Propofol versus thiopental sodium for the treatment ofrefractory status epilepticus
Hemanshu Prabhakar1, Ashish Bindra1, Gyaninder Pal Singh1, Mani Kalaivani2
1Department of Neuroanaesthesiology, All India Institute of Medical Sciences, New Delhi, India. 2Department of Biostatistics, AllIndia Institute of Medical Sciences, New Delhi, India
Contact address: Hemanshu Prabhakar, Department of Neuroanaesthesiology, All India Institute of Medical Sciences, Ansari Nagar,New Delhi, 110029, India. [email protected].
Editorial group: Cochrane Epilepsy Group.Publication status and date: New, published in Issue 8, 2012.Review content assessed as up-to-date: 11 May 2012.
Citation: Prabhakar H, Bindra A, Singh GP, Kalaivani M. Propofol versus thiopental sodium for the treatment of refractory statusepilepticus. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD009202. DOI: 10.1002/14651858.CD009202.pub2.
Failure to respond to antiepileptic drugs in uncontrolled seizure activity such as refractory status epilepticus (RSE) has led to the useof anaesthetic drugs. Coma is induced with anaesthetic drugs to achieve complete control of seizure activity. Thiopental sodium andpropofol are popularly used for this purpose. Both agents have been found to be effective. However, there is substantial lack of evidenceas to which of the two drugs is better in terms of clinical outcome.
Objectives
To compare the efficacy, adverse effects, and short- and long-term outcomes of RSE treated with one of the two anaesthetic agents,thiopental sodium or propofol.
Search methods
We searched the Cochrane Epilepsy Group Specialized Register (10 May 2012), the Cochrane Central Register of Controlled Trials(CENTRAL Issue 4 of 12, The Cochrane Library 2012), and MEDLINE (1946 to May week 1, 2012). We also searched (10 May2012) ClinicalTrials.gov, The South Asian Database of Controlled Clinical Trials, and IndMED (a bibliographic database of IndianMedical Journals).
Selection criteria
All randomised or quasi-randomised controlled studies (regardless of blinding) of control of RSE using either thiopental sodium orpropofol.
Data collection and analysis
Two review authors screened the search results and reviewed abstracts of relevant and eligible trials before retrieving the full textpublications.
Main results
One study was available for review. This study was a small, single-blind, multicentre trial studying adults with RSE and receivingeither propofol or thiopental sodium for the control of seizure activity (Rossetti 2011). This study showed a wide confidence intervalsuggesting that the drugs may differ in efficacy up to more than two-fold. There was no evidence of a difference between the drugswith respect to the outcome measures such as control of seizure activity and functional outcome at three months.
There is lack of robust and randomised controlled evidence that can clarify the efficacy of propofol and thiopental sodium over eachother in the treatment of RSE. There is a need for large, randomised controlled trials for this serious condition.
P L A I N L A N G U A G E S U M M A R Y
Propofol versus thiopental sodium for the treatment of refractory status epilepticus
Persistent convulsions are a major medical emergency associated with significant morbidity and mortality. At times, these convulsionsfail to respond to first- and second-line drug therapy and may be observed in up to 31% of patients suffering from persistent seizureor convulsive activities. Persistent seizure activity may become refractory to antiepileptic drugs. Anaesthetics such as thiopental sodiumand propofol are frequently given for control of seizures in such situations. Both agents have inherent side effects and complications.This review appraises the evidence for the these anaesthetic drugs in controlling seizure activity in patients with RSE.
There is a lack of good-quality evidence to support the choice of anaesthetic drug for the treatment of patients with RSE. Only onetrial could be identified, which was terminated early due to recruitment problems. The two drugs did not show any difference amongeach other. The only difference noted was the requirement of prolonged mechanical ventilation for patients in the thiopental group.This could be due to the long half-life of the drug. There is a clear need for a large randomised controlled trial to study the efficacy ofanaesthetic agents in the treatment of RSE.
B A C K G R O U N D
Status epilepticus (SE) is defined as a condition in which thereis either continuous seizure activity for more than 30 minutes,or two or more seizure activities in a sequence without return offull consciousness between the episodes (Prasad 2005; WorkingGroup 1993). There is no universally accepted definition of SE.There is no consensus on the duration of seizure activity that maybe required to define SE. SE may be broadly classified in two types,convulsive and non-convulsive. The common aetiologies for SEare stroke, traumatic brain injury, brain tumours, central nervoussystem infection, metabolic or toxic encephalopathies and elec-trolyte disorders. SE is a major medical emergency associated withsignificant morbidity and mortality (16% to 23%). Refractorystatus epilepticus (RSE) is defined as SE that fails to respond tofirst- and second-line therapy and it is observed in 9% to 31% ofpatients with SE (Mayer 2002; Treiman 1998). To be categorisedas RSE, some authors have suggested a time frame (Mayer 2002),whereas others have not (Holtkamp 2007; Rossetti 2005). Thefirst line of treatment for SE includes benzodiazepines; the sec-ond line includes antiepileptic drugs such as phenytoin, pheno-barbital or valproic acid. Assistance of an anaesthetist is requiredfor managing RSE, where coma may be induced with anaestheticagents in order to achieve complete control of seizures. The useof anaesthetic agents such as thiopental sodium and propofol formanaging RSE is common in many centres (Parviainen 2002; Van
Gestel 2005). Thiopental sodium belongs to barbiturates groupof drugs unrelated to propofol, which is a phenolic compound.Both agents have been found to be effective in controlling seizuresin RSE (Parviainen 2002; Van Gestel 2005). There is substantiallack of evidence as to which of the two drugs, thiopental sodiumand propofol, is better in terms of clinical outcome of patientswith RSE. In a systematic review published in 2002 by Claassen2002, the authors compared the efficacy of midazolam, propofoland pentobarbital for terminating seizures in RSE patients. Con-sidering all possible limitations, the authors concluded that pen-tobarbital was more effective than any other strategy suggested fortreatment of RSE.
Description of the condition
RSE develops when patients become resistant to antiepilepticdrugs with passage of time. In hospital-based series, it develops in31% to 44% of patients with SE (Mayer 2002). Significant mor-bidity and mortality are associated with RSE. Failure to respondto antiepileptic drugs has led to the use of anaesthetic agents incontrolling seizures. The popular anaesthetic agents are the barbi-turates, propofol and isoflurane.
Anaesthetic agents have been used for the treatment of RSE. Bar-biturates and propofol have been commonly used in this regard.However, most of the published literature is anecdotal. There isno consensus as to which of the two agents is better in terms ofclinical outcome.
How the intervention might work
Thiopental sodium, a barbiturate, is a γ -aminobutyric acid-A (GABAA) agonist with possible actions on calcium channels(Rogowski 2004). Barbiturates have a prolonged duration of ac-tion, mainly due to their accumulation in the body. They are alsoknown to produce hypotension during use. In contrast, propofolis gaining popularity because of its shorter duration of action andlittle tendency to accumulate in the body. Similar to barbiturates,propofol also produces hypotension, and reduces intracranial pres-sure and brain metabolic requirements (Marik 2004). Prolongeduse of propofol as an infusion has been shown to result in poten-tially fatal cardiovascular collapse associated with lactic acidosis,hypertriglyceridaemia and rhabdomyolysis, the so-called “propo-fol infusion syndrome” (Zarovnaya 2007). Both agents are also N-methyl-D-aspartate (NMDA) antagonists in vitro (Zhan 2001).
Why it is important to do this review
The current literature provides enough evidence to suggest thatboth thiopental and propofol are effective in the treatment of RSE(Parviainen 2002; Van Gestel 2005). As both agents are associatedwith inherent side effects and complications, the choice of theagent is usually left at the discretion of the attending anaesthetist.There is a lack of evidence to suggest the superiority of one drugover the other. A systematic review of published literature wouldhelp us reach to some conclusion. To date, no Cochrane systematicreview comparing thiopental and propofol for treatment of RSEhas been published. The aim of this review is to establish which ofthe two commonly used anaesthetic agents, thiopental or propofol,is better suited for the treatment of RSE.
O B J E C T I V E S
To compare the efficacy, adverse effects, and short- and long-termoutcomes of SE treated with one of the two anaesthetic agents,thiopental sodium or propofol.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included all relevant randomised or quasi-randomised con-trolled studies, regardless of blinding. Diagnosis of RSE was basedon any given standard definition specified in the articles and treat-ment consisting either of propofol or thiopental sodium. We ex-cluded studies that did not define RSE, prior treatment with anyother intravenous anaesthetic before treatment with thiopentalsodium or propofol and use of intermittent boluses of thiopentalsodium or propofol for treating RSE.
Types of participants
We included individuals of any age group and gender diagnosedwith RSE of any aetiology.
Types of interventions
Patients receiving either thiopental sodium or propofol for thetreatment of RSE, in addition to standard antiepileptic drugs usedin SE.
Types of outcome measures
Primary outcomes
1. Total control of seizures.2. Mortality.3. Length of ICU stay.
Secondary outcomes
1. Adverse events, such as infection, hypotension and propofolinfusion syndrome.
2. Duration of mechanical ventilatory support.3. Duration of hospital stay.4. Cognitive deficits.5. Long-term outcomes, such as dependence for daily
activities (walking, eating, bathing, dressing and toileting).
Search methods for identification of studies
We searched the following databases:1. Cochrane Epilepsy Group Specialized Register (10 May
2012);2. The Cochrane Central Register of Controlled Trials
(CENTRAL Issue 4 of 12, The Cochrane Library 2012) using thesearch strategy outlined in Appendix 1;
3. MEDLINE (Ovid, 1946 to May week 1, 2012) using thesearch strategy outlined in Appendix 2.We did not apply any language restrictions.
Searching other resources
We searched the following web sites for information about relevantongoing trials:
1. IndMED (www.indmed.nic.in) (10 May 2012) using thesearch terms: ’Propofol AND (thiopental OR thiopentone)AND (epilepsy OR epileptic)’;
2. South Asian Database of Controlled Clinical Trials (www.cochrane-sadcct.org, accessed 10 May 2012) using thesearch term ’propofol’;
3. www.Clinicaltrials.gov (10 May 2012), using the searchterm ’propofol’ for condition ’epilepsy’.
Data collection and analysis
Selection of studies
Using the results of the above searches, we screened all titles andabstracts for eligibility. Two review authors (AB and GPS) inde-pendently performed this screening. We obtained and assessed thefull articles of all eligible RCTs for relevance based on the pre-planned check-list. Each author documented the reason for eachtrial that was excluded. We resolved any disagreement betweenthe two review authors by discussion with a third review author
(HP), who decided on the inclusion or exclusion of the study. Wecompiled a list of all eligible trials.
Data extraction and management
Two review authors (AB and GPS) planned to independently ex-tract the data and assess the trial quality. We resolved any disagree-ment through consultation with the third review author (HP). Incase of additional information being required, AB was chosen tocontact the first author of the relevant trial.
Assessment of risk of bias in included studies
Two review authors assessed the methodological quality of the el-igible trials independently (AB and GPS). We resolved any dis-agreement by discussion with the third review author (HP). Weperformed the assessment as suggested in the Cochrane Handbookfor Systematic Reviews of Interventions (Higgins 2008). We judgedthe quality of the study on the basis of the following:
1. method of randomisation,2. concealment of allocation,3. blinding and outcome,4. incomplete outcome data,5. selective reporting,6. any other bias.
We included a ’Risk of bias’ table as part of the ’Characteristics ofincluded studies’ and a ’Risk of bias summary’ figure (Figure 1),which details all of the judgements made for all included studiesin the review.
Figure 1. Risk of bias graph: review authors’ judgements about each ’Risk of bias’ item presented aspercentages across all included studies.
We planned to record the number (percentage) of participants ex-periencing each categorical outcome and mean (standard deviation(SD))/median (range) for continuous outcome per randomisedgroup. All primary analyses were dealt by ’intention to treat’.
Unit of analysis issues
We planned to include only RCTs in our review with parallel de-sign. The nature of the intervention here suggested that unit ofanalysis issues, such as those associated with cluster randomisa-tion, were unlikely to arise. If we included any cluster randomisedstudies we planned to assess the risk of bias following the sugges-tions in Section 16.3.2 of the Cochrane Handbook for SystematicReviews of Interventions (Higgins 2008), and the approach to anal-ysis suggested in the subsequent sections. We would have taken asimilar approach to any cross-over trials included.
Dealing with missing data
We contacted the first author of the relevant trial and collect therequired information.
Assessment of heterogeneity
We planned to assess the clinical heterogeneity of included studiesas assessed as methodological diversity, such as distribution of pa-tient characteristics (age, seizure type and number of drugs takenat the time of randomisation) and trial factors (randomisation con-cealment, blinding and loss to follow-up). We planned to use theQ statistics to test the statistical heterogeneity between trials andthe I2 statistic to assess the magnitude of heterogeneity (Higgins2002).
Assessment of reporting biases
We planned to assess publication bias/small-study effect in a qual-itative manner, using a funnel plot. Due to limited data, we didnot assess this bias.
Data synthesis
We quantitatively reviewed the included data and combined it byintervention, outcome and population using the Cochrane Col-laboration’s statistical software, Review Manager (RevMan 2011).We planned to assess statistical heterogeneity using the Chi2 statis-tic and consider P values of 0.05 or less as statistically significant.We planned to assess the level of inconsistency across the studies
using the I2 statistic where I2 greater than 50% indicates substan-tial heterogeneity. Had we found statistically significant hetero-geneity that we could not readily explain, we would have assessedit using a random-effects model.Due to only one study meeting our inclusion criteria, we did notperform a meta-analysis.
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analyses for the following: agegroups (children (< 14 years of age) and adults), gender, aetiologyand type of seizure (convulsive or non-convulsive).Due to limited data, we did not perform a subgroup analysis.
Sensitivity analysis
We planned to perform a sensitivity analysis to assess the influenceof including studies judged low in methodological quality andcharacteristic of intervention; that is, the doses of propofol andthiopental used.Due to limited data, we did not perform a sensitivity analysis.
R E S U L T S
Description of studies
See: Characteristics of included studies.See: Characteristics of included studiesThe study conducted by Rossetti et al (Rossetti 2011) was a ran-domised, single-blind, multicentre trial studying adults with RSE.Patients received either propofol or barbiturates for control ofseizures. There primary end point was the proportion of patientswith RSE controlled after first course of study drug and secondaryend point included drug tolerability. The trial was terminated af-ter three years with only 24 patients recruited of the 150 required.The trial was under-sampled and found prolonged mechanicalventilation requirement in the barbiturate arm. The treatment-related complications were comparable for both propofol and bar-biturates.
Results of the search
Our searches yielded 34 references (eight from MEDLINE, threefrom CENTRAL, two from the Cochrane Epilepsy Group Spe-cialized Register, 20 from the South Asian Database of ControlledClinical Trials, and one from ClinicalTrials.gov. The search of In-dMED yielded no references). After de-duplication, 24 referencesremained. After further scrutiny, only one study was identified forinclusion in this review.Figure 2 shows the results of our searches.
Only one study was included in the review (Rossetti 2011). Theoverview of the study is given in Table 1.
Excluded studies
None.
Risk of bias in included studies
The study conducted by Rossetti et al (Rossetti 2011) was a single-blind study. The small sample size and lack of double blindingcould have influenced results.
Allocation
It is difficult to understand how allocation was done, as the au-thors have not commented on this in their paper. Personal com-munication with the author failed to clarify this issue.
Blinding
This was a single-blind study and so there is definitely a chance ofperformance bias and detection bias.
Incomplete outcome data
Attrition bias is unlikely, as there are no incomplete outcome data.
Selective reporting
Reporting bias is unlikely as the authors have reported all theoutcomes they have described in the methodology.
Other potential sources of bias
No other potential sources of bias could be identified.
Effects of interventions
The initial search in May 2011 identified no results. Searchingother databases in July 2011, we identified only one study (Rossetti2011) that met our inclusion criteria. This was a randomised,single-blind study that included patients with RSE treated witheither propofol or barbiturates. The details of the study have beenoutlined above.
Total control of seizures
There was no statistical difference in total control of seizures afterthe first course of study drug between propofol and thiopentalsodium; 6/14 patients versus 2/7 patients in propofol and thiopen-tal sodium group, respectively (RR 1.50; 95% CI 0.40 to 5.61)(Analysis 1.1).
Mortality
There was no statistical difference in mortality between propofoland thiopental sodium; 3/14 patients versus 1/7 patients in propo-fol and thiopental sodium group, respectively (RR 1.50; 95% CI0.19 to 11.93). In the propofol group, deaths presumed to be in-hospital were secondary to Creuzfeldt-Jakob disease (day five), car-diac asystole (day six) and progressive brain tumour (day 11). Inthe thiopental group, one patient died on day five, secondary tocolic ischaemia. Deaths on days 21, 29 and 42 were due to para-neoplastic encephalitis, pneumonia and sepsis, respectively, whichare presumed to be out-of-hospital (Analysis 1.2).
Adverse events
There was no statistical difference in adverse events betweenpropofol and thiopental sodium (Table 2). Infection was seen in 7/14 patients versus 5/7 patients in propofol and thiopental sodiumgroup, respectively (RR 0.70; 95% CI 0.35 to 1.41).Hypotension during administration of study drugs and requiringuse of vasopressors was seen in 7/14 patients versus 4/7 patientsin propofol and thiopental sodium group, respectively (RR 0.87;95% CI 0.38 to 2.00) (Analysis 1.3).The other severe complication noted was non-fatal propofol infu-sion syndrome in one patient.
Duration of mechanical ventilation
The number of days of mechanical ventilation were more in thethiopental group when compared with propofol group (median(range): 17 days (5 to 70 days) with thiopental sodium versus 4days (2 to 28 days) with propofol).
Long-term outcome
There was no statistical difference in the functional outcome be-tween propofol and thiopental sodium at three months; 5/14 pa-tients versus 3/7 patients in propofol and thiopental sodium group,respectively (RR 0.83; 95% CI 0.28 to 2.52) (Analysis 1.4).
Our search identified only one study (Rossetti 2011) that ad-dressed the issue of treatment of RSE using thiopental sodium andpropofol in a randomised, single-blind multicentric trial. This trialwas under-sampled and had to be terminated prior to completion.Twenty-four patients were recruited in five centres; 14 receivedpropofol and seven received thiopental sodium. The primary endpoint, that is, control of seizure with first course of drug treat-ment, was achieved in 43% in the propofol group and 22% in thebarbiturate group (seven patients received thiopental sodium andtwo patients received pentobarbital). The overall mortality was43% and 34% in the propofol and barbiturate group, respectively.However, the authors fail to report the in-hospital mortality. Pa-tients returning to baseline condition at the three months’ follow-up were similar in the two groups. No information was providedon the length of intensive care unit (ICU) and hospital days ofthe patients. However, days of mechanical ventilation were signifi-cantly more in the thiopental group. This could be due to the longelimination half-life of the drug when compared with propofol.The fact that the trial was prematurely stopped could have intro-duced bias. At the same time, the under-sampling resulted in lossof power to detect difference between the two treatment arms.
This study confirms that RSE is a serious clinical condition carry-ing high morbidity and mortality. The authors of the study agreethat a larger multicentric study is needed with larger sample sizeand adequate funding is needed to reach conclusive results. Theauthors also suggest that a third treatment arm using midazolamas the treatment drug may be included in the study that may ad-dress the issue related to tolerability of the drugs, propofol andthiopental.
Summary of main results
Both propofol and thiopental sodium are broadly comparable interms of seizure control, mortality, rate of complications and long-term outcome of patients with RSE. The 95% confidence intervalwas wide and allowed for a up to a more than two-fold differ-ence between the two drugs. Days of mechanical ventilation weremore in patients receiving thiopental sodium when compared withpropofol.
Overall completeness and applicability ofevidence
There is lack of evidence that can clarify the efficacy of propofoland thiopental sodium over each other in the treatment of RSE.We are unable to detect a difference between the two drugs dueto methodological issues. There is a need for a large, randomisedcontrolled trial for this serious condition.
Quality of the evidence
Low.
Potential biases in the review process
None known.
Agreements and disagreements with otherstudies or reviews
To date this is the only eligible study available.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
There are no data from randomised controlled trials that can clarifythe superiority of thiopental sodium and propofol over each otherin the treatment of RSE. Clinicians managing such cases of RSEshould be aware of the adverse effects of the two anaesthetics drugs.
Implications for research
RSE is a serious clinical condition where conducting clinical trialsmay be difficult. Various ethical and methodological issues mayarise. However, the problem itself is important and needs to beresolved. Use of thiopental sodium and propofol in RSE patientsshould be assessed with good-quality multicentric, randomisedcontrolled trials, for their effect and efficacy in terms of total con-trol of seizures, mortality, length of ICU and hospital stay, adverseeffects and long-term outcome, such as dependence for daily ac-tivities. Many centres may have to be involved to enrol a suitablenumber of patients so that adequate power of the study can beachieved. A standard method may have to be followed with uni-form outcome measures.
A C K N O W L E D G E M E N T S
We wish to thank The Cochrane Epilepsy Group for their con-tinuous support in helping us prepare the protocol. We wouldlike to thank Professor A Rossetti for providing the additionaldata and information on the included study. We wish to thankthe South Asian Cochrane Network and Centre, CMC, Vellore,India, who conducted the workshop at the Prof. BV Moses andICMR Center for Advanced Research and Training in Evidence-Informed Healthcare, where this review was completed.
Rossetti 2011 {published data only}Rossetti AO, Milligan TA, Vulliemoz S, Michaelides C,Bertschi M, Lee JW. A randomized trial for the treatmentof refractory status epilepticus. Neurocritical Care 2011;14:4–10. [DOI: 20878265]
Additional references
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Higgins 2002Higgins JPT, Thompson SG. Quantifying heterogeneityin a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. [PUBMED: 12111919]
Higgins 2008Higgins JPT, Green S (editors). Cochrane Handbookfor Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. The Cochrane Collaboration,2011. Available from www.cochrane-handbook.org.
Holtkamp 2007Holtkamp M. The anaesthetic and intensive care of statusepilepticus. Current Opinion in Neurology 2007;20(2):188–93. [PUBMED: 17351490 ]
Lefebvre 2009Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searchingfor studies. In: Higgins JPT, Green S (editors). CochraneHandbook for Systematic Reviews of Interventions Version5.1.0 (updated March 2011). The Cochrane Collaboration,2011. Available from www.cochrane-handbook.org.
Marik 2004Marik PE. Propofol: therapeutic indications and side effects.Current Pharmaceutical Design 2004;10(29):3639–49.[PUBMED: 15579060 ]
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Parviainen 2002Parviainen I, Uusaro A, Kalviainen R, Kaukanen E,Mervaala E, Ruokonen E. High-dose thiopental in thetreatment of refractory status epilepticus in intensivecare unit. Neurology 2002;59(8):1249–51. [PUBMED:12391357 ]
Prasad 2005Prasad K, Al-Roomi K, Krishnan PR, Sequeira R.Anticonvulsant therapy for status epilepticus. CochraneDatabase of Systematic Reviews 2005, Issue 4. [DOI:10.1002/14651858.CD003723.pub2]
RevMan 2011The Nordic Cochrane Centre, The Cochrane Collaboration.Review Manager (RevMan). 5.1. Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2011.
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Van Gestel 2005Van Gestel JP, Blussé van Oud-Alblas HJ, Malingré M,Ververs FF, Braun KP, Van Nieuwenhuizen O. Propofoland thiopental for refractory status epilepticus in children.Neurology 2005;65(4):591–2. [PUBMED: 16116121 ]
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Participants Participants: adults (> 16 years) with RSE not due to cerebral anoxia, who clinicallyrequired comaSex (female/male): propofol group: 50%/50%; barbiturate group: 66%/34%Age (median [range]): propofol group: 57 years (26 to 87 years); barbiturate group: 64years (16 to 78 years)Ethnic groups: not reportedDuration of epilepsy: not reportedInclusion criteria: patients > 16 years of age suffering from RSE receiving at least 1 first-line and 1 second-line drug in adequate dosesExclusion criteria: patients with known pregnancy, known intolerance to the study drugs,mitochondrial disorders, egg allergy, hypertriglyceridaemia (> 5 mmol/L) or significantrhabdomyolysis (creatinine kinase > 1500 U/L) on admissionDiagnostic criteria: RSE not due to cerebral anoxia, defined as ongoing clinical or electro-graphic seizures, or repetitive seizures without return to baseline for at least 30 minutesdespite administration of 1 first-line (benzodiazepine) and 1 second-line antiepilepticdrug (phenytoin, valproate, phenobarbital and levetiracetam) in adequate dosesComorbidities: noneCo-medications: noneTotal randomised: 24 patients; 14 allocated to propofol group and 10 allocated to bar-biturate group; (1 patient in thiopental sodium group did not require treatment and soexcluded, remaining 9 analysed)
Interventions Number of control centre: 2Country/location: Switzerland and USSetting: CHUV et Universite de Lausanne, Lausanne and Brigham and Women’s Hos-pital, Harvard School of Medicaine, BostonIntervention I: 2 mg/kg titrated to burst suppression or 4 mg/kg until EEG was availableIntervention II: 2 mg/kg iv titrated to burst suppression or 5 mg/kg if no EEG availableTreatment before study: first- and second-line antiepileptic drugsTime to treatment since onset of status: not reportedDuration of follow-up: 3 months2 treatment arms: propofol and barbiturates (thiopental sodium or pentobarbital)
Outcomes Primary outcomes (as stated in the publication): to assess the effectiveness (RSE control,adverse events) of a first course of propofol versus barbituratesSecondary outcomes (as stated in the publication): noneAdditional outcomesOutcome used in our review:
• total control of seizures• mortality• adverse events• duration of mechanical ventilation
Notes Stated aim of study: “This prospective study was undertaken to assess the effectiveness(SE control, adverse events) of a first course of PRO versus barbiturates, the two mostcommonly used agents according to the aforementioned surveys”Language of publication: EnglishCommercial funding: yesNon-commercial funding: noPublication status(peer review journal): yesPublication status (journal supplement): noPublication status (abstract): noFunded by AstraZeneca (Switzerland) and UCB (Switzerland)No conflict of interestClinical Trial.gov ID: NCT00265616
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selectionbias)
Low risk “After written consent was obtained byproxy, randomisation was stratified by in-stitution using sealed envelopes”Comment: probably done
Allocation concealment (selection bias) Unclear risk Not mentionedComment: authors contacted. No informa-tion provided
Blinding (performance bias and detectionbias)Subjective Outcomes
High risk Being a single-blind study, only the patientwas blinded. Assessors were not blinded
Incomplete outcome data (attrition bias)All outcomes
Low risk No loss to follow-up. All participants ran-domised completed the study and were in-cluded in final analysis
Selective reporting (reporting bias) Low risk All outcomes that were mentioned in themethodology have been reported
Other bias Unclear risk Trial was terminated before completion dueto inadequate recruitmentFunding by pharmaceutical companies
EEG: electroencephalography; iv: intravenous; RSE: refractory status epilepticus.
roup, death on day 5 (colic ischaemia) and day 21 (Paraneoplastic encephalitis). Presuming deaths on day 5, 6 and 11 as in-hospital deaths. .
(1) Individual patient data for mortality in propofol group: Death on day 5 (Creuzfeld Jakob disease), day 6 (cardiac asystole), day 11 ( progressive brain tumour); other
#1 status epilepticus#2 MeSH descriptor Status Epilepticus explode all trees#3 (thiopental) or (thiopentone)#4 MeSH descriptor Barbiturates explode all trees#5 MeSH descriptor Thiopental explode all trees#6 (#3 OR #4 OR #5)#7 MeSH descriptor Propofol explode all trees#8 (propofol)#9 (#7 OR #8)#10 (#1 OR #2)#11 (#6 AND #9 AND #10)
Appendix 2. MEDLINE search strategy
This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials published in Lefebvre 2009.1. randomized controlled trial.pt.2. controlled clinical trial.pt.3. randomized.ab.4. placebo.ab.5. clinical trials as topic.sh.6. randomly.ab.7. trial.ti.8. 7 or 5 or 2 or 6 or 1 or 4 or 39. exp animals/ not humans.sh.10. 8 not 911. exp Status Epilepticus/12. status epilepticus.tw.13. 11 or 1214. exp Thiopental/15. exp Barbiturates/16. (thiopental or thiopentone).tw.17. 14 or 15 or 1618. exp Propofol/19. propofol.tw.20. 18 or 1921. 17 and 2022. 10 and 13 and 21
• All India Institute of Medical Sciences, New Delhi, India.
External sources
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D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W
The primary outcome in our protocol ’total control of seizures’ is defined as total control of seizures after the first course of the studydrug.
By ’mortality’ we meant only the in-hospital mortality of the patients receiving study drugs. It does not include deaths after the patientswere discharged from the hospital.
A Google Scholar database search has not been conducted and so it has been removed from the list.
