Timing of maintenance phenytoin therapy after intravenous loading dose

Timing of Maintenance Phenytoin Therapy After Intravenous Loading Dose J a m e s J. R i v i e l l o , Jr, M D , E u g e n e J. R o e , Jr, M D , J o y c e I. S a p i n , M D , a n d W a r r e n D. G r o v e r , M D

The specific timing of maintenance phenytoin therapy in children has not been addressed. Prevention of a subtherapeutic phenytoin level is important for seizure control. We devised a protocol using an 18 mg/kg loading dose of phenytoin with serial levels (obtained after 2,6,12 hours) and analyzed the results in 20 consecutive patients. A therapeutic level (> 10 ~tg/ml) was present in all patients at 2 hours, in 16 of 20 at 6 hours, and in 10 of 20 at 12 hours. The patients were divided into 2 groups by the 12-hour levels: group h therapeutic level; and group Ih subtherapeutic level. The mean 2-hour level in group I was 22.7 Bg/ml versus 15.6 ~tg/ml in group II (P < 0.001). The mean decline in plasma concentration in individual patients was 0.7 ~tg/ml/hr in group I versus 1.02 ~tg/ml/hr in group II (P < 0.05). We now use the 2-hour level to decide the timing of maintenance phenytoin therapy and have devised an equation to estimate the duration of the therapeutic range. Phenytoin can be administered at 12 hours when the 2-hour level is satisfactory or earlier when the 2-hour level indicates that a subtherapeutic level will occur. Riviello JJ Jr, Roe EJ Jr, Sapin JI, Grover WD. Timing of maintenance phenytoin therapy after intravenous loading dose. Pediatr Neurol 1991;7:262-5.

Introduction In the treatment of status epilepticus or frequent, recurrent seizures, phenytoin (PHT) is a valuable agent used either alone [1-3] or in combination with a benzodiazepine [4]. The administration of PHT via an intravenous loading dose (LD) will rapidly achieve a therapeutic level without the sedation or respiratory depression observed with other antiepileptic drugs [5]. An additional advantage of PHT is that it may also be used for maintenance therapy. Prevention of recurrent seizures following the termination of status epilepticus or frequent seizures may require the maintenance of a therapeutic antiepileptic drug level. In adult studies, a PHT LD from 13-18 mg/kg has maintained a therapeutic level for at least 12-24 hours [5-7]. In

From the Section of Child Neurology, Departments of Pediatrics and Neurology; Temple University School of Medicine; and St. Christopher's Hospital for Children; Philadelphia, Pennsylvania.

262

PEDIATRIC NEUROLOGY

Vol. 7 No. 4

studies in children, both the initial LD of PHT and the timing of the PHT levels have varied [8-10]. In addition, the specific timing of maintenance therapy has not been addressed. We devised a protocol using serial PHT levels, obtained at specific intervals following a constant LD, to prevent a subtherapeutic PHT level and to determine the timing of maintenance therapy. We present our analysis of the data in 20 consecutive patients.

Methods An 18 mg/kg intravenous LD of PHT in a solution of 0.9% normal saline, administered no faster than 1 mg/kg/min (maximum rate: 25 mg/min), was used to treat status epilepticus, frequent, recurrent seizures, or symptomatic seizures. Patients with status epilepticus were treated with diazepam and PHT. Care was taken to ensure an adequate intravenous site prior to infusion. The heart rate was monitored continuously by electrocardiogram rhythm strip and blood pressure was taken periodically during the infusion. Serum PHT levels were obtained at 2, 6, and 12 hours following the initial LD. The 2-hour level was chosen to avoid obtaining the level during the initial rapid distribution phase [10]. The therapeutic range (TR), 10-20 lag/ml, was divided into a high (16.7-20.0 ~tg/ml), mid (13.3-16.6 ~tg/ml), or low (10.0-13.2 Bg/ml) zone. PHT levels were determined by fluorescence polarization antibody (Abbott TDx). A PHT dose of 5 mg/kg/day in 2 divided doses was used when maintenance PHT was needed. The initiation of maintenance therapy was planned for 12 hours after the LD unless a 2- or 6-hour level was in the low TR range or below. When this occurred, additional PHT was administered and no subsequent levels were obtained in accordance with this protocol. The Student t test was used for determining the significance of continuous variables.

Results Five patients presented with febrile status epilepticus, 3 had seizures associated with meningitis, 2 had new-onset status epilepticus, 2 had seizures secondary to an anoxic encephalopathy related to near-drowning, and 8 had previously treated epilepsy. Table 1 presents the number of PHT levels in each portion of the TR (above, within, and below) at the specific time intervals. The mean PHT level at 2 hours (N = 20) was 19.1 + 5.0 ~tg/ml (mean + S.D.), at 6 hours (N = 18) 15.7 + 4.4 ~tg/ml, and at 12 hours (N -- 14) 13.4 + 4.5

Communications should be addressed to: Dr. Riviello; Section of Pediatric Neurology; Maine Medical Center; Park Medical Building; 180 Park Avenue; Portland, ME 04102. Received January 10, 1991; accepted February 26, 1991.

gg/ml. A therapeutic level was present in all patients at 2 hours, in 16 of 20 (80%) at 6 hours, and in only 10 of 20 (50%) at 12 hours. The mean PHT levels at 6 and 12 hours do not include 2 patients at 6 hours and 4 additional patients at 12 hours who had received additional PHT because their previous PHT levels had been in either the low therapeutic or subtherapeutic range. T h e patients were divided into 2 groups by the 12-hour PHT level: group I had a therapeutic level (> 10 ~tg/ml) and group II a subtherapeutic level (< 10 gg/ml). Tables 2 and 3 present the results in individual patients in each group. The mean 2-hour level in group I was 22.7 + 3.1 gg/ml (mean + S.D.) and in group II was 15.6 _+3.8 ~tg/ml (T = 4.5; P < 0.001; df 18). The mean 12-hour level in group ! was 15.7 + 3.1 ~tg/ml and in group II was 7.8 _+2.0 gg/ml (T = 5.0; P < 0.001; df 12). The mean age in group I was 4.8 years versus 1.7 years in group II. This difference was not significant; therefore, the 2-hour PHT level was predictive of a therapeutic level at 12 hours. The decline in the mean plasma PHT concentration (calculated by the difference between the mean 2-hour and mean 12-hour levels/time difference) was determined separately for all patients, for groups I and II, and for the individual patients within groups 1 and II. The mean decline for all patients was 0.57 gg/ml/hr (Table 1). The decline in mean plasma PHT concentration for group I was 0.7 lag/ml/hr (Table 2) versus 0.78 gg/ml/br in group II (Table 3). This difference was not significant; however, the mean decline in plasma concentration for individual patients within group I (N = 10) and group II (N = 8; calculated by the difference between the 2 PHT levels in each patient divided by the time difference) was 0.7 gg/ml/hr in group I versus 1.02 lag/ml/hr in group II (T = 2.2; P < 0.05; df 16). Patients 5 and 9 in group II had only a single 2-hour level done and an individual decline in plasma concentration could not be calculated. No patient had recurrent seizures. As previously noted, 2 patients in group II received additional PHT and had no further levels as per this protocol. Neither had been on previous maintenance medications. Five patients in group I and 3 in group II had been receiving medications (Table 4).

Table I.

PHT levels in various portions of the therapeutic range

2 Hours

Time after Loading Dose 6 Hours 12 Hours

PHT Levels: > 2(1 gg]ml

11

2

1

16.7-20

2

7

2

13.3-16.6

3

2

6

10.0-13.2

4

5

I

<10

0

2

4

2(1

18

14

0

2

6

19.1 _+5.0 11.1 - 28.7

15.7 + 4.4 9.0 25.5

13.4 _+4.5 5.0 - 21.7

N Removed* Mean i S.D. Range

* Indicates additionalPHT was administeredbecause of a previously

low level.

to achieve a level of 10 ~g/ml for longer than 12 hours [6]. Cranford et al. reported a therapeutic PHT Level in 23 of 28 adult patients 24 hours after 18 mg/kg of PHT; the PHT level at 24 hours was dose-dependent, with the mean level increasing from 7.1-15.0 lag/ml as the LD was increased from 12-18 mg/kg [7]. They concluded that PHT d o s e s based on body weight resulted in a narrower and more predictable range of serum levels. Wilder et al. found lhat the mean PHT level was 10.2 ~tg/ml 12 hours after the

Table 2.

Group h Therapeutic PHT levels*

Pt. No.

Pt. Age

PHT Level at 2 Hours

PHT Level at 6 Hours

PHT Level at 12 Hours

1

2 yrs

20.4

18.7

17.6

2

22 mos

20.3

13.2

I I. 1

3

11 yrs

26.2

17.6

14.7

4

21 mos

21.6

18.7

14.9

Discussion

5

13 mos

23.5

2(t.3

17.5

This protocol was devised to prevent a subtherapeutic PHT level after several patients with symptomatic seizures had a recurrence of seizure activity within 12 hours following an initial 18 mg/kg LD and had a subtherapeutic PHT level. Our analysis of the first 20 patients revealed that a therapeutic level was present at 2 hours in all patients; however, that number declined to 16 of 20 (80%) at 6 hours and only 10 of 20 (50%) at 12 hours. Of special interest, the 2-hour post-LD level was predictive of a therapeutic level at 12 hours. A therapeutic level up to 24 hours has been reported in adults following an initial LD of PHT. Wallis et al. used a combination of intravenous, intramuscular, and oral PHT

6

5 mos

2(/.9

19.9

15.7

7

16 yrs

18.0

16.8

16.0

8

1 mo

23.4

18.2

13.6

9

4 yrs

23.9

18.9

14.0

10

10 yrs

28.7

25.5

21.7

Mean

4.8

22.7

18.8

15.7

Median

1.9

22.5

18.7

15.3

S.D.

5.5

3.1

3.1

2.8

* > 10 Bg/mlat 12 hours.

Rivielloet al: MaintenancePhenytoinTherapy 263

Table 3.

Group I1: Subtherapeutic PHT level*

Pt. No.

Pt. Age

PHT Level at 2 Hours

PHT Level at 6 Hours

PHT Level at 12 Hours

1

16mos

16.0

11.8

ND

2

11 mos

18.3

14.4

8.9

3

15 mos

22.1

15.0

9.4

4

4 yrs

14.8

10.8

ND

5

8 mos

12.9

ND

ND

6

3 mos

21.0

11.4

5.0

7

9 mos

12.8

9.7

ND

8

7 yrs

11.3

9.0

7.8

9

5 mos

11.1

ND

ND

10

4 mos

15.5

12.9

ND

Mean

1.7

15.6

11.9

7.8

Median

0.8

15.2

11.6

8.4

S.D.

2.2

3.8

2.1

2.0

* < 10 ~tg/mlat 12 hours. Abbreviation: ND = Not done

infusion of 13 mg/kg, with the TR present in 9 of 14 patients [5]. Only 2 previous studies in children evaluated the use of intravenous LD of PHT for either status epilepticus or recurrent seizures. Albani administered an average of 31.5 mg/kg (range: 18.2-46.1 mg/kg) in 3 divided doses (during the first 24 hours) and obtained a level prior to the first dose the next day [8,9]. Higher doses were necessary to maintain a therapeutic level in those infants. In a study of the kinetics of intravenous PHT in children, Koren et al. administered a single dose of PHT ranging from 9.4-21.3

Table 4. Patient Number

Patients receiving chronic medications

Group

Medication

1

I

Tbeophylline

2

I

Carbamazepine

3

I

Carbamazepine/haloperidol

7

I

Valproic acid

10

I

Carbamazepine

1

II

Lorazepam

3

II

Phenobarbital

7

It

Valproic acid/clonazepam

264 PEDIATRIC NEUROLOGY Vol.7 No. 4

mg/kg in 24 patients and obtained serum levels at various times over 24 hours [10]. They found that a therapeutic level was present for more than 10 hours in only 15 of 24 patients and the volume of distribution significantly declined with age. They suggested an age-adjusted LD, using 18 mg/kg below age 5 years and 10 mg/kg above age 8 years of age. Our findings using a standard single intravenous LD suggest that this dosage may not be adequate because 50% of our patients had a subtherapeutic level by 12 hours. Differences in PHT metabolism between adults and children that result in a more rapid elimination in children include an increased volume of distribution, enhanced drug metabolism, and decreased protein binding. With increasing age, both the volume of distribution and drug metabolism decrease and protein binding increases [10, 11 ]. In our patients, the mean decline in plasma concentration for individual patients was 1.02 ~tg/ml/hr in group II versus 0.7 ~tg/ml/hr in group I, and the mean age was 1.7 years in group II versus 4.8 years in group I. The mean decline in serum PHT was faster in group II, in which the patients were younger, although the age difference was not statistically significant. Our original protocol, which was designed to prevent a subtherapeutic PHT level, divided the TR into zones to decide whether additional PHT was necessary. Following this analysis, we have since discarded the arbitrary subdivision of the TR and now use the 2-hour post-LD level to estimate the duration of the TR by the following equation: Time (hours)

=

2-hour level (~g/ml) - 10 ~tg/ml mean decline in PHT concentration (gg/ml/hr)

This equation estimates the duration, in hours, of a therapeutic PHT level using 10 ~tg/ml as the lower limit of the TR. We used the mean decline in individual patients for this equation which may vary depending on patient age: 1.02 ~tg/ml/hr in group II, in which the patients were younger, and 0.7 gg/ml/hr in group I. For example, with a 2-hour post-LD level of 22.7 ~tg/ml (mean value for group I), the duration of a therapeutic level would vary from 12.5-16.3 hours, depending on patient age; with a 2-hour post-LD level of 15.6 gg/ml (mean value for group II), the duration of a therapeutic level would vary from 5.5-7.2 hours. PHT begun before this should maintain a therapeutic level. We caution that this equation is only a guideline for estimating the duration of a therapeutic level and assumes a constant decline in the serum concentration of PHT; however, nonlinear, dose-dependent saturation kinetics have been demonstrated in PHT metabolism [ 12,13]. We cannot claim that the use of our protocol resulted in the absence of seizure recurrence because diazepam was used in combination with PHT to control status epilepticus and patients with epilepsy had been previously treated with maintenance antiepileptic drugs. Our protocol was originally designed and subsequently modified to prevent a subtherapeutic PHT level in the acute situation. Avoiding

a subtherapeutic P H T level should result in better seizure control, although a larger study with a h o m o g e n e o u s group o f patients w o u l d be necessary to p r o v e this. The advantages o f P H T include the absence o f sedation or respiratory depression f o l l o w i n g an intravenous LD; h o w e v e r , P H T m a y cause phlebitis and cardiovascular complications. It is also unstable and may crystallize and precipitate in various diluents, including dextrose. Phlebitis is related to the size and patency of the injected vein and the P H T concentration o f the solution. The intravenous access site should be functioning well because extravasation of P H T may cause tissue injury. In 200 adult patients, Earnest et al. reported 29 instances o f a c o m p l a i n t o f burning at the injection site which r e s o l v e d f o l l o w i n g a decrease in the infusion rate [14]. T h e y suggested that a P H T concentration of less than 6.7 m g / m l o f diluent fluid, administered no faster than 40 m g / m i n through a freeflowing, well-positioned needle should m i n i m i z e complications. We do not infuse P H T through scalp veins and only administer it in 0.9% normal saline. Cardiovascular complications o f P H T include either arrhythmias or myocardial depression with hypotension. In the series by Earnest et al., 7 patients d e v e l o p e d hypotension or arrhythmias, controlled by decreasing the infusion rate [14]. In the series by Cranford et al., hypotension invariably responded to a decrease in the infusion rate [7]. B e c a u s e cardiovascular toxicity is related to the rapidity o f injection, we do not e x c e e d the r e c o m m e n d e d rate of 1 m g / k g / m i n [8,9]. In addition, we prefer other antiepileptic drugs in patients with cardiac disease, especially in the perioperative period. We r e c o m m e n d using a 2-hour p o s t - L D P H T level to d e t e r m i n e the timing of m a i n t e n a n c e P H T therapy following an intravenous dose of 18 mg/kg. M a i n t e n a n c e P H T can be administered at 12 hours w h e n the 2-hour level is satisfactory. Alternatively, when the 2-hour level suggests that a subtherapeutic level may be present at 12 hours, the duration of a therapeutic level m a y be estimated and maintenance P H T b e g u n before this level is reached.

References

[1] Wilder BJ. Efficacy of phenytoin in treatment of status epilepticus. In: Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status epilepticus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;441-6. [2] Leppik IE, Patrick BK, Cranford RE. Treatment of acute seizures and status epilepticus with intravenous phenytoin. In: DelgadoEscueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status epileptitus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;447-51. [3] Lockman LA. Status epilepticus. In: Morselli PL, Pippenger CE, Penry JK, eds. Antiepileptic drug therapy in pediatrics. New York: Raven Press, 1983;173-9. [4] Delgado-Escueta AV, Enrile-Bascal F. Combination therapy for status epilepticus: Intravenous diazepam and phenytoin. In: DelgadoEscueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds. Status epilepticus: Mechanisms of brain damage and treatment. New York: Raven Press, 1983;477-85. [5] Wilder BJ, Ramsay RE, Willmore LJ, Feussner GF, Perchalski RJ, Shumate JB. Efficacy of intravenous phenytoin in the treatmenl of status epilepticus: Kinetics of central nervous system penetration. Ann Neurol 1977;1:511-8. [6] Wallis W, Kutt H, McDowell E intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology 1968;18:513-25. [7] Cranfnrd RE, Leppik IE, Patrick B, Anderson CB, Kostick B. Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology 1978;28:874-80. [8] Albani M. An effective dose schedule for phenytoin treatment of status epilepticus in infancy and childhood. Neuropaediatrie 1977;8: 286-92. [9] Albani M. How to use phenytoin. In: Morselli PL, Pippenger CE, Penry JK, eds. Antiepileptic drug therapy in pediatrics. New York: Raven Press, 1983;253-62. [10] Koren G, Brand N, Halkin H, Dany S, Shahar E, Barzilay Z. Kinetics of intravenous phenytoin in children. Pediatr Phamlacol 1984; 4:31-8. [11] Woodbury DM. Phenytoin: Absorption, distribution, and excretion. In: Wnodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs, 2nd ed. New York: Raven Press, 1982;191-207. [12] Dodson WE. Phenytoin elimination in childhood: Effect of concentration-dependent kinetics. Neurology 1980;30:196-9. [13] Dodson WE. Nonlinear kinetics of phenytoin in children. Neurology 1982;32:42-8. [14] Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures. JAMA 1983;249: 762-5.

Riviello et al: Maintenance Phenytoin Therapy 265