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Inappropriate fosphenytoin use in the ED
Inappropriate Fosphenytoin Use in the ED JEFFREY JOHNSON, MD AND KEITH WRENN, MD The objective of the study was to evaluate how often intravenous (IV) fosphenytoin is used when oral phenytoin loading is possible. The methods included a retrospective chart review of all patients receiving IV fosphenytoin in the emergency department. We prospectively derived criteria that identify patients with seizures who could receive oral phosphenytoin loading (awake on arrival, alert, no emesis, and lack of endotracheal intubation, repeated seizures, or status epilepticus after arrival). The setting of the study was at an urban, university hospital emergency department with an annual census of 55,000 patients. The outcomes included the number of patients receiving iV fosphenytoin who could have received oral phenytoin loading. From February 1997 to June 1999, 55 patients received IV fosphenytoin. Thirty of these patients (55%, 95% confidence interval 41%-68%) were felt to have received fosphenytoin appropriately. The remaining 25 (45%, 95% confidence interval 32%-59%) patients could have been loaded orally with phenytoin. In a single institution, fosphenytoin administration is inappropriate almost half the time. Oral phenytoin loading is less expensive and safe. (Am J Emerg Med 2001;19:293-294. Copyright © 2001 by W.B. Saunders Company) In many patients with seizures, a hydantoin drug such as phenytoin is used for control. In some cases it is necessary to administer the drug intravenously, for example, status epilepficus or when altered mental status or other factors preclude using the drug orally. Phenytoin has a very poor solubility and must be combined with sodium hydroxide, 40% propylene glycol, and 10% alcohol. Intravenous (IV) phenytoin use is associated with hypotension and bradycardia when infused too rapidly, partly because of its diluent, propylene glycol. In addition, when it infiltrates into tissue, phenytoin can cause devastating tissue necrosis because of its diluents, hyperosmolarity, and pH of more than 12.1.2 In 1996, fosphenytoin, a new IV form of hydantoin, was introduced. This drug is a phenytoin prodrug. It is watersoluble and is able to be infused more rapidly because of a more physiologic pH of 8.1-3 Unfortunately, fosphenytoin is more than 3 times as expensive as an equivalent dose of IV phenytoin l and 15 times as expensive as an equivalent dose of oral phenytoin. It is not known how the cost of oral phenytoin balances against the cost of the adverse effects of IV phenytoin. Oral phenytoin loading is also possible but should only be used when rapid attainment of therapeutic drug levels is not required. Bioavailability is slower because of slower dissolution rates due to its insolubility in the acid environment of the upper gastrointestinal tract and its tendency to coa-
From the Department of Emergency Medicine, Vanderbilt University, Nashville, TN. Manuscript received January 12, 2001, accepted January 26, 2001. Address reprint requests to Keith Wrenn, MD, 703 Oxford House, Vanderbilt University Medical Center, Nashville, TN 37232-4700. Key Words: Anticonvulsants, fosphenytoin, phenytoin, seizures. Copyright © 2001 by W.B. Saunders Company 0735-6757/01/1904-0010535.00/0 doi:l 0.1053/ajem.2001.24471
lesce. 4,5 The rate at which therapeutic levels are obtained has to do with both the size of the dose and the repetitive intervals of dosing. 4,5 Nevertheless, oral loading is preferable in most patients with single seizures due to its low cost and safety profile. 6.7 We were interested in how often fosphenytoin was being used when it was possible to use oral phenytoin loading. METHODS A list of criteria was prospectively derived which we felt defined patients with seizures who were candidates for oral phenytoin loading. These criteria were (1) the patient was awake and alert on arrival, (2) there was no mention of emesis, (3) the patient had not been endotracheally intubated, and (4) there were no repeated seizures or status epilepticus after arrival in the emergency department (ED). All criteria had to be met for a patient to be considered a candidate for oral loading, which we considered "'inappropriate" for IV fosphenytoin use. We considered fosphenytoin use "appropriate" when any one of these criteria was not met. We used pharmacy records to identify all patients who received fosphenytoin in the ED between February 1997 and June 1999. The charts of these patients were retrospectively reviewed and abstracted for the aforementioned criteria. We report the number and percentage (with 95% confidence intervals [CI]) of patients who received fosphenytoin appropriately and inappropriately. When data are significantly skewed, medians and interquartile ranges are reported. Comparisons between groups were performed using a t-test for continuous data and chi-square tests for nominal data. This study was suitable for exemption from informed consent by the Committee for the Protection of Human Subjects by virtue of its retrospective nature and maintenance of strict anonymity. RESULTS During the study period, 55 patients were identified who had received fosphenytoin in the ED. Of these, 4 patients were felt to have had inadequate information documented to apply the criteria for appropriate use of fosphenytoin. To be conservative, we assumed these patients received the drug appropriately. The demographic data for these patients can be seen in Table 1. Table 2 shows the number of patients meeting our criteria for appropriate use of phenytoin. Thirty of 55 patients (55%) were deemed to have received fosphenytoin appropriately (95% CI 41%-68%). Conversely, 25 patients (45%, 95% CI 32%-59%) received fosphenytoin inappropriately. DISCUSSION Phenytoin acts primarily on the motor cortex to inhibit the spread of seizure activity. Because phenytoin has a long 293
294
AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 19, Number 4 • July 2001
TABLE 1. Demographic Data for Patients Receiving Fosphenytoin Inappropriately and Appropriately
Age (years, median) Male gender (%) Ethnicity (%) White African American (%) Other (%) Insurance (%) Private Medicaid (%) None (%) Prior seizure disorder (%)
Inappropriate Use
Appropriate Use
17 (IQR 33) 65
28 (IQR 29) 56
.69 .97
70 26 4
79 21 0
.28
48 36 16 72
45 32 23 69
.15
and somewhat variable "half-life" of approximately 22 hours, steady-state levels cannot be reached for a considerable length of time when using maintenance dosing. Therefore, loading doses are necessary to rapidly achieve therapeutic levels. The IV form of phenytoin has been associated with severe side effects including local tissue necrosis ("purple glove syndrome") 1. It is also associated with hypotension necessitating infusion rates of less than 50 mg/min. 1,2 At first glance, fosphenytoin appears to be an ideal substitute for IV phenytoin. It has a more physiologic pH and can be infused more rapidly. Unfortunately, fosphenytoin is more expensive than phenytoin, especially oral phenytoin. Our hospital charges $9.90 for 1,000 mg of oral phenytoin and $171.21 for 1,000 phenytoin equivalent units of fosphenytoin. In addition, because fosphenytoin is a prodrug that must be converted to phenytoin, therapeutic levels of phenytoin are reached no more quickly than with phenytoin loading. When compared with equal amounts of phenytoin infused at 50 mg/min, 15 to 20 phenytoin equivalent U/kg infused at 100 to 150 phenytoin equivalent U/h yield virtually identical concentrations of phenytoin over time. 8 Therefore, the main advantages of fosphenytoin are twofold: (1) less 1:1 nursing time because of speed of administration and (2) lack of tissue necrosis. Oral phenytoin loading is both safe and effective without associated hypotension, tissue necrosis, or the need for 1:1 nursing. In a study of 44 patients, a single 18 mg/kg dose of oral phenytoin resulted in a mean phenytoin level of 12.3 /xg/mL at 8 hours. Therapeutic levels of at least 10 tzg/mL TABLE 2. Patients Meeting Criteria for Administration of Fosphenytoin No.* Not awake and alert Vomiting Recurrent seizures/status epilepticus Endotracheal intubation
P Value
20 5 10 5
* The total number of patients meeting criteria was 26. The numbers listed add up to more than 26 because several patients met more than 1 criterion. Four more patients were missing complete documentation and were assumed to have received the drug appropriately.
.73
were reached in 57% of patients within 4 hours postloading. 6 There was minimal toxicity with this regimen. Only 2 patients had emesis and no ataxia was reported. In another study, a single dose of 15 mg/kg of oral phenytoin produced a therapeutic level of 10 tzg/mL in a mean time of 2.65 hours (standard deviation 1.25 hours). Higher doses (18.7 mg/kg in males and 24.8 mg/kg in females) produced therapeutic levels of 15/xg/mL in an average time of 2.04 hours in men and 2.35 hours in women. 7 The higher dose in women was due to an apparent larger volume of distribution. There were minimal side effects (4 of 14 with dizziness, ataxia, or tinnitus). Because this study was retrospective, its conclusions are limited by what is reported in the chart. We attempted to decrease the risk of recording bias by assuming patients without adequate information had received the drug appropriately. Because our institution is an urban, university hospital, it may be difficult to extrapolate our results to other settings. The rate of inappropriate use of fosphenytoin was 45% in this study from the ED of a single institution. Oral phenytoin loading in these patients would result in significant cost savings with no expected increase in adverse effects. Patients who have seized and are alert, not vomiting, not intubated, and not repeatedly seizing are candidates for oral phenytoin loading when it is believed this drug is indicated. Fosphenytoin should not be used in this situation. REFERENCES 1. Meek PD, Davis SN, Collins M, et al: Guidelines for nonemergency use of parenteral phenytoin products. Proceedings of an expert panel consensus process. Arch Intern Med 1999;159:2639-2644 2. Fierro LS, Savulich DH, Benezra DA: Safety of fosphenytoin sodium. Am J Health-Syst Pharm 1996;53:2707-2712 3. Labiner DM: Data vs opinion, phenytoin vs fosphenytoin. The saga continues. Arch Intern Med 1999;159:2631-2632 4. Horton MW, Godley PJ: Advocating single-dose phenytoin loading. Ann Emerg Med 1988;17:295-296 5. Jung D, Powell R, Walson P, Perrier D: Effect of dose on phenytoin absorption. Clin Pharmacol Ther 1980;28:479-485 6. Osborn HH, Zisfein J, Sparano R: Single-dose oral phenytoin loading. Ann Emerg Med 1987;16:407-412 7. Ratanakorn D, Kaojarern S, Phuapradit P, Mokkhavesa C: Single oral loading dose of phenytoin: A phamacokinetics study. J Neurol Sciences 1997;147:89-92. 8. Parke-Davis: Parke-Davis Product Information-Cerebyx, in Physicians Desk Reference (ed 52). Montvale, NJ, Medical Economics Company, Inc, 1998, pp 2077-2080
From the Department of Emergency Medicine, Vanderbilt University, Nashville, TN. Manuscript received January 12, 2001, accepted January 26, 2001. Address reprint requests to Keith Wrenn, MD, 703 Oxford House, Vanderbilt University Medical Center, Nashville, TN 37232-4700. Key Words: Anticonvulsants, fosphenytoin, phenytoin, seizures. Copyright © 2001 by W.B. Saunders Company 0735-6757/01/1904-0010535.00/0 doi:l 0.1053/ajem.2001.24471
lesce. 4,5 The rate at which therapeutic levels are obtained has to do with both the size of the dose and the repetitive intervals of dosing. 4,5 Nevertheless, oral loading is preferable in most patients with single seizures due to its low cost and safety profile. 6.7 We were interested in how often fosphenytoin was being used when it was possible to use oral phenytoin loading. METHODS A list of criteria was prospectively derived which we felt defined patients with seizures who were candidates for oral phenytoin loading. These criteria were (1) the patient was awake and alert on arrival, (2) there was no mention of emesis, (3) the patient had not been endotracheally intubated, and (4) there were no repeated seizures or status epilepticus after arrival in the emergency department (ED). All criteria had to be met for a patient to be considered a candidate for oral loading, which we considered "'inappropriate" for IV fosphenytoin use. We considered fosphenytoin use "appropriate" when any one of these criteria was not met. We used pharmacy records to identify all patients who received fosphenytoin in the ED between February 1997 and June 1999. The charts of these patients were retrospectively reviewed and abstracted for the aforementioned criteria. We report the number and percentage (with 95% confidence intervals [CI]) of patients who received fosphenytoin appropriately and inappropriately. When data are significantly skewed, medians and interquartile ranges are reported. Comparisons between groups were performed using a t-test for continuous data and chi-square tests for nominal data. This study was suitable for exemption from informed consent by the Committee for the Protection of Human Subjects by virtue of its retrospective nature and maintenance of strict anonymity. RESULTS During the study period, 55 patients were identified who had received fosphenytoin in the ED. Of these, 4 patients were felt to have had inadequate information documented to apply the criteria for appropriate use of fosphenytoin. To be conservative, we assumed these patients received the drug appropriately. The demographic data for these patients can be seen in Table 1. Table 2 shows the number of patients meeting our criteria for appropriate use of phenytoin. Thirty of 55 patients (55%) were deemed to have received fosphenytoin appropriately (95% CI 41%-68%). Conversely, 25 patients (45%, 95% CI 32%-59%) received fosphenytoin inappropriately. DISCUSSION Phenytoin acts primarily on the motor cortex to inhibit the spread of seizure activity. Because phenytoin has a long 293
294
AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 19, Number 4 • July 2001
TABLE 1. Demographic Data for Patients Receiving Fosphenytoin Inappropriately and Appropriately
Age (years, median) Male gender (%) Ethnicity (%) White African American (%) Other (%) Insurance (%) Private Medicaid (%) None (%) Prior seizure disorder (%)
Inappropriate Use
Appropriate Use
17 (IQR 33) 65
28 (IQR 29) 56
.69 .97
70 26 4
79 21 0
.28
48 36 16 72
45 32 23 69
.15
and somewhat variable "half-life" of approximately 22 hours, steady-state levels cannot be reached for a considerable length of time when using maintenance dosing. Therefore, loading doses are necessary to rapidly achieve therapeutic levels. The IV form of phenytoin has been associated with severe side effects including local tissue necrosis ("purple glove syndrome") 1. It is also associated with hypotension necessitating infusion rates of less than 50 mg/min. 1,2 At first glance, fosphenytoin appears to be an ideal substitute for IV phenytoin. It has a more physiologic pH and can be infused more rapidly. Unfortunately, fosphenytoin is more expensive than phenytoin, especially oral phenytoin. Our hospital charges $9.90 for 1,000 mg of oral phenytoin and $171.21 for 1,000 phenytoin equivalent units of fosphenytoin. In addition, because fosphenytoin is a prodrug that must be converted to phenytoin, therapeutic levels of phenytoin are reached no more quickly than with phenytoin loading. When compared with equal amounts of phenytoin infused at 50 mg/min, 15 to 20 phenytoin equivalent U/kg infused at 100 to 150 phenytoin equivalent U/h yield virtually identical concentrations of phenytoin over time. 8 Therefore, the main advantages of fosphenytoin are twofold: (1) less 1:1 nursing time because of speed of administration and (2) lack of tissue necrosis. Oral phenytoin loading is both safe and effective without associated hypotension, tissue necrosis, or the need for 1:1 nursing. In a study of 44 patients, a single 18 mg/kg dose of oral phenytoin resulted in a mean phenytoin level of 12.3 /xg/mL at 8 hours. Therapeutic levels of at least 10 tzg/mL TABLE 2. Patients Meeting Criteria for Administration of Fosphenytoin No.* Not awake and alert Vomiting Recurrent seizures/status epilepticus Endotracheal intubation
P Value
20 5 10 5
* The total number of patients meeting criteria was 26. The numbers listed add up to more than 26 because several patients met more than 1 criterion. Four more patients were missing complete documentation and were assumed to have received the drug appropriately.
.73
were reached in 57% of patients within 4 hours postloading. 6 There was minimal toxicity with this regimen. Only 2 patients had emesis and no ataxia was reported. In another study, a single dose of 15 mg/kg of oral phenytoin produced a therapeutic level of 10 tzg/mL in a mean time of 2.65 hours (standard deviation 1.25 hours). Higher doses (18.7 mg/kg in males and 24.8 mg/kg in females) produced therapeutic levels of 15/xg/mL in an average time of 2.04 hours in men and 2.35 hours in women. 7 The higher dose in women was due to an apparent larger volume of distribution. There were minimal side effects (4 of 14 with dizziness, ataxia, or tinnitus). Because this study was retrospective, its conclusions are limited by what is reported in the chart. We attempted to decrease the risk of recording bias by assuming patients without adequate information had received the drug appropriately. Because our institution is an urban, university hospital, it may be difficult to extrapolate our results to other settings. The rate of inappropriate use of fosphenytoin was 45% in this study from the ED of a single institution. Oral phenytoin loading in these patients would result in significant cost savings with no expected increase in adverse effects. Patients who have seized and are alert, not vomiting, not intubated, and not repeatedly seizing are candidates for oral phenytoin loading when it is believed this drug is indicated. Fosphenytoin should not be used in this situation. REFERENCES 1. Meek PD, Davis SN, Collins M, et al: Guidelines for nonemergency use of parenteral phenytoin products. Proceedings of an expert panel consensus process. Arch Intern Med 1999;159:2639-2644 2. Fierro LS, Savulich DH, Benezra DA: Safety of fosphenytoin sodium. Am J Health-Syst Pharm 1996;53:2707-2712 3. Labiner DM: Data vs opinion, phenytoin vs fosphenytoin. The saga continues. Arch Intern Med 1999;159:2631-2632 4. Horton MW, Godley PJ: Advocating single-dose phenytoin loading. Ann Emerg Med 1988;17:295-296 5. Jung D, Powell R, Walson P, Perrier D: Effect of dose on phenytoin absorption. Clin Pharmacol Ther 1980;28:479-485 6. Osborn HH, Zisfein J, Sparano R: Single-dose oral phenytoin loading. Ann Emerg Med 1987;16:407-412 7. Ratanakorn D, Kaojarern S, Phuapradit P, Mokkhavesa C: Single oral loading dose of phenytoin: A phamacokinetics study. J Neurol Sciences 1997;147:89-92. 8. Parke-Davis: Parke-Davis Product Information-Cerebyx, in Physicians Desk Reference (ed 52). Montvale, NJ, Medical Economics Company, Inc, 1998, pp 2077-2080