Comparing Methods of Loading Phenytoin in Seizure Patients

Abstract & Commentary

Source: Swadron SP, et al. A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med 2004;11:244-252.

The authors have tackled a common problem in the emergency department (ED): finding the most effective phenytoin-loading technique. They enrolled patients with sub-therapeutic phenytoin concentrations who presented within 48 hours of a seizure. They received either 20 mg/kg of oral phenytoin (PO), divided in maximum doses of 400 mg every two hours, 18 mg/kg of intravenous phenytoin (IVP) at an initial infusion rate of 50 mg/min, or 18 mg/kg (phenytoin equivalents) of intravenous fosphenytoin (IVF) at an initial infusion rate of 150 mg/min. Forty-five patients were included: 16 in the PO group, 14 in the IVP group, and 15 in the IVF group. Therapeutic drug concentrations were achieved in (mean ± standard deviation [SD]) 5.62 ± 0.28 hours (PO), 0.24 ± 0.3 hours (IVP), and 0.21 ± 0.28 hours (IVF). A total of 17, 27, and 32 adverse drug events were observed in the PO, IVP, and IVF groups, respectively; this rate was significantly lower in the PO group.

No significant difference was found between the numbers of necessary adjustments to the infusions in the two intravenous groups. Time to safe ED discharge was significantly faster for the intravenous groups compared with the PO group (p < 0.001). Interestingly, four patients experienced a seizure after phenytoin loading (three in the fosphenytoin group, one in the oral phenytoin group, and none in the intravenous phenytoin group). All of these patients had therapeutic phenytoin levels. The main differences between the oral route and the intravenous routes were directly related to two side effects: irritation at the infusion site (called phlebitis) for the IVP group and pruritis (generalized and perineal) in the IVF group. There were two episodes of hypotension in the IVP and one episode in the IVF. The authors conclude that the oral loading leads to less frequent adverse drug events than either intravenous loading technique, but when therapeutic concentrations are required quickly, oral loading may be disadvantageous.

Although IVF loading is faster, from an adverse-drug event perspective, no advantage of IVF over IVP was apparent.

Commentary by Richard J. Hamilton, MD, FAAEM, ABMT

There are a great many strongly held opinions on loading phenytoin in patients who have sub-therapeutic concentrations. I have used all of the techniques studied in this paper, plus unique combinations of the two—for example, loading half of the dose intravenously and the rest by mouth. In my experience, there are two key determinants in rapid disposition of patients: rapid determination of a phenytoin level and intravenous loading of phenytoin or fosphenytoin. However, while this approach may result in the rapid restitution of therapeutic phenytoin levels, there is little evidence that it is of any value to patients or protects them from subsequent seizures. Furthermore, since side effects from intravenous loading are not trivial and include side effects that are potentially life-threatening, oral phenytoin may have the greatest risk benefit/ratio for the patient. My approach is to establish intravenous access on a seizure patient, obtain a phenytoin level, use an intravenous benzodiazepine if seizures reoccur, and consider intravenous loading with phenytoin when a reliable intravenous line can be established in a large forearm vein. If such a line is not available, or the intravenous line is in a tenuous wrist or hand location, the oral loading technique should be employed. Fosphenytoin offers its greatest advantage via the intramuscular route.

Dr. Hamilton, Associate Professor of Emergency Medicine, Residency Program Director, Department of Emergency Medicine, Drexel University College of Medicine, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.