Predicting Unbound Phenytoin Concentrations in the Critically Ill Neurosurgical Patient

Mlynarek, Mark; Peterson, Edward L.; Zarowitz, Barbara J.

doi:10.1177/106002809603000301

Cited by 23 publications

(36 citation statements)

References 16 publications

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“…Despite this widespread use, there has been considerable controversy over whether inaccuracies in the model justify its use or not. Some authors have argued that since PHT free levels may not be readily available, the adjustment in cases of known hypoalbuminemia provides better guidance in dosing than the total PHT level obtained in the usual assay used for therapeutic drug monitoring [9,15,17]. In a population of "critically ill neurosurgical patients", Mlynarek et al concluded that the Sheiner-Tozer equation provided "an unbiased, precise clinical estimate" in cases where the PHT free level "is unavailable or impractical" [17].…”

Section: Resultsmentioning

confidence: 99%

“…Some authors have argued that since PHT free levels may not be readily available, the adjustment in cases of known hypoalbuminemia provides better guidance in dosing than the total PHT level obtained in the usual assay used for therapeutic drug monitoring [9,15,17]. In a population of "critically ill neurosurgical patients", Mlynarek et al concluded that the Sheiner-Tozer equation provided "an unbiased, precise clinical estimate" in cases where the PHT free level "is unavailable or impractical" [17]. For rural clinics in sub-Saharan Africa where malnutrition and AIDS are frequent, Fedler and Stewart concluded that the corrected value should be reported rather than the total phenytoin [9].…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have focused on more limited sample sizes and patient populations [14,17,18,20]. Our study included a population of mainly adults in the inpatient setting, including patients with refractory epilepsy and/or who were on multiple other anti-epileptic medications in addition to phenytoin.…”

Section: Resultsmentioning

confidence: 99%

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Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

Krasowski

Penrod

2012

BMC Med Inform Decis Mak

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BackgroundTherapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard.ResultsIn this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations.ConclusionsThe results suggest that a measured free phenytoin should be obtained where possible to guide phenytoin dosing. If this is not feasible, then an adjusted phenytoin can supplement a total phenytoin concentration, particularly for patients with low plasma albumin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

Krasowski

Penrod

2012

BMC Med Inform Decis Mak

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“…Corrected total phenytoin ϭ total phenytoin ͑g/mL͒ ͕͓albumin ͑g/dL͒/4.4͔ ϫ 0.9͖ ϩ 0.1 [1] Based on the corrected concentration of total phenytoin, the estimated free phenytoin concentration can be obtained by multiplying by 0.1 (24). Statistical Analysis.…”

Section: Methodsmentioning

confidence: 99%

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children*

Wolf

McClain

Zurakowski

et al. 2006

Pediatric Critical Care Medicine

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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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“…The Sheiner-Tozer equation corrects the total phenytoin level for the corresponding serum albumin level, and has been found to be a useful tool to guide phenytoin dosing. [9][10][11] Phenytoin is primarily metabolised in the liver (>95%). Stowe et al, showed that children with severe, neurotrauma were found to have markedly altered protein binding and phenytoin metabolism, [12] and Markowsky et al, also demonstrated that phenytoin binding was significantly more variable with critical and convalescent patients with head injuries than healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Phenytoin toxicity in patients with traumatic brain injury

Abraham

Vidyasagar

Lakshmanan³

et al. 2014

Neurol India

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Predicting Unbound Phenytoin Concentrations in the Critically Ill Neurosurgical Patient

Abstract: These results indicate that, in this population, the Sheiner-Tozer estimate of dphEF provides an unbiased, precise clinical estimate of dphF in patients for whom measured dphF is unavailable or impractical.

Cited by 23 publications

References 16 publications

Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children*

Phenytoin toxicity in patients with traumatic brain injury

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