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Single-dose oral phenytoin loading for uncomplicated patients
Opinions expressed in the Correspondence section are those of the authors, and not necessarily of the editors, ACEP, or UAEM. The editor reserves the right to edit and publish letters as space permits. Letters not meeting submission criteria will not be considered for publication. See "Instructions for Authors."
CORRESPONDENCE Single-Dose Oral Phenytoin Loading for Uncomplicated Patients To the Editor: The article "Single-Dose Oral Phenytoin Loading" [April 1987; 16:407-412] indeed provides us with data that address the concept of a single oral 18 mg/kg loading dose of phenytoin for uncomplicated, alert, seizure patients who have no detectable serum phenytoin levels. The authors state that therapeutic levels of more than 10 mg/mL were obtained at two, four, eight, and 24 hours in the following percentages of patient s receiving phenytoin capsules: 22%, 57%, 64%, and 60%, respectively. In this study toxicity appears to be minimal, with only two patients experiencing vomiting and four patients complaining of mild dizziness from a total of 44 patients. Given the ever-increasing need for cost containment, the oral route for phenytoin loading may avoid the additional expense of IV loading if its efficacy in the prevention of seizures and attainment of therapeutic levels can be proven in further studies. However, several issues remain to be resolved before oral loading of phenytoin becomes an everyday emergency department procedure.
KiIbourn Gordon III, MD Department of Medicine Section of Emergency Medicine University of California Irvine Medical Center Orange, California Tim Kaczmar III, MS California College of Medicine Irvine, California
Joseph F Waeckerle, MD, FACEP- Editor Kansas City, Missouri Of particular note is the relatively slow absorption and wide intersubject variation in phenytoin bioavailability found in patients given phenytoin by the oral route. Gugler et al 1 examined the pharmacokinetics of a single 300-mg dose of phenytoin given either as orally ingested capsules or as an IV infusion in healthy volunteers. They discovered that the oral dosage form of phenytoin had slower absorption than many other drugs (range of tv2absorption, .6 to 2.6 hours) and that the absolute bioavailability of orally dosed phenytoin ranged from 58% to 86% (mean, 70%). The effect of the sl0w absorption as well as the large intersubject variation in bioavailability of phenytoin as elucidated by Gugler et al 1 are possible reason s why Osbom's group found that only 22% of their capsule-loaded subjects attained therapeutic levels at the second hour. Further studies using oral loading doses of more than 18 mg/kg as suggested by Osborn are therefore likely to once again uncover a high percentage of subtherapeutic levels during the first two hours after loading. Should these results be found, the oral loading technique would necessitate several hours of ED observation before therapeutic levels are theoretically present in the serum of most patients. This would result in prolonged patient processing delays, and, therefore, increased expense and possible greater morbidity from recurrent seizure while under observation in the ED. The IV approach to phenytoin loading dose has been well studied, and although the side effects of hypotension, arr h y t h m i a , apnea, and Cardiac arrest are well known, the attainment of rapid therapeutic phenytoin serum levels are also found within the first few minutes following the dose. 17:3 March 1988
Crawford et al 2 discovered that a single 18 mg/kg dose of IV phenytoin resulted i n therapeutic serum levels in all of their 28 patients at one-half, two, four, and eight hours after infusion. In conclusion, future studies of phenytoin oral loading will need to carefully address the attainment of therapeutic serum levels and efficacy in preventing further seizure activity during the first two to four hours following the institution of therapy. Recommendations regarding initial dosage, length of observation, an d necessity for repeat serum level prior to discharge need to be formulated through further studies before oral loading of phenytoin in seizure patients can be considered safe as well as efficient practice in the ED.
1. GnglerR, Manion CU, AzarnoffDL: Phenytoin: Pharmacokineticsand bioavailability. Clin Pharm Ther 1975;19:135-141. 2. Crawford RE, Leppik IC, Patrick B, et ah Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology 1978;28:874-880.
In Reply: We appreciate the interest shown in our article on singledose oral phenytoin loading by Dr Gordon and Mr Kaczmar. They are correct to point out the slower, more erratic, and unpredictable absorption of orally administered phenytoin. In our own study we also found a wide range of bioavailability. The standard deviations for the mean phenytoin levels at two, four, and eight hours after loading were 2.5, 4.5, and 5.0 ~g/mL, respectively. Certainly the oral loading technique is not as reliable as IV nor can it offer the achievement of therapeutic levels as rapidly. The IV method, despite its significant side effects and toxicity, remains the method of choice for those patients who require anticonvulsant control on an emergency basis. Patients with serial seizures, status epilepticus, and seizures associated with an acute underlying process fall into this category. If IV loading is to be used it should be performed at doses of 18 mg/kg diluted in normal saline and administered through an infusion pump at rates not exceeding 30 to 40 mg/minute, and with continuous ECG and blood pressure monitoring. We performed our study to find a safe and efficient way to load stable patients who do not require emergency anticonvulsant control. Presently, patients who experience uncomplicated and limited seizures and who require ongoing treatment are handled in a variety of ways: some are loaded in the ED with IV phenytoin, some are simply placed on
Annals of Emergency Medicine
294/169
CORRESPONDENCE Single-Dose Oral Phenytoin Loading for Uncomplicated Patients To the Editor: The article "Single-Dose Oral Phenytoin Loading" [April 1987; 16:407-412] indeed provides us with data that address the concept of a single oral 18 mg/kg loading dose of phenytoin for uncomplicated, alert, seizure patients who have no detectable serum phenytoin levels. The authors state that therapeutic levels of more than 10 mg/mL were obtained at two, four, eight, and 24 hours in the following percentages of patient s receiving phenytoin capsules: 22%, 57%, 64%, and 60%, respectively. In this study toxicity appears to be minimal, with only two patients experiencing vomiting and four patients complaining of mild dizziness from a total of 44 patients. Given the ever-increasing need for cost containment, the oral route for phenytoin loading may avoid the additional expense of IV loading if its efficacy in the prevention of seizures and attainment of therapeutic levels can be proven in further studies. However, several issues remain to be resolved before oral loading of phenytoin becomes an everyday emergency department procedure.
KiIbourn Gordon III, MD Department of Medicine Section of Emergency Medicine University of California Irvine Medical Center Orange, California Tim Kaczmar III, MS California College of Medicine Irvine, California
Joseph F Waeckerle, MD, FACEP- Editor Kansas City, Missouri Of particular note is the relatively slow absorption and wide intersubject variation in phenytoin bioavailability found in patients given phenytoin by the oral route. Gugler et al 1 examined the pharmacokinetics of a single 300-mg dose of phenytoin given either as orally ingested capsules or as an IV infusion in healthy volunteers. They discovered that the oral dosage form of phenytoin had slower absorption than many other drugs (range of tv2absorption, .6 to 2.6 hours) and that the absolute bioavailability of orally dosed phenytoin ranged from 58% to 86% (mean, 70%). The effect of the sl0w absorption as well as the large intersubject variation in bioavailability of phenytoin as elucidated by Gugler et al 1 are possible reason s why Osbom's group found that only 22% of their capsule-loaded subjects attained therapeutic levels at the second hour. Further studies using oral loading doses of more than 18 mg/kg as suggested by Osborn are therefore likely to once again uncover a high percentage of subtherapeutic levels during the first two hours after loading. Should these results be found, the oral loading technique would necessitate several hours of ED observation before therapeutic levels are theoretically present in the serum of most patients. This would result in prolonged patient processing delays, and, therefore, increased expense and possible greater morbidity from recurrent seizure while under observation in the ED. The IV approach to phenytoin loading dose has been well studied, and although the side effects of hypotension, arr h y t h m i a , apnea, and Cardiac arrest are well known, the attainment of rapid therapeutic phenytoin serum levels are also found within the first few minutes following the dose. 17:3 March 1988
Crawford et al 2 discovered that a single 18 mg/kg dose of IV phenytoin resulted i n therapeutic serum levels in all of their 28 patients at one-half, two, four, and eight hours after infusion. In conclusion, future studies of phenytoin oral loading will need to carefully address the attainment of therapeutic serum levels and efficacy in preventing further seizure activity during the first two to four hours following the institution of therapy. Recommendations regarding initial dosage, length of observation, an d necessity for repeat serum level prior to discharge need to be formulated through further studies before oral loading of phenytoin in seizure patients can be considered safe as well as efficient practice in the ED.
1. GnglerR, Manion CU, AzarnoffDL: Phenytoin: Pharmacokineticsand bioavailability. Clin Pharm Ther 1975;19:135-141. 2. Crawford RE, Leppik IC, Patrick B, et ah Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology 1978;28:874-880.
In Reply: We appreciate the interest shown in our article on singledose oral phenytoin loading by Dr Gordon and Mr Kaczmar. They are correct to point out the slower, more erratic, and unpredictable absorption of orally administered phenytoin. In our own study we also found a wide range of bioavailability. The standard deviations for the mean phenytoin levels at two, four, and eight hours after loading were 2.5, 4.5, and 5.0 ~g/mL, respectively. Certainly the oral loading technique is not as reliable as IV nor can it offer the achievement of therapeutic levels as rapidly. The IV method, despite its significant side effects and toxicity, remains the method of choice for those patients who require anticonvulsant control on an emergency basis. Patients with serial seizures, status epilepticus, and seizures associated with an acute underlying process fall into this category. If IV loading is to be used it should be performed at doses of 18 mg/kg diluted in normal saline and administered through an infusion pump at rates not exceeding 30 to 40 mg/minute, and with continuous ECG and blood pressure monitoring. We performed our study to find a safe and efficient way to load stable patients who do not require emergency anticonvulsant control. Presently, patients who experience uncomplicated and limited seizures and who require ongoing treatment are handled in a variety of ways: some are loaded in the ED with IV phenytoin, some are simply placed on
Annals of Emergency Medicine
294/169