Pharmacokinetic changes 
in critical illness. Crit Care Clin 2006;22:255‑71.
20. Edwards DJ, Lalka D, Cerra F, Slaughter RL. Alpha1‑acid 
glycoprotein concentration and protein binding in trauma. 
Clin Pharmacol Ther 1982;31:62‑7.
21. Gabay C, KushnerI. Acute‑phase proteins and other systemic 
responses to inflammation. N Engl J Med 1999;340:448‑54.
22. Bailey DN, Briggs JR. The binding of selected therapeutic 
drugs to human serum alpha‑1 acid glycoprotein and to 
human serum albumin in vitro. Ther Drug Monit 2004;26:40‑3
Journal of Research in Pharmacy Practice
Volume 2, Issue 3
Summer 2013
Pages 106-109

Home

Guide for Authors

Submit Manuscript

Reviewers

Contact Us