British Journal of Obstetrics and Gynaecology November 1992, Vol. 99, pp. 881-886

OBSTETRICS

The efficacy of phenytoin in relation to serum levels in severe pre-eclampsia and eclampsia S. N A I D U Registrar

J. MOODLEY Professor Department of Obstetrics and Gynaecology

J. B O T H A Senior Lecturer Department of Pharmacology Faculty of Medicine University of Natal Durban, South Africa

L. M c F A D Y E N Senior Lecturer Department of Pharmacology University of Durban-Westville South Africa

ABSTRACT Objectives To investigate the efficacy of phenytoin in relation to total and free serum levels in patients with severe pre-eclampsia and eclampsia. Design Prospective descriptive study. Setting Labour Ward, King Edward VIII Hospital, Durban, South Africa. Tertiary referral centre serving an underprivileged community. Subjects Eleven patients admitted with a hypertensive crisis. Four patients had eclampsia and 7 had impending eclampsia. Main outcome measures Free and total phenytoin levels; efficacy of phenytoin as an anticonvulsant and side-effects of therapy. Results Although total phenytoin levels were within the therapeutic range, free phenytoin levels were abnormally high in all patients. Three patients (2 with eclampsia and 1 with imminent eclampsia) each had a seizure after phenytoin treatment had been initiated. Conclusion Neither total nor free phenytoin levels were good predictors of seizure control. It is postulated that the poor performance of phenytoin as an anticonvulsant in severe eclampsia may relate to inadequate distribution of the drug to the brain as a result of cerebral oedema and poor cerebral perfusion rather than paradoxical seizure activity associated with high free phenytoin levels.

Phenytoin sodium is well recognized as a specific drug for the prevention and control of seizures in epilepsy. It acts centrally, and therapeutic levels are obtained rapidly after an intravenous load. Recent studies have advocated its use in the management of eclampsia and severe pre-eclampsia (Slater 1987; Ryan 1988; Coyaji & Otio 1990; Robson 1990). However, other reports have expressed caution in the widespread use of phenytoin before proper assessment, due to its apparent lack of efficacy in preventing seizures in eclampsia (Tuffnell 1989; Dommisse 1990), although in both of the last named studies, total serum phenytoin concentrations were within the usual therapeutic range. In eclampsia because of the hypoproteinaemia, elevated free levels could be expected to be associated with these normal total values. In view of this, the present study set out t o investigate the efficacy of phenytoin in relation to the serum levels achieved in patients with hypertensive crisis in pregnancy.

underprivileged community. In 1990, 14 258 women were delivered in this unit, of whom 126 (0.9%) were admitted with eclampsia. The study included 11 patients. All had eclampsia or impending eclampsia, i.e. hypertension and proteinuria with one of the following: persistent headaches; visual disturbances and epigastric pain; clonus andlor hyperreflexia. No patient was on phenytoin or magnesium sulphate before inclusion in the study and all patients were managed by conventional methods, which included a central venous pressure line to correct any hypovolaemia and lowering of high blood pressure with dihydralazine o r nifedipine when indicated as described previously by Moodley et al. (1983). Prophylactic phenytoin therapy was started and the patient was delivered when she was haemodynamically stable.

Subjects and methods

Haemoglobin, haematocrit and platelet count were measured and renal function was assessed by measurement of serum urea and electrolytes. Serum albumin levels were measured on admission and 24 h later.

This study was approved by the ethics committee of the University of Natal, and was conducted in the obstetric unit of King Edward VIII Hospital, Durban, South Africa (KEH). This is a large urban tertiary referral hospital serving an

Laboratory investigations

Drug administration Correspondence: J. Moodley, Department of Obstetrics & Gynaecology, Faculty of Medicine, P 0 Box 17039, Congella 4013, South Africa.

Each patient received a loading dose of 18 mg/kg body weight of phenytoin sodium (Epanutin, Parke-Davis) diluted

881

882 s.

N A I D U ET A L .

Table 1. Demographic and clinical details of patients. ~~~~

~

Patient no.

Age (years)

1 2 3* 4 5* 6 7 8 9 10 11*

30 22 18 26 21 32 23 23 28 21 32

Weight

0%) -

89 81 65 68 89 85 80 69 71 70

Gestation (weeks) 36 28 38 38 32 33 34 36 38 36 32

Admission Parity

Diagnosis

BP (mmHg)

0

Imm. eclampsia

0 0 0 2 1 1 0 3 0 4

Imm. eclampsia Eclampsia Imm. eclampsia Imm. eclampsia Eclampsia Imm. eclampsia Imm. eclampsia Eclampsia Imm. eclampsia Eclampsia

150190 2001130 150190 1901110 1801110 1701130 2101140 1601120 1301190 2001140 1701130

No. of seizures Proteinuria GCS before admission 3+ 3+ 3+ 4+ 4i 4+ 2i 3+ Nil 3+ 3+

15 15

-

15 15

2 -

15 15

-

15 15 13 15

-

13

-

2 -

1

3

*Indicatespatients who convulsed after phenytoin. Imm. eclampsia = imminent eclampsia: GCS = Glasgow coma scale: BP = blood pressure. in 200 ml of normal saline. Patients with impending eclampsia were weighed and for the eclamptic patients, the last recorded weight at the antenatal clinic was used. No infusion pumps were available at this institution, and the loading dose was infused as an intravenous ‘piggy-back arrangement’ over 15-20 min as described by Earnest et al. (1983). Maintenance doses of 6 mg/kg body weightlday were given intravenously in four divided doses every 6 h over 24 h.

Monitoring precautions During the infusion of phenytoin, the electrocardiogram (lead 11) was monitored visually for arrhythmias. The blood pressure was measured automatically approximately every 5 min (Dynamap, Critikon Inc. Tampa, Florida). O n e of the authors (S.N.) was present at each infusion, and the occurrence of all side-effects was recorded.

Phenytoin levels Serial blood sampling for total and free phenytoin levels was performed by venepuncture 30 min after completion of the loading dose, then every 2 h for 6 h and then every 6 h for 24 h. A single specimen was also taken at 48 h. In addition maternal blood for phenytoin levels was drawn at delivery Table 2. Obstetric outcome.

Mode of delivery

Birthweight (kg)

Neonatal outcome

1 2 3 4 5 6” 7

CIS NVD

Alive FSB Alive

8

NVD CIS

2.7 1.45 3.35 3.0 1.75 1.611.1 2.1 2.2 2.4 1.5 1.9

Patient no.

9 10 11

CIS CIS

CIS CIS

CIS CIS CIS

Alive

Alive AlivelFSB Alive Alive Alive FSB FSB

C/S=caesarean section; NVD=normal vaginal delivery; FSB=fresh stillbirth, *=twins.

and cord blood samples were obtained whenever possible. Blood was spun at 2000-3000 r.p.m. for 5 min to yield serum which was stored at -18°C.

Phenytoin assay Totalphenytoin levels. These were measured using the Cobas Mira (Roche) with reagents for the enzyme-multiplied immunoassay technique supplied by the Syva Company. Standard curves were generated weekly with a one point daily check. The co-efficient of variation for the assay was less than 10%. Freephenytoin levels. Prior to analysis, an ultrafiltrate containing free phenytoin had been obtained using an Amicon free-level filter (Amicon Corp., Danvers, Massachusetts) and centrifuging at 25°C. Free phenytoin levels were determined using the T D X Free Phenytoin immunoassay (FPIA) method. Since the binding of phenytoin to albumin is temperature-dependent and free phenytoin was separated at 25”C, a correction factor was necessary to correct to body temperatures: Free at 37°C = 0.166 + 1.190 x Free at 25°C (Coleman et al. 1984).

Results The demographic and clinical data are shown in Table 1.Two patients presented in labour and the remainder were not in labour. Four patients had eclampsia and the remainder, impending eclampsia. Three patients (two with eclampsia and one with imminent eclampsia) each had a seizure after phenytoin treatment had been initiated. These treatment failures are described below. The obstetric outcome is shown in Table 2. The two patients admitted in labour had vaginal deliveries and the remainder were delivered by caesarean section. Eight of the 12 babies (one set of twins) were born alive and there were four fresh stillbirths. Two patients (numbers 10, 11) were diagnosed as having intrauterine deaths on admission. The other two deaths (numbers 2, 6) were related to fetal immaturity. The phenytoin dosage regimen, maternal side-effects and serum albumin levels are shown in Table 3. Cardiovascular side-effects were hypotension ( n = 7), tachycardia ( n = 5) and arrhythmias ( n = 3). Sedation was experienced by all the

SERIJM LEVELS OF P H E N Y T O I N

883

IN ECLAMPSIA

Table 3. Phenytoin doses, albumin levels and maternal complications. Albumin levels W1)

Loading dose (mg) (infusion rate) (mgimin)

Maintenance dose (mgI6 h)

1 2

1200 (63) 1600 (73)

3 4

Patient no.

Hour 0

Hour 24

100 125

NIA

NIA

10

15

1400 (100) 1200 (30)

125 100

29 28

NIA

5

1200 (75)

100

NIA

NIA

6 7

1600 (36) 1600 (46)

100 100

24 16

NIA

8 9

1400 (47) 1200 (34)

100 100

23 21

28

10

1200 (60)

100

23

13

11

1300 (37)

120

26

13

Maternal complications Arrhythmia. sedation Nystagmus, sedation, hypotension (16011 15- 1401 90), restlessness, disorientation) Sedation Arrhythmias, tachycardia (140- 150), hypotension

18

(150190- 130164)

Sedation, nausea, restlessness, tachycardia (68- 126), hypotension (160197- 161187) Sedation Sedation, tachycardia, hypotension

21

(1 80/110+95/88)

15

Thrombophlebitis, sedation, tachycardia Sedation, hypotension (142/87+ 123169). tachycardia (110) Sedation, restlessness, tachycardia (98- 158), hypotension (198/125+154/95) Sedation, arrhythmia. hypotension (1771123- 1241 78) (subcapsular haemorrhage)

NIA=not available.

patients. Other neurological side-effects were restlessness in three patients and nystagmus in one patient. All these adverse events were transient and had no long term sequelae. Total phenytoin levels

within what is normally considered t o be the therapeutic range of 10 to 20 mg/l for at least 24 h and in many cases for up to 48 h after the loading infusion. Total phenytoin levels at delivery in maternal and cord serum are shown in Table 4. Free phenytoin concentrations

Immediately after termination of the initial infusion, average serum levels were 28 mg/l(l7-35 mg/l). This was followed in most patients by a rapid fall off in the first 4 h to average levels of 15.1 mg/l after four further doses of 100 o r 125 mg had been given serum levels were maintained at an average level of 13.4 and 12.4 mg/l at 12 h and 24 h respectively. Despite no further dosing after 24 h, total serum levels averaged 11.7 mg/l in nine patients in whom 48 h levels were available (range 7.6-16.6 mgil). Fig. 1is a graph of total phenytoin concentrations in the three patients ( 3 , s and 11) who experienced seizures after phenytoin administration. Fig. 2 shows total phenytoin concentrations in four of the patients ( 1 , 2 , 4 , 7 ) who did not have seizures. In most patients, the total serum phenytoin levels were

In people with normal albumin levels and normal renal function, the percentage of phenytoin which is unbound in the serum is consistently close to 10% at 37°C (Rall & Schleifer 1991). This equates to a therapeutic range for free phenytoin of 1 to 2 mg/l. In all seven patients in whom free phenytoin levels were measured, the temperature corrected free levels were above 2 mg/l at all times. A t certain times in some of the patients free levels were above 6 mgil. Figs. 3 and 4 show the free phenytoin levels for the three patients who experienced seizures subsequent to phenytoin administration and for four patients who did not. Table 4 shows the free levels in maternal serum and cord serum at the time of delivery.

-

30

40[ I

1

0

I

I

I

I

I

I

I

I

I

5

10

15

20

25

30

35

40

Time after infusion (h)

Fig. 1. Total phenytoin levels in patients who had seizures. patient 3: -0-, patient 5; -A-, patient 11.

0

I

-.-, 45

I

I

I

I

I

I

I

I

I

5

10

15

20

25

30

35

40

45

Time after infusion (h)

-.--,

Fig. 2. Total phenytoin levels in patients who did not have seizures. patient 1: -A- patient 7: --C patient, 4: patient

-+-, 2.

884 s. N A I D U Table 4.

ET A L .

Free and total phenytoin concentrations and free fraction (%) at delivery in maternal and umbilical cord serum. Total phenytoin (mm

Patient no.

Free phenytoin (mg/l)

Free fraction

("/.I

Maternal

Umbilical cord

Maternal

Umbilical cord

Maternal

Umbilical cord

9.1 16.3 15.9 12.2 14.7 8.7 17.2 16.6 15.0 9.9 9.4

8.3 11.1 15.0 14.7 15.5 10.4 16.6 22.7 14.3 10.2 *NA

2.83 4.18 2.96 3.24 3.26 NA 4.22 NA NA NA 3.33

2.83 4.40 2.68 345 2.75 NA 3.55 NA NA NA NA

31 26 19 27 22 NA 25 NA NA NA 35

34 40 18 21 18 NA 21 NA NA NA NA

1 2 3 4 5 6 7 8 9 10 11

*Stillbirth. NA = not assayed

In all seven patients in whom free levels were measured, the percentage of phenytoin which was free was around 20% on entry and increased further during the study, in one case to over 40%. The free fraction expressed as a percentage of total phenytoin concentration in most patients fluctuated between 15 and 30% during the 48 h of the study. In the case of patient 11,the albumin level which was 26 g/l at the start of dosing declined to 13 g/l at 24 h. The free phenytoin fraction which started at about 20%, increased after delivery (4.5 h) and reached a maximum of 48% at Y h. This patient's free levels were above the usually recognised therapeutic range for most of the study. A t the times that patients 3 , 5 and 11 experienced seizures their free levels were 3.2,4.2 and 3.7 mg/l respectively.

total phenytoin level was 17.4 mg/l (free phenytoin 3.2 mg/l) and her blood pressure was 150/90 mmHg at the time of the convulsion.

Description of lreatment failures

A 32-year-old multiparous woman was admitted after three convulsions. She had a blood pressure of 170/130 mmHg, proteinuria (3+) and was fully conscious. She had a convulsion 21 h after the loading dose of phenytoin of 1300 mg and 3 h after an intravenous maintenance dose of 120 mg. Her blood pressure was 140/105 mmHg and the maternal serum total phenytoin level was 12.0 mg/l (free phenytoin 3.7 mg/l) at the time of the convulsion.

Patient no. 3

A n 18-year-old primigravida was admitted after two convulsions at home. On admission her blood pressure was 150/ YO mmHg. She had proteinuria (3+) and was fully conscious. She had a convulsion 2 h and 15 min after an infusion of 1400 mg phenytoin given over 15 min. The maternal serum

0

I

I

I

I

I

I

I

I

I

I

5

10

15

20

25

30

35

40

45

Time after infusion (h)

Fig. 3. Free phenytoin levels in patients who had seizures. -W-, patient 3; -0-,

patient 5; -A-,

patient 11.

Patient no. 5

A 21-year-old multiparous woman was admitted with a diagnosis of imminent eclampsia. She had a blood pressure of 180/ 110 mmHg and proteinuria (4+). She had a convulsion 30 min after the infusion of 1200 mg phenytoin given over 15 min. The maternal serum total phenytoin level was 23.4 mg/l (free phenytoin 4.2 mg/l) and her blood pressure was 160/ 97 mmHg at the time of the convulsion. Patient no. 1I

0

I

I

I

I

I

I

I

I

I

5

10

15

20

25

30

35

40

45

Time after infusion ( h )

Fig. 4. Free phenytoin levels in patients who did not have seizures.

-+-, n

L.

patient 1; -A-,

patient 7; --C, patient 4; -m-,

patient

S E R U M L E V E L S O F P H E N Y T O I N i~ E C L A M P S I A

Discussion Although recent studies have suggested phenytoin as a useful anticonvulsant for eclampsia, its use has not been fully assessed. In a randomised study comparing phenytoin with magnesium sulphate, Dommisse (1990) reported that phenytoin sodium was not an effective anticonvulsant in 4 of 11 patients with eclampsia. In addition, Tuffnell (1989) showed that 3 of 18 patients had further convulsions despite phenytoin prophylaxis. In both studies, the treatment failures had total phenytoin serum levels within the therapeutic range and no explanation was advanced for the lack of efficacy of phenytoin in these patients. Likewise, in the present study, despite total serum concentrations within or very close to the therapeutic range, 3 of 1 1 patients still had seizures. Is it possible that eclamptic seizures may be more difficult to control with phenytoin than other seizures? Eclampsia, with its profound metabolic, haemodynamic and biochemical changes may present a similar picture t o that of a patient critically ill as a result of cerebral trauma. Young etal. (1983) found that there was no difference in the percentage of patients having seizures in the first week after head injury in a group receiving placebo and a group receiving phenytoin despite more than 78% of serum levels being over 10 mgil. They suggest that levels of 25 to 30 mgil are often necessary to control early seizures in this situation. In eclampsia, Coyaji & Otio (1990) have shown a relation between severity of eclampsia and serum levels of phenytoin and its anticonvulsant efficacy. In their group of mild eclamptics, two patients with levels less than 10 mg/l had convulsions, whereas levels of greater than 10 mgil in 11 patients resulted in a 100°/o early seizure control. In severe eclampsia, levels of more than 10 mg/l achieved only a 40% success rate in immediate seizure control. It is interesting to note that two of three patients who had a fit during infusion in the present study had already had eclampsia before treatment. As phenytoin is highly bound to plasma protein, it is the free fraction which is actually able to leave the plasma compartment and exert an effect. Under normal circumstances, approximately 10% of the phenytoin in the plasma is free and thus the optimal free concentration associated with seizure control is between 1 and 2 mgil. In the present study, because of the hypoproteinaemia associated with eclampsia, free levels were much higher than normal and should have been more than sufficient for seizure control. In fact, because the levels of 3.2,3.7 and 4.2 mgil recorded at the time of the fit in the three treatment failures were all above the upper limit of normal, we considered the possibility that these high free levels may have caused the seizures. In reality, the frequency of seizures as a result of phenytoin toxicity appears to be fairly low. While some authors (Stilman & Masden 1985) have suggested an incidence of about l o % , Osorio et al. (1989) found that the figure was much lower (about 2%). It is thus unlikely that the seizures in the present study were associated with high free phenytoin levels. In any case, free levels were equally high in the patients who did not have a fit. It is possible, that despite adequate plasma phenytoin levels , amounts in the brain may be insufficient. Sironi et al. (1 980) cite Sherwin etal. (1973) to support the possibility that seizure activity may be associated with low brain levels of

885

phenytoin. However, Sironi et al. (1980), using gas chromatography to measure phenytoin levels in the brains of medically uncontrolled epileptics, found that although levels were therapeutic or greater, phenytoin was pharmacologically ineffective. Obviously efficacy must eventually depend on how much free phenytoin gets to the site of action and therefore brain binding of phenytoin as well as regional blood flow will be important. Patients with severe eclampsia have cerebral oedema and decreased cerebral perfusion which may interfere with drug distribution in the brain, thus leading to poor control of convulsions despite high serum levels of phenytoin. O n the other hand, patients with severe pre-eclampsia have little o r no oedema and better cerebral perfusion and therefore phenytoin may be more effective in these patients. This hypothesis is supported by the fact that phenytoin has been less successful in severe eclamptics (Coyaji & Otio 1990; Dommisse 1990; Tuffnell et al. 1989; and the present study) than in mild eclamptics (Coyaji & Otio 1990), and in studies where patients were predominantly severe pre-eclamptics (Slater et al. 1987; Ryan et al. 1989, and the present study). It is well known that individual epileptics vary in their response to phenytoin and that the so-called therapeutic range of 10 to 20 mg/l is only a guide. The present study has shown that in eclampsia, despite total levels in the therapeutic range, free levels are much higher and that neither are good predictors of seizure control. The side-effects (hypotension, tachycardia, sedation), noted during the administration of the initial infusion, are recognised complications of administering phenytoin in small volumes at a relatively rapid rate (Earnest et al. 1983). No serious irreversible complications were observed. Some of these complications could probably be avoided with the use of infusion pumps where the rate could be accurately controlled. We conclude that although high free levels of phenytoin were achieved in patients with hypertensive crisis, monitoring of neither total nor free levels is a good predictor of seizure control. It appears that phenytoin is more useful as an anticonvulsant in severe pre-eclampsia and mild eclampsia than in severe eclampsia. Lack of efficacy in the latter may be a result of altered drug distribution of phenytoin in the brain due to cerebral oedema and poor cerebral perfusion.

References Coyaji K. J. & Otio S. R. (1990) Single high dose of intravenous phenytoin sodium for the treatment of eclampsia. Actu Obstet Gynaecol Scand 69,115-118. Coleman R. W., Krewsun I. & Kelber R.L. (1984) Single feedback Bayerian forecasts with free and total phenytoin concentrations. Clin Pharmacokinet 9 (suppl), 90-92. Dommisse J. (1990) Phenytoin sodium and magnesium sulphate in the management of eclampsia. Br J Obstet Gynaecol97,99-101. Earnest M. €?, Marx J. A. & Drury L. R. (1983) Complications of intravenous phenytoin for acute treatment of seizures. JAMA 249,762-765. Moodley J., Naicker R. S. & Mankowitz E. (1983) Eclampsia-a method of management. S Afr Med J 63,530-535. Osorio I., Burnstine T. H., Remler B., Manon-Espaillat R. & Reed R. C. (1989) Phenytoin induced seizures: a paradoxical effect at toxic concentrations in epileptic patients. Epilepsia 30 (2), 230-234.

886 s .

N A I D U ET A L

Rall T. W. & Schleifer L. S. (1991) Drugs effective in the therapy of the epilepsies. In Goodman and Gilman’s: The pharmacological basis of therapeutics (8th edition), Pergamon Press, New York, Oxford, p. 441. Robson S. C., Walkinshaw S., Redfern N., De Swiet M. & Rodeck C. (1 990) Seizure prophylaxis using phenytoin in severe pre-eclampsia and eclampsia. J Obstet Gynuecol 10,449-490. Ryan G., Lange I. 13. & Naugler M. A. (1989) Clinical experience with phenytoin prophylaxis in severe pre-eclampsia. A m J Obstet Gynecol161,1297-1304. Sherwin A. L., Eisen A. A. & Sokolowski C. D. (1973) Anticonvulsant drugs in human epileptogenic brain. Correlation of phenobarbital and diphenylhydantoin levels with plasma. Arch Neurol 29,73-77. Sironi V. A,, Cabrini G., Porrow M. G., Ravagnati L. & Marossero F.

(1980) Antiepileptic drug distribution in cerebral cortex. Ammon’s horn and amydala in man. J Neiirosurg 52,686-692. Slater R. I. A,, Wilcox F. L., Smith D. W., et al. (1987) Phenytoin infusion in severe pre-eclampsia. Lancet i, 1417-1421. Stilman N. & Masden J. C. (1985) Incidence of seizures with phenytoin toxicity. Neurology 35,1769-1772. Tuffnell D., O’Donovan P., Lilford R. J., Prys-Davies A. & Thornton J. G. (1989) Phenytoin in pre-eclampsia. Lancet ii, 273-274. Young B., Rapp R. P., Norton J. A,, Haack D., Tibbs P. A. & Bean J. R. (1983) Failure of prophylactically administered phenytoin to prevent early post-traumatic seizures. J Neurosurg 58,231-235.

Received 13 Junuury 1992 Accepted 30 March 1992