الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
The overall incidence of traumatic brain injury (TBI) in the United States was
estimated to be 538.2 per 100,000 population or around 1.5 million new cases in 2003.
Somewhat lower rates are reported in Europe (235 per 100,000) and Australia (322 per
100,000).
In Egypt, a one year period study showed that the incidence of traumatic brain injury
was 844 per four months in 2010 while another study found that the overall incidence of
traumatic brain injury in January 2010 and 2011 was 487 and 471 cases respectively. Both
studies concluded that traumatic brain injury is a serious public health problem in Egypt.
Moderate and severe TBIs are associated with neurologic and functional
impairments. The prevalence of long-term disability related to TBI in the United States is
variably estimated to be between 3.2 to 5.3 million or approximately 1 to 2 percent of the
population.
Early post-traumatic seizures are defined by their occurrence within one week of
head trauma. Overall, the incidence of early post-traumatic seizures is about 6 to 10 % but
may be as high as 30 % in some groups, such as those with depressed skull fracture and
intracerebral hematoma.
Patients with early seizures are often treated with anti-seizure drugs because of the
risk of status epilepticus or aggravation of a systemic injury. In practice phenytoin is often
used because it does not cause significant sedation and can be loaded intravenously. The
optimal duration of therapy is not clear and depends in part upon the severity of injury.
Anti-seizure drugs are generally continued throughout the hospital stay and are gradually
withdrawn within the first few weeks.
Critically ill patients, including those with traumatic brain injury have alterations in
multiple organ systems that can affect serum phenytoin concentrations resulting in drug
levels above or below the target level.
Phenytoin has an unpredictable metabolism due to its nonlinear pharmacokinetics
and high affinity for plasma proteins. Wide variation has been reported in serum levels
especially in intensive care unit patients in whom co-administration of multiple drugs and
possible organ dysfunction is common.
Phenytoin undergoes hepatic metabolism so that polymorphisms within cytochrome
P450 enzymes can affect phenytoin concentrations in patients with traumatic brain injury.
The population pharmacokinetic parameters estimated in other countries may not be
applicable to our own Egyptian population due to unpredictable nonlinear phenytoin
pharmacokinetics and wide variability in phenytoin serum concentration among traumatic
brain injury patients, also as this variability is related to polymorphisms within cytochrome
enzymes.
The aim of this study is to estimate the pharmacokinetic parameters of phenytoin in
Egyptian patients with early traumatic brain injury within seven days after trauma to guide
appropriate dose adjustment without repeated serum measurements.
Summary
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This is a population pharmacokinetic modeling study conducted in the intensive care
unit, Faculty of medicine, Alexandria University, Egypt.
Fifty consecutive adult (age ≥ 18 ) patients having traumatic brain injury within 7
days after head injury admitted to the intensive care unit were included in the study.
Demographic data including age, weight and gender had been collected. Drug related
data including Phenytoin loading and maintenance doses had been documented.
Phenytoin serum trough concentration (minimum serum concentration at the end of
dosing interval) was measured for each patient in 200 blood samples just before the next
due maintenance dose 24, 72, 120 and 168 hours after the initial loading dose. Also
laboratory investigations that may be associated as covariates with phenytoin
pharmacokinetic parameters had been measured.
The statistical analysis was done using Pharsight Phoenix® NLMETM (Nonlinear
Mixed Effects Models) software as it enables users to perform pharmacokinetic analysis.
The pharmacokinetic parameters were estimated including Km = 4.25 (CI 95% =
4.0025 - 4.4975), Vmax = 7.92 (CI 95% = 7.3355 - 8.5045) and Vd = 0.719 (CI 95% =
0.693 – 0.745). None of the potential covariates had a statistically significant effect on the
estimation of the parameters.