OBJECTIVE: To compare plasma drug levels and pharmacodynamics of fosphenytoin or phenytoin when given intraosseously or intravenously in doses relevant to children. DESIGN: Prospective controlled randomized study. SETTING: University hospital animal laboratory. SUBJECTS: A total of 40 mixed-breed piglets (age, 4-6 months; weight, 20-40 kg). INTERVENTIONS: The animals were anesthetized, after which they underwent intubation, instrumentation, and mechanical ventilation. A central venous catheter and an arterial catheter were placed for monitoring and blood sampling. A peripheral intravenous catheter with a 15-gauge intraosseous needle was inserted for drug infusion. A total of 40 animals (ten per group) were randomly assigned to receive intravenous or intraosseous phenytoin or fosphenytoin infusions. Phenytoin (20 mg/kg) was infused over 20 mins, and fosphenytoin (20 mg phenytoin equivalent kg) was infused over 7 mins. All infusions were followed by the administration of a 5-mL normal saline flush. MEASUREMENTS AND MAIN RESULTS: Blood samples (3 mL) were drawn for use in determining drug levels before infusions (baseline) and 0, 5, 10, 15, 20, 30, 40, 50, 60, and 75 mins after the infusion had been completed. Repeated measures of analysis of variance were used to evaluate statistical significance (p <.05). Phenytoin levels were undetected at baseline. Free (10 to 20 &mgr;g/mL) and total (80 to 110 &mgr;g/mL) phenytoin levels were well above the therapeutic range (free, 1 to 2 &mgr;g/mL; total, 10 to 20 &mgr;g/mL) after infusion in the animals that received fosphenytoin. Significant differences in values were seen in free phenytoin levels at 0 to 10 mins (p <.05) and in total phenytoin levels at 0 to 20 mins (p <.05) between intraosseous phenytoin or fosphenytoin administration. Similar differences were also seen when piglets that received intravenous phenytoin were compared with those that received intravenous fosphenytoin. From 20 to 75 mins, all groups had free and total levels within the therapeutic range. There were no significant differences among heart rate and blood pressure in the groups. CONCLUSION: There is no need to adjust standard drug doses of phenytoin when given intraosseously. The initial high levels of phenytoin in the fosphenytoin groups are of concern because neurologic toxic effects may occur in humans at those levels. Slower infusion rates of fosphenytoin may be needed to avoid toxic levels.