Intravenous valproate as an innovative therapy in seizure emergency situations including status epilepticus—experience in 102 adult patients

  • Christian N.A. Peters
    Correspondence
    Corresponding author. Present address: Neurologische Universitätsklinik Mannheim, 68135 Mannheim, Germany. Tel.: +49 621 383 3205; fax: + 49 621 383 2158.
    Affiliations
    Department of Neurology, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany
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  • Bernd Pohlmann-Eden
    Affiliations
    Department of Neurology, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany

    Epilepsy Research Foundation, Bethel Epilepsy Center, Bielefeld, Germany
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      Summary

      Purpose:

      The emergency treatment of seizures is an important practical issue, in particular the therapy of status epilepticus. Antiepileptic drugs for this condition should be easy to use, show rapid action, have a long-lasting antiepileptic effect, and have minimal cardiopulmonary and other side-effects. Unfortunately, none of the presently available medications such as phenytoin and barbiturates seems to have all of these four properties. Intravenous valproate became available some years ago and first experiences show promising safety data and efficacy results.

      Methods:

      We report a series of 102 adult patients who received standardized high dosage intravenous valproate in various emergency situations, including status epilepticus. The therapeutic goal was persistent seizure control, defined as successful interruption of clinical seizure activity within less than 15 min, followed by seizure freedom during intravenous therapy for at least 12 h. All side effects were documented.

      Results:

      In 83/97 patients (85.6%) the therapeutic goal was achieved. Serious side effects were not documented in any patient. In particular there was no evidence of sedation, cardiorespiratory disturbances and hypotension as often seen in barbiturates and phenytoin. Mild side effects occurred in seven cases (6.9%).

      Conclusions:

      The intravenous application of VPA seems to be an easy-to-use, safe and efficient formulation as an alternative to phenytoin in all seizure emergency situations including status epilepticus. Further controlled comparison studies have to be performed in the future.

      Keywords

      Introduction

      Valproate (VPA) is a well established first-line antiepileptic drug (AED) effective in a wide range of focal and generalized seizures.
      • Chadwick D.
      Standard approach to antiepileptic drug treatment in the United Kingdom.
      There are several conditions under which a parenteral preparation of an AED is necessary, either because the patient is unable to take oral medication or because a rapid loading is required, e.g. in status epilepticus (SE). Beside short-acting benzodiazepines, only phenytoin and phenobarbital are in wide use as an intravenous preparation. Unfortunately, these have a narrow therapeutic window and a range of complicating side effects significantly limiting their practical administration. Phenobarbital may lead to major sedation and respiratory problems including apnoea and is reported to increase the risk of infections. Phenytoin can cause cardiac arrhythmias, requires an extra intravenous-line, has to be given very slowly and may induce severe problems at the injection site including the “purple glove syndrome”.
      Since the autumn of 1996, intravenous VPA is available in Germany. The reported experiences demonstrate a broad spectrum of indications ranging from a rapid switch of oral to parenteral application (e.g. children with severe gastroenteritis), to series of seizures and life-threatening grand-mal SE with promising safety data and efficacy results.
      • Chadwick D.
      Standard approach to antiepileptic drug treatment in the United Kingdom.
      • Rosenfeld W.E.
      • Leppik I.E.
      • Gates J.R.
      • Mireles R.E.
      Valproic acid loading during intensive monitoring.
      • Price D.J.
      Intravenous valproate. Experience in neurosurgery.
      • Giroud M.
      • Gras D.
      • Escousse A.
      • Dumas R.
      • Venaud G.
      Use of injectable valproic acid in status epilepticus: a pilot study.
      • Czapinski P.
      Intravenous valproate acid administration in status epilepticus.
      • Ueberall M.A.
      • Trollmann R.
      • Wunsiedler U.
      • Wenzel D.
      Intravenous valpraote in pediatric epilepsy patients with refractory status epilepticus.
      Experimental data supported this clinical observations revealing both a fast and long-lasting antiseizure effect for VPA.
      • Hönack D.
      • Löscher W.
      Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin.
      Therefore, the goals of this retro- and prospective study were to test, (1) if intravenous VPA is a safe and efficient treatment in heterogeneous conditions of seizure activity including SE, and (2) if these preliminary findings deliver promising results for further controlled clinical trials.

      Methods

       Patients

      Data were available for 102 patients treated during a 4-year period between December 1996 and December 2000. Sixty-one patients (59.8%) were male, 41 female (40.2%). The mean age was 54.8 years, range 18–85 years. The data of all patients originated from a retrospective chart review. In 24 patients additional data from a prospective application survey was available, 21 patients were supervised during treatment by the authors with regard to this study.
      Indication for rapid intravenous VPA treatment ranged from (1) urgent need for or switch to intravenous VPA (n = 25), (2) series of seizures, (n = 34), (3) status epilepticus in n = 35, to (4) others (n = 8) such as brainstem seizures (n = 1), posthypoxic myoclonia (n = 2), and probably non-epileptic seizure episodes (n = 5). These five patients were excluded from the efficacy analysis. SE was operationally defined according to the most recent classification as ongoing seizure activity for more than 10 min.
      • Lowenstein D.H.
      • Alldredge B.K.
      Status epilepticus.
      Series of seizures were defined as two or more distinct seizures within 24 h with interseizure intervals of regaining either consciousness or related functions. For an exact overview see Table 1.
      Table 1Indications for intravenous valproate in 102 treatment episodes.
      Treatment indicationPatients
      Status epilepticus35
       Simple-partial12
       Complex-partial14
       Generalized tonic–clonic6
       Absence3
      Series of seizures (two or more seizures within 24 h)34
       Simple-partial4
       Complex-partial2
       Generalized tonic–clonic27
       Atonic seizures1
      Switch to intravenous therapy25
      Others8
      Total102

       Procedures

      All patients were either admitted as emergency cases or were already hospitalized. Intravenous VPA therapy was always applied under supervision of an experienced epileptologist (BP or CP). Routine clinical laboratory tests including electrolytes, blood cell count, coagulation parameters, liver enzymes and kidney function were conducted in all patients, AED levels were measured in 97 of 102 patients. EEG (21-channel surface, Nihon Kohden Co.) was performed in all 35 SE patients and in 85 patients out of all 102 patients.
      The patients received commercially available intravenous VPA (Orfiril® Injektionslösung, Desitin, Germany). The initial bolus application varied between 4 and 16 mg/kg BW (body weight) dependent on the severity of the clinical condition with the majority (74%) of patients receiving 15 and 16 mg/kg BW, given within 5–10 min, followed by a continuous infusion (flow control pump) of 0.5–4 mg/kg BW/h maintenance dosage within 2 h to 10 days.
      Precise data of individual dosage is given for all 35 patients being diagnosed with SE (Table 2). Twenty-nine patients with SE or series of seizures had been pretreated without success by standard initial dosages for SE
      • Lowenstein D.H.
      • Alldredge B.K.
      Status epilepticus.
      of benzodiazepines (11 patients clonazepam, 6 patients diazepam, 4 patients clonazepam and diazepam and 3 patients midazolam), phenytoin (4 patients) or clonazepam and phenytoin (1 patient), before receiving the VPA infusion. Sixty-seven patients had a known history of seizures and were already treated with other oral AED than VPA such as carbamazepine and lamotrigine.
      Table 2Clinical data, dosage management and duration of intravenous valproate in 35 patients treated for status epilepticus.
      CaseAgeSexDiagnosisSeizure typeBolus (mg)Infusion rate (mg/h)Duration
      166fSubdural haematomaSPS500
      267mBrain abscessSPS5024 h
      367mBrain abscessSPS1204 h
      2404 h
      1208 h
      423mArteriitis nodosaGTCS900187.54 d
      575mTheophyllin–intoxicationGTCS90062.52 d
      600
      658mCerebral venous thrombosisCPS90012512 h
      760fIntracranial haemorrhageGTCS9005024 h
      818mEpilepsyAbsence900
      962fEpilepsyCPS9001508 h
      300
      1060mWernicke's encephalopathySPS90012524 h
      1166fAstrozytoma °IIISPS60037.52 d
      1268fEpilepsyCPS600
      1368fEpilepsyCPS60010012 h
      1468fEpilepsyCPS5024 h
      1561mAlcoholism, SVECPS5024 h
      1675fAlzheimer's diseaseCPS90012512 h
      1739mBrain injuryGTCS900753 d
      1847mFamilial microangiopathyCPS90012512 h
      1980fStrokeGTCS90010012 h
      2075fGlioblastomaSPS900
      900
      2175fGlioblastomaSPS900
      2237mEpilepsyAbsence90083.324 h
      2346fMultiple sclerosisCPS90012512 h
      2454mEpilepsyCPS12512 h
      2574mCerebral metastasisSPS60062.524 h
      2663mIntracranial haemorrhageSPS/GTCS9001252 d
      2785fMeningiomaCPS6001253 d
      2883fStrokeGTCS/SPS90020012 h
      900 (90 min)
      2949mDown-syndromeCPS62.524 h
      3083fStrokeCPS90062.52 d
      3163mEncephalopathyCPS600756 d
      600 (1 h)
      3255mEpilepsyGTCS900753 d
      3354mEpilepsyAbsence12521 h
      3466fAstrozytoma °IIISPS15012 h
      3577fSubcort. vasc. enceph.SPS60087.53 d
      Second bolus directly after the first bolus, except where mentioned. SPS: simple partial seizure; CPS: complex partial seizure; GTCS: generalized tonic–clonic seizure.

       Analysis

      We analyzed efficacy and side effects of intravenous VPA. Primary outcome was defined as successful interruption of clinical seizure activity within less than 15 min, followed by seizure freedom during intravenous therapy for at least 12 h in those patients with SE. In those patients with series of seizures or those undergoing medication changes, the goal was seizure freedom during intravenous therapy for at least 12 h. All patients were asked if they experienced or had experienced any problems, which they thought were attributable to their medication. All individual adverse events were documented and analyzed.

      Results

       Tolerability and safety

      Serious side effects were not documented in any patient. In none of the 35 SE patients and in none of the 34 patients with series of seizures were significant cardiorespiratory side effects including hypotension observed.
      Mild side effects, reported by individuals being conscious, occurred in 7 out of 102 applications (6.8%): Three patients complained of an unspecific feeling of warming with dizziness for some seconds during fast bolus injection. One patient had to be withdrawn because of a moderate generalized allergic skin reaction, which disappeared within a few hours after discontinuation of therapy. Another patient had nausea and vomiting for 3 h which stopped despite of continuation of the therapy and one patient had mild fatigue. In one patient we observed a transient tremor of both hands. There were no reactions at the injection site.

       Efficacy

      Ninety-seven of the 102 patients were eligible for efficacy analysis, as five patients had to be excluded retrospectively because of the non-epileptic nature of their seizures. In 83 of 97 patients (85.6%) the primary outcome criterion of seizure freedom as defined was achieved. Sub-group analysis showed efficacy of intravenous VPA in 27 out of 35 patients with SE (77.1%), in 29 out of 34 patients with series of seizures (85.3%), and in all but one out of 25 patients who were switched to intravenous treatment (96.0%), which is illustrated in Fig. 1. In the last group of patients, two were seizure free, the others had had seizures before the switch. Within the SE group, patients with complex-partial SE responded best (92.9% or 13/14 patients seizure free), compared to simple-partial SE (83.3% or 10/12 seizure free), generalized tonic–clonic (GTC) SE (66.7% or 4/6 patients) and atypical absence-status (0/3).
      Figure thumbnail gr1
      Figure 1Efficacy of intravenous valproate in 35 patients with SE, in 34 patients with series of seizures, and in 25 patients who underwent switch from oral to intravenous treatment (grey bars: seizure control and black bars: treatment without success).
      Looking at the 14 cases with primary treatment failure, the following three subgroups can be recognized:
      • 1.
        Late responders: In five patients VPA was efficient, but only after a delay. In three out of those (two with a series of GTC, one with intravenous VPA substitution) a GTC seizure recurred within 15 min: increased dosage of VPA finally led to complete seizure freedom. In the remaining two a simple-partial SE required the administration of an additional bolus of 12 mg/kg BW VPA to achieve complete seizure control.
      • 2.
        Highly drug resistant SE: Of these seven patients, five were absolutely refractory to any AED treatment: Two died still in SE due to their underlying illness, two had an absolutely pharmacoresistant SE (complex-partial and generalized tonic–clonic, respectively) to any drug treatment lasting for months and died later, one was discharged while still having an intermittent atypical absence-status and was lost to follow-up. Of the other two patients, one had a complex-partial SE due to a ganglioglioma and the other simple-partial SE due to a brain abscess. Both patients became seizure-free after surgical treatment.
      • 3.
        Responders to other AEDs than VPA: Only two patients were in this group. One patient had an atypical absence-status, promptly reacting to benzodiazepines, the other one had several GTC seizures which got controlled by high dosage of VPA, however, ending into a complex-partial SE, which could be easily interrupted by a standard dosis of intravenous phenytoin.
      Twenty-nine patients had received benzodiazepines or intravenous phenytoin in standard adult dosages
      • Lowenstein D.H.
      • Alldredge B.K.
      Status epilepticus.
      without success before treatment with intravenous VPA. Five of these were refractory to benzodiazepines and intravenous phenytoin in a maximum dose and became seizure-free under intravenous VPA.

      Discussion

      The emergency treatment of seizures is an important practical issue. This is particularly true for SE, where the mortality rates may be still as high as 25%. Early aggressive treatment seems to be absolutely necessary in this life-threatening condition. The AED should ideally fulfill the following criteria: (1) be easy to use, (2) show rapid action, (3) have a long-lasting antiepileptic effect, (4) finally, have minimal cardiopulmonary and other side-effects. Unfortunately, none of the presently available medications such as phenytoin and barbiturates seems to have all of these four properties.
      • Lowenstein D.H.
      • Alldredge B.K.
      Status epilepticus.
      In our opinion, intravenous VPA might be an interesting alternative in this context for several reasons. It is well known to have a variety of action sites in the experimental setting
      • Ramsay R.E.
      • Uthman B.M.
      • Leppik I.E.
      • et al.
      The tolerability and safety of valproate sodium injection given as an intravenous infusion.
      explaining its excellent efficacy in most seizure types. In an electrically induced SE-model in animals, VPA suppressed seizure activity after 30 s,
      • Hönack D.
      • Löscher W.
      Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin.
      being faster than diazepam and phenytoin, both of which showed more prominent sedation.
      The history of intravenous application of VPA in patients is a fairly recent one. Since the first observations of its high efficacy combined with excellent safety data in a small study group of patients with SE by Price
      • Price D.J.
      Intravenous valproate. Experience in neurosurgery.
      , a few uncontrolled open studies followed,
      • Giroud M.
      • Gras D.
      • Escousse A.
      • Dumas R.
      • Venaud G.
      Use of injectable valproic acid in status epilepticus: a pilot study.
      • Czapinski P.
      Intravenous valproate acid administration in status epilepticus.
      • Rosenfeld W.E.
      • Leppik I.E.
      • Gates J.R.
      • Mireles R.E.
      Valproic acid loading during intensive monitoring.
      • Ueberall M.A.
      • Trollmann R.
      • Wunsiedler U.
      • Wenzel D.
      Intravenous valpraote in pediatric epilepsy patients with refractory status epilepticus.
      all of them confirming the therapeutic value of this new formulation.
      Our own preliminary data have shown its good antiepileptic effects both in a series of seizures and in different kinds of SE including GTCS-SE, with a success rate of approximately 80%. Interestingly, intravenous VPA could terminate seizure activity in most of the cases where different established AEDs (benzodiazepines and intravenous phenytoin) had previously failed. Our efficacy rates of up to 80% and more correspond to other recent studies in adults
      • Rosenfeld W.E.
      • Leppik I.E.
      • Gates J.R.
      • Mireles R.E.
      Valproic acid loading during intensive monitoring.
      • Price D.J.
      Intravenous valproate. Experience in neurosurgery.
      • Giroud M.
      • Gras D.
      • Escousse A.
      • Dumas R.
      • Venaud G.
      Use of injectable valproic acid in status epilepticus: a pilot study.
      • Czapinski P.
      Intravenous valproate acid administration in status epilepticus.
      and children,
      • Ueberall M.A.
      • Trollmann R.
      • Wunsiedler U.
      • Wenzel D.
      Intravenous valpraote in pediatric epilepsy patients with refractory status epilepticus.
      where most patients had also been pretreated unsuccessfully with standard benzodiazepines. Treatment failure in our study population mainly occurred in those individuals, who were either refractory with any AED, had an underlying life-threatening condition or revealed a highly epileptogenic lesion such as a brain abscess. Only two patients showed seizure control after a switch to an alternative medication.
      In the two small adult case series
      • Czapinski P.
      Intravenous valproate acid administration in status epilepticus.
      • Giroud M.
      • Gras D.
      • Escousse A.
      • Dumas R.
      • Venaud G.
      Use of injectable valproic acid in status epilepticus: a pilot study.
      (n = 20 and 23, respectively), a treatment regimen with an initial bolus treatment of 15 mg/kg BW and a subsequent infusion with 1 mg/kg BW/h of either 5–6 h
      • Czapinski P.
      Intravenous valproate acid administration in status epilepticus.
      or 24 h,
      • Giroud M.
      • Gras D.
      • Escousse A.
      • Dumas R.
      • Venaud G.
      Use of injectable valproic acid in status epilepticus: a pilot study.
      interrupted on-going SE in 80–85% of cases controlled by EEG-monitoring in one study.
      • Giroud M.
      • Gras D.
      • Escousse A.
      • Dumas R.
      • Venaud G.
      Use of injectable valproic acid in status epilepticus: a pilot study.
      Major systemic side effects were not observed in either study. Ueberall et al.
      • Ueberall M.A.
      • Trollmann R.
      • Wunsiedler U.
      • Wenzel D.
      Intravenous valpraote in pediatric epilepsy patients with refractory status epilepticus.
      treated 41 children in SE, who had been refractory to benzodiazepines, phenytoin and barbiturates before, by means of intravenous VPA, using an initial bolus of 20–40 mg/kg BW, followed by an infusion with 5 mg/kg BW/h. SE could be successfully interrupted in 78% (32 out of 41) of the children, in the majority (n = 27) within 2–6 min. Seizure control was assessed by EEG-monitoring in all patients.
      There were no major safety problems in our entire study group of 102 patients with a wide spectrum of therapeutic indications. This is in perfect agreement with all above mentioned efficacy studies, even in studies where very high dosages of up to 9.6 g/d were applied,
      • Price D.J.
      Intravenous valproate. Experience in neurosurgery.
      and with those studies, in which the safety aspect of intravenous VPA was particularly addressed.
      • Devinsky O.
      • Leppik I.E.
      • Willmore L.J.
      • et al.
      Safety of intravenous valproate.
      • Ramsay R.E.
      • Uthman B.M.
      • Leppik I.E.
      • et al.
      The tolerability and safety of valproate sodium injection given as an intravenous infusion.
      Due to the mainly retrospective character of our study, we might have missed some minor side effects, which may not have been documented in the charts but there have clearly been no serious adverse events.
      More recent experiences with high bolus application of intravenous VPA with up to 40 mg/kg BW and rapid loading with a rate of up to 6 mg/kg BW/min
      • Naritoku D.K.
      • Mueed S.
      Intravenous loading of valproate for epilepsy.
      • Venkataraman V.
      • Wheless J.W.
      Safety of rapid intravenous infusion of valproat loading doses in epilepsy patients.
      • Wheless J.W.
      • Venkataraman V.
      Safety of high i.v. loading doses of valproate.
      • Limdi N.A.
      • Faught E.
      The safety of rapid valproic acid infusion.
      demonstrate both excellent efficacy and safety. The two manufacturers in Germany now recommend an initial loading dose of 15 mg/kg BW over a time period of up to 30 min followed by an infusion at 1–2 mg/kg BW/h over 12–24 h, which is close to the regimen we used in our study. Meanwhile we have administered dosages of 4800 mg up to 9600 mg over 24 h in cases of SE that were difficult to treat, without any evidence of severe side effects.
      The above reported high efficacy rates of >80% including our own experience are very promising, but have to be interpreted with caution, as they are still results from open study designs, or retrospective small case series.

      Pohlmann-Eden B, Peters CNA. Use of Intravenous valproate in status epilepticus. Akt Neurologie 2001;28:480–6.

      It is also difficult to compare them with other data, as most publications with regard to any antiepileptic treatment in SE are either anecdotal case reports or open studies with only a small number of patients. Systematic prospective comparisons of different AEDs, randomized and double-blind, are extremely rare: to our knowledge there are only three studies,
      • Leppik I.E.
      • Derivan A.T.
      • Homan R.W.
      • Walker J.
      • Ramsay R.E.
      • Patrick B.
      Double-blind study of lorazepam in status epilepticus.
      • Shaner D.M.
      • McCurdy S.A.
      • Herring M.O.
      Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin.
      • Treiman D.M.
      • Meyers P.D.
      • Walton N.Y.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus.
      and only one with a larger population.
      • Treiman D.M.
      • Meyers P.D.
      • Walton N.Y.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus.
      In this prospective multi-centre, double-blinded comparison study, 570 patients randomly received different therapeutic regimens (phenytoin, diazepam + phenytoin, phenobarbital and finally lorazepam), but unfortunately VPA was not included. The reported low efficacy rate of only 55% in this study, independent of the chosen drug, is mainly due to the selection of patients in this study and the long duration of the SE before recruitment.
      • Treiman D.M.
      • Meyers P.D.
      • Walton N.Y.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus.
      Against this background it now seems necessary to perform a controlled randomized double-blind trial in SE to compare the efficacy and tolerability of intravenous VPA with phenytoin or fosphenytoin. Several open questions, such as loading and maintenance dosis, target groups and time point of application in a new decision algorithmus for SE have to be addressed in the future.
      In conclusion, the intravenous application of VPA seems to be a highly efficient and safe treatment in many seizure emergency situations including SE. Our data strongly support that the profile of VPA includes a fast action beside the well known slow-acting mechanisms.
      • Loescher W.
      Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action.
      It can have an effect even in cases when other first-line AEDs have failed, but shows a significantly better tolerability, is easier to handle and can be switched directly to a long-term antiepileptic therapy of first choice. Further controlled comparison studies have to be performed in the future.

      Acknowledgement

      We are very grateful to Dr. Peter Carlen, Professor of Neurology, Toronto Western Hospital, University of Toronto, who carefully reviewed this manuscript and gave helpful suggestions.

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