Intravenous sodium valproate in status epilepticus: review and Meta-analysis

Abstract

Objective: Status epilepticus (SE) is a common neurologic emergency. The present study constitutes a meta-analysis of published randomized control trials (RCTs) evaluating the use of intravenous sodium valproate (VPA) in SE.

Methods: MEDLINE and Cochrane databases were comprehensively searched, while retrieved RCTs and meta-analyses were manually screened. Prespecified outcome measures included seizure-cessation, 24?h-efficacy, constitute (liver enzyme increase, arrhythmias, bone-marrow suppression, hypotension and respiratory depression) and severe (life-threatening) adverse events (AEs). Evidence synthesis was performed when appropriate, using Random-Effects (RE) or Fixed-Effects (FE) model based on heterogeneity between trials (homogeneity assumed when PQ > 0.1 and I² < 50%). Outcomes were assessed using Odds-Ratios (ORs) and 95%Confidence-Intervals (95% CIs). Every available comparison was investigated in terms of efficacy and tolerability.

Results:Thirteen studies were retrieved and five comparisons were available, four of which involved two or more studies. Results were compatible with no significant difference between VPA and Phenytoin both in terms of efficacy and tolerability [seizure-cessation: FE-OR = 1.99, 95% CI = (0.83–4.75), 24?h-efficacy: FE-OR = 1.32, 95% CI = (0.60–2.89), composite AEs: FE-OR = 0.45, 95% CI = (0.17–1.21)]. Phenobarbital proved more commonly associated with composite AEs than VPA [seizure-cessation: RE-OR = 0.68, 95% CI = (0.05–9.44), 24?h-efficacy: RE-OR = 0.88, 95% CI = (0.02–33.9), composite AEs: FE-OR = 0.26, 95% CI = (0.09–0.82), severe AEs: FE-OR = 0.30, 95% CI = (0.04–2.28)]. Diazepam was determined inferior to VPA concerning safety issues [seizure-termination: FE-OR = 0.77, 95% CI = (0.34–1.79), severe respiratory depression: FE-OR = 0.06, 95% CI = (0.01–0.48), severe hypotension: FE-OR = 0.09, 95% CI = (0.01–0.72)]. The combination of Lorazepam (LZP) with VPA and the combination of LZP with Levetiracetam presented no difference in efficacy [24h-efficacy: FE-OR = 0.68, 95% CI = (0.37–1.24)].

Conclusions: Although, additional high-quality RCTs are warranted, according to our results, VPA can be considered a safe and effective option in the management of SE.     

Treatment of status epilepticus by sodium valproate

The authors studied the action of valproate with single loading dose of 25 mg/kg, by oral or rectal way, in the treatment of a status epilepticus occurring in 22 patients: 12 patients with generalized status epilepticus, 2 patients with myoclonic status, 2 patients with absence status and 6 patients with motor partial status. In 8 cases, an EEG was performed during the treatment. Results were satisfactory: the status was controlled in 16 cases (73%) in a mean time of 19 min. Plasma levels of valproate approached 55 mg/l at the 20th min after the loading dose. In 6 cases (27%), the status was not controlled, with a plasma level of 33 mg/l at the 20th min. No side effect was observed. This work shows that, for the treatment of status epilepticus, a loading dose of valproate by oral or rectal way is therapeutically equivalent to diazepam and clobazam.     

Intravenous sodium valproate in mainland China for the treatment of diazepam refractory convulsive status epilepticus

The purpose of this study was to identify the short-term safety and efficacy of treating patients with intravenous (i.v.) sodium valproate (VPA) for diazepam (DZP) refractory convulsive status epilepticus (CSE). We prospectively registered 48 patients with refractory CSE who were treated at West China Hospital with i.v. VPA (30 mg/kg, 6 mg/kg per hour) after a loading dose of i.v. DZP and intramuscular phenobarbitone (PBT) failed. VPA stopped seizures in 87.5% of patients within 1 h, and patients regained baseline mental status within 1 h of seizure cessation. CSE did not recur in patients within the next 12 h, and no significant VPA-related systemic or local side effects were found during their hospital stay. In conclusion, this study suggests that i.v. VPA is a promising option for DZP refractory CSE in mainland China, since i.v. PBT is unavailable in most hospitals, and anesthesia is unacceptable to most of the Chinese population.     

Intravenous valproate is well tolerated in unstable patients with status epilepticus

The authors reviewed hospital records of 13 patients with status epilepticus and hypotension who received IV valproate therapy. Most patients were elderly (74.4 +/- 12.5 [SD] years) and received a loading dose of valproate of 25.1 +/- 5.0 mg/kg (range 14.7 to 32.7), at a rate of 36.6 +/- 25.1 mg/min (range 6.3 to 100). There were no significant changes in blood pressure, pulse, or use of vasopressors. The data suggest that valproate loading is well tolerated, even in patients with cardiovascular instability.     

Intravenous valproate associated with significant hypotension in the treatment of status epilepticus

Intravenous valproate has been suggested for the treatment of status epilepticus in part because of its relatively good cardiovascular safety profile. We report a case of severe hypotension associated with intravenous valproate used to treat status epilepticus in an 11-year-old girl. Valproate 960 mg (30 mg/kg) was infused over 1 hour. The patient's blood pressure decreased from a baseline of 130/80 mm Hg to 70/55 mm Hg, 39 minutes into the infusion. Although her seizures stopped, her blood pressure fluctuated between 90/60 mm Hg and 60/30 mm Hg over the next several hours, requiring treatment with intravenous fluids and pressor therapy. Endotracheal intubation eventually was performed. Once her blood pressure stabilized, the patient improved clinically. To our knowledge, this is the first report of significant hypotension associated with intravenous valproate in the treatment of status epilepticus in the pediatric population.     

Intravenous sodium valproate versus diazepam infusion for the control of refractory status epilepticus in children: a randomized controlled trial

An open-label, randomized controlled study was conducted at a tertiary care teaching hospital to compare efficacy and safety of intravenous sodium valproate versus diazepam infusion for control of refractory status epilepticus. Forty children with refractory status epilepticus were randomized to receive either intravenous sodium valproate or diazepam infusion. Refractory status epilepticus was controlled in 80% of the valproate and 85% of the diazepam patients. The median time to control refractory status epilepticus was less in the valproate group (5 minutes) than the diazepam group (17 minutes; P < .001). None of the patients in the valproate group required ventilation or developed hypotension, whereas in the diazepam group 60% required ventilation and 50% developed hypotension after starting diazepam infusion. No adverse effects on liver functions were seen with valproate. It is concluded that intravenous sodium valproate is an effective alternative to diazepam infusion in controlling refractory status epilepticus in children and is free of respiratory depression and hypotension.     

Intravenous ketamine in status epilepticus

Status epilepticus (SE) is among the most common neurological emergencies. In refractory SE, due to subcellular maladaptive changes, γ‐aminobutyric acidergic drugs are no longer effective, and there is an increase in synaptic N‐methyl‐d ‐aspartate (NMDA) receptors. Ketamine (KET) is a noncompetitive N‐methyl‐d ‐aspartate receptor antagonist that could be of value in the treatment of refractory SE. The aim was to analyze all published studies on KET in the treatment of SE. A systematic search (PubMed) of the literature identified 25 studies (from December 1996 to March 2017); with the exception of two prospective studies, all studies were retrospective in nature and published as a full paper. To date, PubMed lists a total number of 244 episodes of SE treated with KET (13 case reports and five case series in adults; four case reports and three case series in children); the overall success rate was 74% (153/207) in adults and 73% (27/37) in children. Adverse events were rare. Current evidence on the use of KET in acute seizures and SE is mostly restricted to retrospective case reports and case series, except for two prospective case series without control (class IV). Further prospective studies to inform clinicians are necessary.     

Comparison of lacosamide versus sodium valproate in status epilepticus: A pilot study

PurposeThe purpose of this study was to compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)-resistant SE.MethodsPatients with LOR-resistant SE were randomized to intravenous LCM 400mg at the rate of 60 mg/kg/min or SVA 30 mg/kg at the rate of 100 mg/min. The SE severity score (STESS), duration of SE and its etiology, and MRI findings were noted. Primary outcome was seizure cessation for 1 h, and secondary outcomes were 24 h seizure remission, in-hospital death, and severe adverse events (SAE).ResultsSixty-six patients were included, and their median age was 40 (range 18–90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One-hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs 69.7%; P = 0.79). Twenty-four-hour seizure freedom was insignificantly higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%). Death (10 vs 12) and composite side effects (4 vs 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (1 patient), and SVA with liver dysfunction (6).ConclusionIn patients with LOR-resistant SE, both LCM and SVA have comparable efficacy and safety.     

丙戊酸钠与地西泮治疗癫痫持续状态的系统评价

目的 系统评价丙戊酸钠与地西泮治疗癫痫持续状态(Status Epilepticus,SE)的有效性和安全性.方法 按照Cochrane系统评价的要求,制定纳入与排除标准.计算机检索Cochrane图书馆、Medline、Embase、中国生物医学文献数据库、中国学术期刊全文数据库等,收集国内外关于丙戊酸钠与地西泮治疗SE的随机或半随机对照试验.按系统评价的方法,由三名研究者独立进行质量评价和资料提取,采用Rev Man 5.1软件进行Meta分析.结果 共纳入9篇文献,包括400例SE患者.Meta分析结果显示:①丙戊酸钠组SE控制的有效率与地西泮组类似[RR=1.03,95％CI(0.91,1.16),P=0.65];②丙戊酸钠组SE复发率明显低于地西泮组[RR=0.41,95％ CI(0.22,0.79),P=0.007];③丙戊酸钠组药物的不良反应发生率明显低于地西泮组[RR =0.17,95％ CI(0.08,0.34),P＜0.0001].结论 丙戊酸钠可有效控制SE,药物不良反应少,癫痫复发率低,是治疗SE的理想药物.     

Intravenous Lacosamide in refractory nonconvulsive status epilepticus

BackgroundMany patients present with refractory Status epilepticus (SE) despite multiple anti-epileptic drugs (AEDs). Lacosamide (LCM) was recently approved as an adjunct AED for partial-onset seizures. It has unique mechanism of modulating voltage-gated sodium channels by enhancing their slow inactivation. LCM has demonstrated efficacy in animal models of pharmacoresistant seizures. To date, there are isolated anecdotal reports of LCM use in SE.ObjectiveTo report a single center experience with IV Lacosamide in patients with NCSE.MethodsPharmacy records were reviewed to identify patients with SE who received IV LCM in our institution. Data on demographics, response to therapy and adverse effects/outcomes were analyzed. All patients had continuous EEG monitoring.Results10 patients (4 men, 6 women), age 16–90 years with refractory SE were given LCM. Eight patients were in focal non-convulsive SE (NCSE), 2 were in generalized non-convulsive SE. The etiologies included anoxic brain injury, idiopathic, encephalitis, tumor, posterior reversible encephalopathy syndrome (PRES), stroke, and AVM. IV LCM was added after traditional AEDs, including drug-induced coma in some, failed to control the SE. NCSE resolved in 7/10 patients whereas 1/10 patient showed partial response with cessation of NCSE but still frequent electrographic seizures and 2/10 patients were resistant to therapy.ConclusionsLCM is a useful adjunct in refractory NCSE. The IV formulation allows prompt administration in the intensive care unit setting. Response was seen especially in focal SE. Similar to other AEDs, response was poor in patients with postanoxic injury. Our data is limited by the small number of patients. Larger controlled studies are necessary to assess accurately the efficacy of IV LCM as an early treatment of SE.     

Intravenous sodium valproate aborts migraine headaches rapidly

Shahien R, Saleh SA, Bowirrat A. Intravenous sodium valproate aborts migraine headaches rapidly.
Acta Neurol Scand: 2011: 123: 257–265.
© 2010 John Wiley & Sons A/S. Objectives – This preliminary study was designed to evaluate the efficacy and safety of intravenous sodium valproate in managing severe migraine headache. Design/methods – In a preliminary prospective open‐label study, we treated patients with severe migraine headache using intravenous sodium valproate, after obtaining written informed consent. Thirty‐six patients, hospitalized with acute established migraine, were infused with sodium valproate. The diagnosis of migraine was based on the International Headache Society classification criteria. Severity of headache was reported on 10‐point visual analog. Disability was assessed on a five‐point scale. Primary and secondary endpoints were measured as sustained pain relief and symptoms improvement at 2 h, respectively. Results  – The study participants had a mean ± SD age of 35.7 ± 9.3 years. The loading dose of sodium valproate was 900–1200 mg, and the average time to best response for headache severity was 50 min. A reduction in pain from severe or moderate to mild or no pain in 60 min was reported in 75% of patients [OR = 7.187 (95% confidence intervals: 1.32–38.95)]. After treatment with sodium valproate, headache severity was significantly decreased (P < 0.0001). No serious adverse events were reported. Conclusions – Intravenous Sodium Valproate (iVPA) seems to be safe and rapidly effective for intractable migraine attack. Randomized, double‐blinded, controlled studies are warranted.     

Intravenous lacosamide for treatment of status epilepticus

Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F, Rossetti AO, Tilz C, Trinka E. Intravenous lacosamide for treatment of status epilepticus.
Acta Neurol Scand: 2011: 123: 137–141.
© 2010 John Wiley & Sons A/S. Objectives – Treatment of established status epilepticus (SE) requires immediate intravenous anticonvulsant therapy. Currently used first‐line drugs may cause potentially hazardous side effects. We aimed to assess the efficacy and safety of intravenous lacosamide (LCM) in SE after failure of standard treatment. Methods – We retrospectively analyzed 39 patients (21 women, 18 men, median age 62 years) from the hospital databases of five neurological departments in Germany, Austria and Switzerland between September 2008 and January 2010 who were admitted in SE and received at least one dose of intravenous LCM. Results – Types of SE were generalized convulsive (n = 6), complex partial (n = 17) and simple partial (n = 16). LCM was administered after failure of benzodiazepins or other standard drugs in all but one case. Median bolus dose of LCM was 400 mg (range 200–400 mg), which was administered at 40–80 mg/min in those patients where infusion rate was documented. SE stopped after LCM in 17 patients, while 22 patients needed further anticonvulsant treatment. The success rate in patients receiving LCM as first or second drug was 3/5, as third drug 11/19, and as fourth or later drug 3/15. In five subjects, SE could not be terminated at all. No serious adverse events attributed to LCM were documented. Conclusions – Intravenous LCM may be an alternative treatment for established SE after failure of standard therapy, or when standard agents are considered unsuitable.     

Intravenous lacosamide in status epilepticus and seizure clusters

Status epilepticus (SE) and seizure clusters (SC) represent neurologic emergencies with a case fatality rate up to 34%, depending on cause and comorbidity. As SE becomes more refractory to treatment over time, appropriate medication is important. This study aimed to investigate efficacy and tolerability of intravenous (IV) lacosamide (LCM) in treatment of SC and SE. Data of patients with SE or SC who were treated with IV LCM between December 2009 and February 2011 in two Austrian centers were analyzed retrospectively. Clinical information was extracted from patients' charts. Forty-eight patients (26f/22m) aged median 62 years (range 17-95 years) were identified. Thirty-five percent of patients (17 of 48) had SC and 65% (31 of 48) had SE. SE was nonconvulsive in 10 (32%), convulsive in 11 (36%), and focal in 10 (32%) patients. SE was acute symptomatic in six (20%) and remote symptomatic in 11 (35%) patients. Fourteen (45%) had preexisting epilepsy. Median initial bolus dose was 200 mg (range 200-400 mg) in patients with SE and 200 mg in patients with SC. Maximum infusion rate was 60 mg/min. Cessation was observed in 42 patients (88%). Success rate in patients with SE receiving LCM as first or second drug was 100% (8 of 8), as third drug 81% (11 of 15), and as fourth or later drug 75% (6 of 8). There were no side effects observed except for pruritus and skin rash in two patients. These data support use of IV LCM as a potential alternative to standard antiepileptic drugs for acute treatment of seizure emergency situations, although randomized controlled studies are needed.     

Intravenous levetiracetam as treatment for status epilepticus

There are established drugs for the treatment of status epilepticus (SE) but their potentially hazardous side-effects are well known. Levetiracetam (LEV) is a novel anticonvulsant available for intravenous (i.v.) application. It could be an alternative when standard drugs fail or should be avoided. We retrospectively identified patients from two German teaching hospitals who were treated with LEV i.v. for SE. Their charts were reviewed regarding sociodemographic data, type, etiology, onset and duration of SE, dose of LEV, concurrent antiepileptic drugs (AED) treatment, tolerability, and outcome. Thirty-two patients (15 female) were found who were treated with i.v. LEV for SE (median age 71 years). Two patients were exclusively treated with LEV. Eight received a low and further 20 patients a high dose of benzodiazepines before LEV. Two patients were treated with LEV to enable discontinuation of narcosis. SE was generalized convulsive in five, nonconvulsive in 20, and simple focal in seven patients. Etiology was acute 13 times and remote symptomatic 16 times; three SE were of unknown etiology. Therapy was initiated within a median time of 3 h and LEV i.v. was applied within a median time of 6 h. Median LEV bolus was 2,000 mg; median total dose on day 1 was 3,500 mg. Benzodiazepines plus i.v. LEV terminated SE in 23 patients without application of additional anticonvulsants, 10 within 30 min. LEV could not terminate SE in seven patients. We documented nausea and emesis in one and elevation of liver enzymes in another patient that were likely to be attributed to LEV. LEV i.v. seems to be safe with relevant efficiency for the treatment of SE in elderly and multimorbid patients when comorbidity and respiratory insufficiency precludes high doses of benzodiazepines or phenytoin.     

Intravenous lidocaine for status epilepticus during childhood

The clinical efficacy of lidocaine for convulsive status epilepticus in 53 convulsive episodes was examined in 37 children (17 males, 20 females). Mean age of patients receiving lidocaine was 3 years 7 months (SD 3y 5mo). Lidocaine administration achieved control of status epilepticus in 19 of 53 convulsive episodes (35.8%). Seizures ceased within 5 minutes of lidocaine administration in all 19 patients who were responsive to the drug. Regarding aetiology of status epilepticus and types of seizures, there was no statistical difference in effectiveness. Mild decrease of oxygen saturation, monitored by pulse oximetry, was observed in one patient, which improved by oxygenation using a mask. Lidocaine is a useful anticonvulsive agent; however, the response rate to lidocaine appears to be quite low, as less than half of the seizures were effectively controlled by lidocaine. Favourable properties of the drug include prompt responses, less alteration of consciousness, and fewer adverse effects, including less respiratory depression.     

醒脑静注射液辅助静脉用丙戊酸钠治疗癫(癎)持续状态效果观察

目的:探讨醒脑静注射液配合丙戊酸钠治疗癫(癎)持续状态的疗效.方法:选择我院2013年8月～2016年1月收治的癫(癎)持续状态患者74例为研究对象,以随机数字表法分组,观察组37例,对照组37例,对照组单用丙戊酸钠治疗,观察组采取醒脑静注射液辅助静脉用丙戊酸钠治疗,对两组患者疗效进行观察.结果:观察组总有效率为92％,对照组为81％,两组比较差异有统计学意义(P＜0.05);观察组起效时间及完全控制时间均较对照组短,两组比较差异有统计学意义(P＜0.05);观察组复发率与不良反应发生率分别为8％和11％,对照组分别为11％和21％,两组比较差异均有统计学意义(P＜0.05).结论:醒脑静注射液辅助静脉用丙戊酸钠治疗癫(癎)持续状态效果显著,此两药具有相互协同作用,可快速起效,安全性高,利于远期预后.