Variability of serum phenytoin levels in critically ill head injured patients in intensive care unit

Abstract

Patients with large variations in phenytoin levels despite standard doses may prove to become difficult clinical problems. Our study of 34 head injury patients whose serum phenytoin levels were measured on day one and day five following intravenous loading and maintenance dose of phenytoin, showed 38.24% patients, to have therapeutic phenytoin levels on day one, while 20% were in toxic range. On day five, 23% patients were in toxic and 29.41% were in therapeutic range. Only 21% patients remained in the therapeutic range during the monitoring period. This study shows that there is a wide variability of phenytoin levels in the ICU patients with a difference of more than 100% between the highest and lowest phenytoin level in individual cases (in four patients the difference exceeded 500%) raising concern about the safety of the drug. Hence it is recommended that intensive care unit patients receiving phenytoin therapy should have periodic serum phenytoin obtained even in absence of seizures or classic signs phenytoin toxicity.

Evaluation of Goal Phenytoin Levels After an Initial Intravenous Loading Dose at an Academic Medical Center

“…In addition, unpredictable patient-specific factors identified by previous studies in non-critically ill patients including renal dysfunction, concomitant medications, hypoalbuminemia, and hyperbilirubinemia affect phenytoin levels. 5,[9][10][11][12][13][14][15][16] Consideration of these factors may explain the wide range of dosing recommendations suggested to achieve the goal phenytoin level in the previous studies. By including a comprehensive list of potential factors, our study was able to represent a more accurate percentage of critically ill patients achieving the goal phenytoin level, enhancing the generalizability of the study and suggesting a narrower dose range required to achieve the goal level in this patient population.…”

“…1 However, despite the widespread use of phenytoin for seizure management, there are still limited data on the standard loading dose in critically ill patients with doses ranging from 10 to 20 mg/kg. 5-7,14,23 Pillai et al 14 performed a prospective study including ICU patients with moderate to severe head injuries and observed that administering a phenytoin loading dose of 15 to 20 mg/kg followed by a maintenance IV dose of 300 mg/day led to a subtherapeutic level in 41.18% of the patients on day one although the level was not corrected. In contrast, Levati et al 24 observed that all patients who received a 15-mg/kg load achieved a not-corrected therapeutic level of 10 to 20 mcg/mL, and most patients who received a 10-mg/kg load had subtherapeutic levels.…”

“…Due to the lack of standardized equations to calculate the corrected phenytoin level in this patient population, there were differences in reporting phenytoin levels in prior studies that used various versions of the Sheiner-Tozer equation or free serum phenytoin level. 5,14,16,24 To most accurately represent the results in the setting of inconsistencies in obtaining free serum phenytoin level at our institution, our analysis used the original Sheiner-Tozer equation to assess the major endpoint, as suggested by our institution-specific drug administration guideline. However, the accuracy of the Sheiner-Tozer equation remains uncertain, and the corrected phenytoin level using this equation should be interpreted with caution given the scarcity of studies to show a correlation between free, measured, and calculated phenytoin levels in ICU patients.…”

“…The original Sheiner-Tozer equation was used to account for hypoalbuminemia and renal dysfunction: phenytoin level/([0.2 × albumin] + 0.1). [14][15][16] Hypoalbuminemia requiring phenytoin level correction per our institution guideline was defined as an albumin level less than 3.5 g/ dL, and renal dysfunction was defined as creatinine clearance less than 25 mL/min using the Cockroft-Gault equation. Minor outcomes included the incidence of achieving the therapeutic level, defined as a corrected level of 10 to 20 mcg/mL, the median phenytoin weight-based loading dose, time from loading dose to collecting data on the first total phenytoin level, and time from loading dose to obtaining the corrected goal level.…”

“…However, there are limited studies that analyze the effect of these factors comprehensively. 5,[9][10][11][12][13][14][15][16] The objectives of this analysis were to determine the incidence of achieving goal phenytoin levels after the initial loading dose and to characterize factors that may contribute to achieving the goal level in adult patients presenting to the emergency department or admitted inpatient.…”