Importance of Unbound Phenytoin Serum Levels in Head Trauma Patients

Bauer, Larry A.; Edwards, William; Dellinger, E. Patchen; Raisys, Vidmantas A.; Brennan, Cynthia

doi:10.1097/00005373-198312000-00007

Cited by 24 publications

(9 citation statements)

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“…Our results confirm previous findings that the free fraction of valproate is inversely related to albumin concentration and suggest that the saturable protein binding of valproate results in a profound non-linear effect on valproate free fraction. The effect of hypoalbuminaemia on valproate binding was several fold greater than has been found for phenytoin in a similar population [18,21,22]. Valproate binding constants have been evaluated previously by Scatchard analysis in populations of otherwise healthy patients with epilepsy [7,[26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…As part of the acute phase reaction following traumatic head injury, plasma albumin concentrations decrease over time [19,20]. A two-fold increase in the free fraction of phenytoin following head injury has been reported in small numbers of adult [21,22] and paediatric patients [18]. However, there are no data available on the effect of head injury on the plasma protein binding of valproate.…”

Section: Introductionmentioning

confidence: 99%

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Decreased plasma protein binding of valproate in patients with acute head trauma.

Anderson

Gidal

Hendryx

et al. 1994

Brit J Clinical Pharma

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1. One hundred and ten plasma samples were obtained from 50 patients treated with valproate for prophylaxis of post‐traumatic head injuries. The samples were selected to include a wide range of albumin concentrations and were assayed for free and total valproate concentrations. Valproate binding parameters were determined from the Scatchard equation for one binding site using reweighted least squares analysis. 2. Plasma albumin concentrations were measured in 130 patients with head trauma. They started to decrease immediately after trauma, reaching a minimum at 5‐7 days of approximately 24% of baseline value and did not return to normal until 1 month. 3. The free fraction of valproate varied six to seven‐fold as albumin concentration ranged from 1.5 to 4.8 g 100 ml‐1 (218‐696 mumol l‐1). The mean association constant for binding (Ka) was 0.008 mumol l(‐1) and the mean number of binding sites (N) was 2.0. There values were similar to those reported for valproate in otherwise healthy patients with epilepsy. 4. Because of saturable protein binding of valproate, hypoalbuminaemia may necessitate the monitoring of free valproate concentrations to avoid toxicity when valproate is used in patients with acute head injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased plasma protein binding of valproate in patients with acute head trauma.

Anderson

Gidal

Hendryx

et al. 1994

Brit J Clinical Pharma

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“…49 This has particularly been supported for the use of phenytoin and valproic acid, anticonvulsants frequently used in patients with brain injury. 51,52 Disease states and therapies can alter hepatic blood flow, impacting the hepatic clearance of drugs with high extraction ratios. For example, during severe sepsis and septic shock, cardiac output can increase early and decrease during the late stage, resulting in alterations in hepatic blood flow.…”

Section: General Alterations With Neurotraumamentioning

confidence: 99%

Optimizing Medication Outcomes in Neurocritical Care: Focus on Clinical Pharmacology

2016

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Drug dosing in neurocritically ill patients presents enormous challenges for clinicians due to the complex pathophysiological alterations. These alterations are dynamic both between and within patients. Unpredictable exposure from standard dosing regimens, which were extrapolated to intensive care unit patients from healthy volunteer studies, may influence medication outcomes. Knowledge of potential alterations in pharmacokinetics/pharmacodynamics in these patients could be applied to maximize the clinical response and minimize adverse effects. Recognizing potential confounding clinical and treatment factors affecting drug response is an important step, but it is not enough. Overcoming absorption and distribution challenges by using specialized formulations and delivery systems is an area of active research. Improved methods for measuring drug concentrations in clinical settings across different matrices are also needed. Even with these advances, defining endogenous mediators signaling drug-target activation is necessary. Identifying biomarkers in disease and changes when a drug has reached its target will be pivotal. This information will improve our understanding of the pharmacogenomic and pharmacokinetic variables affecting pharmacodynamic endpoints across a spectrum of neurologic diseases.

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“…• Partial plasma exchange transfusion has no clear long term benefit in asymptomatic polycythaemia or hyperviscosity, though evidence either way is weak and inconsistent. A 12 year old boy is admitted to the paediatric intensive care unit after a motor vehicle collision, where he sustained a severe closed head injury. He lost consciousness at the scene and was intubated in the emergency department for a Glasgow Coma Score of 8 and no gag reflex.…”

Section: Commentarymentioning

confidence: 99%

“…This may be associated with a higher rate of side effects at normal "therapeutic" concentrations. 12 Recently, a consensus guideline was published stating that "the routine use of seizure prophylaxis later than 1 week following head injury is not recommended". 13 The guideline recommends using a risk-benefit analysis to decide whether phenytoin or carbamazepine should be considered for high risk patients in the first week post-injury.…”

Section: Commentarymentioning

confidence: 99%

Phenytoin in traumatic brain injury

Hunt

2002

Archives of Disease in Childhood

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Importance of Unbound Phenytoin Serum Levels in Head Trauma Patients

Cited by 24 publications

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Decreased plasma protein binding of valproate in patients with acute head trauma.

Decreased plasma protein binding of valproate in patients with acute head trauma.

Optimizing Medication Outcomes in Neurocritical Care: Focus on Clinical Pharmacology

Phenytoin in traumatic brain injury

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