The Efficacy of Intravenous Sodium Valproate and Phenytoin As The First-Line Treatment in Status Epilepticus: A Comparison Study
The Efficacy of Intravenous Sodium Valproate and Phenytoin As The First-Line Treatment in Status Epilepticus: A Comparison Study
The Efficacy of Intravenous Sodium Valproate and Phenytoin As The First-Line Treatment in Status Epilepticus: A Comparison Study
RESEARCH ARTICLE
Open Access
Abstract
Background: Status epilepticus (SE) is a serious neurological condition and requires prompt treatment. Sodium
valproate has been used to treat SE successfully but its role as the first-line antiepileptic drug (AED) is still
controversial. This study evaluated the efficacy of intravenous sodium valproate to determine if it is non-inferior to
intravenous phenytoin in SE treatment.
Methods: Patients diagnosed as SE during 20032010 who were of an age of more than 15 years and received
either intravenous sodium valproate or intravenous phenytoin as the first-line treatment were enrolled. Clinical
characteristics and outcomes of SE were recorded and analyzed. The differences of outcomes between sodium
valproate and phenytoin group were determined by descriptive statistics.
Results: During the study period, there were 37 and 17 SE patients who received intravenous phenytoin and
intravenous sodium valproate as the first-line treatment, respectively. All patients received diazepam 10 mg
intravenously as a rescue medication before starting the antiepileptic agents if uncontrolled except one patient in
the sodium valproate group. There were no significant differences between the phenytoin and sodium valproate
groups in all outcome variables including numbers of patients with clinically-controlled seizures, non-dependent
patients, time to seizure control, and duration of hospitalization, and death. No serious cardiovasculars event such
as hypotension occurred in either group.
Conclusion: Intravenous sodium valproate is non-inferior to intravenous phenytoin as the first-line treatment in SE
with no significant cardiovascular compromises.
Keywords: Phenytoin, Sodium valproate, Efficacy, Status epilepticus, Comparison
Background
Status epilepticus (SE) is an emergency condition that
requires proper and prompt treatment to prevent morbidity and mortality. Intravenous phenytoin is a main medication to treat SE. Recent and new antiepileptic drugs (AED)
such as sodium valproate, lacosamide, levetiracetam or
topiramate have potential benefits in treatment of SE [1-4].
Previous studies showed that intravenous sodium valproate may be a potential AED to be effective in SE [1,5].
It may be used as the first-line AED in SE with a good
seizure control [5]. Unlike phenytoin [6-8], sodium
* Correspondence: [email protected]
1
Department of Medicine, Faculty of Medicine, Integrated Epilepsy Research
Group, Khon Kaen University, Khon Kaen, Thailand
2
Department of Medicine, Faculty of Medicine, Khon Kaen University, 123
Mitraparp Road, Khon Kaen 40002, Thailand
2013 Tiamkao et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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Methods
SE patients treated at Srinagarind Hospital, Khon Kaen
University, Thailand between 2003 and 2010 were enrolled.
The inclusion criteria were patients with an age of more
than 15 years and received either intravenous phenytoin
or intravenous sodium valproate as the first-line treatment.
Status epilepticus (SE) is a condition with persistent
seizure more than 5 minutes or the patient does not gain
the consciousness during the interictal period [13]. Generalized convulsive SE is defined as recurrent convulsive
seizures that may be overt or subtle, symmetric or asymmetric, and are associated with profound coma and bilateral, although often has asymmetric, ictal discharges
on electroencephalogram (EEG) [14]. Non-convulsive SE
is defined as SE with a change in behavior and/or mental
processes from baseline associated or associated with
continuous epileptiform discharges in the EEG or in response to treatment [15].
Data were retrieved from medical records including
baseline characteristics, previous medical illnesses, causes
of SE, laboratory findings, numbers of AED usage, and
outcomes of treatment. The outcomes of treatment were
numbers of patients with clinically-controlled seizure, time
Table 1 Baseline characteristics of status epilepticus (SE) patients treated with intravenous phenytoin or intravenous
sodium valproate as the first-line treatment
Variables
Phenytoin group N = 37
Sodium valproate N = 17
p value
Age;(years)
40 (1685)
42 (1676)
0.852
17 (45.95)
10 (58.82)
0.379
5 (13.51)
3 (17.65)
0.696
6 (16.22)
7 (41.18)
0.084
4 (10.81)
5 (29.41)
0.121
14 (37.84)
6 (35.29)
1.000
37 (100)
16 (94.12)
0.315
Weight (kgs)*
55.5 (4075)
50 (3997.5)
0.343
5 (590)
10 (535)
0.127
28 (75.68)
17 (100)
0.177
31 (15.6-45.7)
36.5 (2649.4)
0.273
Laboratory findings
Hematocrit, g/dL*
3
11610 (410029700)
8965 (110014500)
0.168
127 (37568)
131 (73251)
0.926
1 (0.5-6.1)
0.9 (0.5-7)
0.445
8.4 (5.3-10.2)
8.2 (0.9-10.7)
0.976
3.3 (1.2-7.4)
4.0 (2.2-5.1)
0.072
ALT, U/L*
30 (5375)
18 (4165)
0.242
AST, U/L*
56 (11473)
25.5 (0.3-2.2)
0.115
276 (541500)
174.5 (44500)
0.396
17 (58.62)
7 (53.85)
1.000
Electroencephalogram, N*
9 (24.32)
5 (29.42)
0.745
Note. Data presented as median (range) or number (percentage), Data in phenytoin or sodium valproate group may not equal to 37 or 17, respectively due to
missing data, ALT serum alanine transaminase, AST serum aspartate transaminase, CT computed tomography, * indicates missing data.
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Table 2 Causes of status epilepticus (SE) patients treated with intravenous phenytoin or intravenous sodium valproate
as the first-line treatment
Causes
Phenytoin group N = 37
Sodium valproate N = 17
p value
4 (10.81)
5 (29.41)
0.121
Sepsis
7 (18.92)
0.084
Uremia
1 (5.88)
0.315
Cardiac arrest
5 (13.51)
2 (11.76)
1.000
Alcohol withdrawal
1 (2.70)
1.000
CNS infection
9 (24.32)
3 (17.65)
0.584
Head injury
2 (5.41)
1.000
Metabolic causes
9 (24.32)
1 (5.88)
0.105
Others*
10 (27.03)
6 (35.29)
0.537
Note. Data presented as median (range) or number (percentage); *phenytoin group: hypoxic encephalopathy 3, CNS vasculitis 2, epidural hematoma 1,
postcraniotomy 1, tuberculous encephalitis 1, venous thrombosis 1, ischemic stroke 1; sodium valproate group: postcraniotomy 2, saggital sinus thrombosis 1,
subarachnoid hemorrhage 1, intracerebral hemorrhage 1, pregnancy with eclampsia.
Results
During the study period, there were 92 patients diagnosed
as SE. Of those 37, 17 SE patients received intravenous
phenytoin and 20 received intravenous sodium valproate
as the first-line treatment. All patients received diazepam
10 mg intravenously as a rescue medication before starting
antiepileptic agents if uncontrolled except one patient in
the sodium valproate group.
There were no statistically significant differences in the
baseline clinical variables between both groups (Table 1).
The median age was higher and the median time to start
SE treatment was longer in sodium valproate group. The
percentages of patients with male gender, epilepsy, and
antiepileptic drug withdrawal were also higher in sodium
valproate group. EEG was done in 14 patients (25.93%).
There were no statistically significant differences, however,
in terms of causes and pre-existing conditions of SE in
both groups (Table 2). Details of history of AED usage in
Table 3 Antiepileptic drug usage in status epilepticus
treated by intravenous phenytoin and intravenous
sodium valproate as the first-line treatment
Phenytoin group
1. Phenytoin
1. Sodium valproate
2. Phenytoin, Phenobarbital
2. Sodium valproate
3. Phenytoin, Phenobarbital
3. Phenytoin, Phenobarbital
4. Phenytoin
5. Phenytoin, Phenobarbital
6. Phenytoin, Sodium valproate
Phenytoin group
N = 37
13 (35.14)
9 (52.94)
6. Topiramate
14 (37.84)
3 (17.65)
7. Topiramate
9 (24.32)
4 (23.53)
1 (2.70)
1 (5.88)
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Rescuer
Diazepam 37
Diazepam 16
First-line
Phenytoin 37
Sodium valproate 17
Second- line
Phenytoin 9
Sodium valproate 7
Phenobarbital 8
Phenytoin 1
Sodium valproate 7
Third- line
Phenobarbital 7
Phenobarbital 5
Sodium valproate 1
Sodium thiopenthal 1
Propofol 1
Fourth- line
Phenobarbital 1
Sodium thiopenthal 1
of hospitalization, the number of non-dependent patients or death were better in sodium valproate group
(p value > 0.05) as shown in Table 6. There were 13
patients who died during the admission; 2 patients in
the sodium valproate group. The median hospitalization
days of all 13 patients were 9 days (range 331 days). Two
patients died from acute renal failure and rhabdomyolysis,
while the others died from septicemia. No serious cardiovascular eventd such as hypotension occurred in
either group.
Discussion
This study showed that intravenous sodium valproate
has non-inferior efficacy to intravenous phenytoin as the
first-line treatment of SE. The intravenous sodium valproate group had better outcomes in all five variables
(Table 6). Numbers of patients with clinically-controlled
seizures was almost statistically significant (p value 0.057).
A previous study by the present authors [5] showed that
intravenous sodium valproate can control SE better if
used as the first-line compared to the second-line treatment (75% vs 35%). Even though some causes or preexisting conditions such as AED withdrawal induced SE
may be easier to control [16], there was no statistical
Table 6 Six outcome variables of status epilepticus patients treated by intravenous phenytoin or sodium valproate as
the first-line treatment
Outcomes
Phenytoin N = 37
Sodium valproate N = 17
p value
Seizure controlled, N
8 (21.62)
8 (47.06)
0.057*
30 (2030)
20 (1540)
0.173***
Hospitalization (days)
12 (3109)
9 (276)
0.434***
Non-dependent status, N
20 (54.05)
13 (76.47)
0.143**
20 (54.05)
7 (41.18)
0.559**
Death, N
11 (29.73)
2 (11.76)
0.189**
Note. Data presented as median (range) or number (percentage); p value was calculated by *Chi-square, **Fisher Exact test, or ***Wilcoxon rank sum test.
Conclusion
Intravenous sodium valproate is non-inferior to intravenous phenytoin as the first-line treatment in SE with no
significant cardiovascular compromises.
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9.
10.
11.
12.
13.
14.
15.
16.
17.
doi:10.1186/1471-2377-13-98
Cite this article as: Tiamkao et al.: The efficacy of intravenous sodium
valproate and phenytoin as the first-line treatment in status epilepticus:
a comparison study. BMC Neurology 2013 13:98.
Competing interests
The authors declare that they have no competing interests.
Authors contributions
ST: designed the study, verified data, interpreted data, and drafted the
manuscript. KS: designed the study, analyzed data, and drafted the
manuscript. AC: data collection. All authors read and approved the final
manuscript.
Acknowledgement
The authors would like to thank Professor James A. Will (University of
Wisconsin, USA) for his kind assistance in English-language editing.
Received: 4 January 2013 Accepted: 26 July 2013
Published: 27 July 2013
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