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A comparison of lorazepam and diazepam asinitial therapy in convulsive status epilepticus

H.R. COCK1 and A.H.V. SCHAPIRA1,2

From the 1Department of Clinical and Experimental Epilepsy, Institute of Neurology, London,and 2University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK

Received 4 January 2002 and in revised form 1 February 2002

Summary

Background: Previous trials have suggested loraze-pam may be superior to diazepam as first-linetreatment of convulsive status epilepticus (CSE), withimproved seizure outcome, and a lower incidenceof side-effects. Many published guidelines howeverstill recommend diazepam.Aim: To compare the efficacy, safety and costof lorazepam compared to diazepam, in adultswith CSE.Design: Retrospective case note audit.Methods: Cases of CSE were retrospectively identi-fied over two 18-month periods either side of theintroduction of a new management protocol inMay 1997, in which lorazepam 4 mg i.v. wassubstituted for diazepam 10 mg i.v. as first-linetreatment for CSE. Diagnostic codes for all admis-sions and casualty presentations of patients over

16 years of age were examined for primary orsecondary codes including ‘epilepsy’, ‘fits’ or‘status epilepticus’. Medical records and casualtynotes were reviewed to identify CSE cases. Treat-ment groups were compared using ANOVA and aTukey post hoc analysis. Treatment success wasdefined as cessation of seizures without recurrencein the subsequent 12 h.Results: In both premonitory and established CSE,both drugs were equally effective at terminatingseizures, but significantly fewer seizure recurrencesfollowed lorazepam, and fewer repeat doses wereneeded. There were no differences in reportedadverse events or in drug costs.Discussion: We recommend that lorazepam be thefirst-line therapy in preference to diazepam inadults with CSE.

IntroductionConvulsive status epilepticus (CSE) is recognizedas requiring prompt diagnosis and treatment, as

seizure duration is an important prognosticfactor.1,2 Traditionally, parenteral benzodiazepineshave been used as first-line therapy, and a numberof studies3–6 have suggested that lorazepam issuperior to diazepam as first-line therapy, withimproved seizure outcome and less respiratorydepression. However many published guidelinesstill recommend diazepam,7,8 and there are fewdata about the use of lorazepam in routine clinicalpractice in adults, and no published cost analysis

data. We report a comparison of the efficacy, safetyand cost of lorazepam and diazepam, undertaken

as part of a London teaching hospital audit on themanagement of CSE in adults.

MethodsCases of CSE were retrospectively identifiedover two 18-month periods either side of theintroduction of a new management protocol(May 1997) (Figure 1). The main change was the

Association of Physicians 2002

Address correspondence to Dr H.R. Cock, Department of Clinical and Experimental Epilepsy, Institute of Neurology,

Queen Square, London WC1N 3BG. e-mail: [email protected]

Q J Med 2002; 95:225–231

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recommendation of lorazepam (4 mg i.v., repeatedup to 2 times) in place of diazepam (10 mg i.v.,repeated up to 3 times) as first-line treatment forCSE. Phenobarbitone was also recommended inpreference to phenytoin, as cardiac monitoring wasnot easily available on all medical wards, and it wasfelt this might delay second-line treatment in someinstances. The protocol was endorsed by all theNeurology Consultant staff at the hospital, approved

with the hospital pharmacy and local statutorycommittees, and then widely distributed and

publicized during two months prior to May 1997.All relevant senior staff (Medical and Accident &Emergency Consultants) were personally informedby letter, along with a copy of the protocol. All

junior staff were given a ‘filofax’-sized copy for theirown use, and it was included in the hospital

formulary and junior doctors handbook given toall new staff. The protocol was also presented alongwith a detailed rationale at the hospital medicalgrand round, and separately to Accident &Emergency junior doctors. Subsequent to May1997, new staff continued to receive the samedocuments, and copies of the protocol weredisplayed prominently in Accident & EmergencyDepartment. Teaching sessions to junior doctors(Medical and Accident & Emergency SHOs),occurring every 6 months, continued to reinforcethe protocol.

The diagnostic codes for all admissions andcasualty presentations of patients over 16 yearsof age admitted between 1.10.95–31.3.97 and1.6.97–31.11.98 were examined, and patientswith primary or secondary codes including‘epilepsy’, ‘fits’ or ‘status epilepticus’ identified.Medical records and casualty notes of these caseswere reviewed by a single assessor (HC), andthose with premonitory (p)CSE or established(e)CSE were identified. Premonitory SE (pCSE) wasdefined as new onset convulsive seizures lastingmore than 5 min, two or more seizures without

recovery of consciousness in between, or anincreased frequency of convulsive seizures inpatients with known epilepsy of sufficient magni-tude to warrant urgent medical intervention, as

judged by the assessing clinician. Established CSE(eCSE) was defined as convulsive seizures, eithercontinuously or recurrently without regaining con-sciousness, lasting more than 30 min.9,10 Patientssubsequently considered to have non-epilepticattacks were excluded from the study.Demographic, clinical, and treatment details fromall identified patients were recorded anonymouslyon a computer database for subsequent analysis.The treatment groups were compared usingANOVA and a Tukey post hoc analysis. Treatmentsuccess was defined as cessation of seizures with-out recurrence in the subsequent 12 h. The out-comes following diazepam or lorazepam as earlytherapy were compared using x2 and a two-sidedFishers exact test or Pearson’s test. Values of p -0.05 were considered significant.

Results

At total of 720 coded episodes were identified,from which medical records were retrieved for

Figure 1. Protocol for management of status epilepticus

in adults.

H.R. Cock and A.H.V. Schapira226

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590 (82%). From the examined records, therewere 90 episodes of CSE identified (37 eCSE and53 pCSE) during the study period. In 13/90 episodes(all pCSE), no benzodiazepine was given, and afurther five did not receive either i.v. lorazepamor diazepam as part of their initial treatment (four

chlormethiazole, one midazolam). Comparisonsbetween lorazepam and diazepam outcomes havebeen made based on the remaining 72 episodes(Figure 2). Details of these cases are given inTable 1, subgrouped according to initial benzo-diazepine treatment. There were no significantdifferences in clinical characteristics between thetreatment groups.

In the entire study period, 34 doses of lorazepamwere given to 26 patients (17 as first dose of benzo-diazepine given, 13 as second, and 4 as third), allbut one dose being after the new protocol; 96 doses

of diazepam were given to 56 patients (55 as firstdose, 31 as second and 10 as third); 9 patientsreceived both diazepam and lorazepam duringinitial benzodiazepine treatment. Second-linetherapy (Table 2) was only given where initialbenzodiazepine therapy had failed to achieve

control in established cases. This did not differsignificantly between the two groups.

Where lorazepam was the first benzodiazepinegiven, treatment success was significantly morelikely than for diazepam (9/17 doses lorazepam vs.14/55 doses diazepam; p = 0.042). There was no

difference in the likelihood of either drug ter-minating the seizures (11/17 lorazepam vs. 41/55diazepam), but following initial seizure control,seizure recurrence within the subsequent 12 h wassignificantly less likely to occur after lorazepam(2/11 vs. 31/45 diazepam; p = 0.005, Pearson’s).

For any individual dose of lorazepam (whethergiven as first, second or third dose of benzodia-zepine, with prior use of diazepam in some cases)the incidence of seizure recurrence was againsignificantly reduced (7/34 doses vs. 53/96 dosesdiazepam; p = 0.0006). In keeping with this, where

a second or third dose of benzodiazpine wasrequired, this occurred significantly less oftenafter lorazepam than after diazepam (8/31 dosesvs. 49/86 diazepam; p = 0.0034). Separate analysisof eCSE and pCSE cases did not change theconclusions, although numbers were then toosmall reach significance (data not shown).

There was no significant difference in theoccurrence of documented complications such ashypotension, sedation or respiratory depressionfollowing benzodiazepine administration betweenthe treatment groups (Table 2). The frequencies of

other complications, as documented in the notesduring the patients admission, are also given inTable 2. Four patients, two treated with diazepamand two with lorazepam, all with eCSE, diedwithin 1 month of presentation, giving a mortalityof 11% in this group. Associated morbidities inthese patients included encephalitis (1), cerebro-vascular disease (2), and a subdural haematoma (1).Two of the fatalities also had a history of alcoholabuse. All the surviving patients were dischargedfrom hospital back to their prior residence, butfurther follow-up data on level of function/disabilitywere not obtainable from this retrospective study.

Prior to the introduction of the new protocol,all but one (treated by HC) of the cases receivedonly diazepam as first-line treatment. After May1997, 43% of cases (19/44) received lorazepam asthe first hospital-administered benzodiazepine, inkeeping with the protocol. This included 12 patientswho had been given diazepam by paramedics/carestaff prior to arrival at the hospital. However, theremaining cases were not managed according tothe protocol and in these diazepam was the firsthospital-administered benzodiazepine.

The hospital cost of lorazepam was £0.78 for

4 mg, compared to £0.45 for 10 mg for diazepam atthe time of the study. However, when used as theFigure 2. Case retrieval and classification.

Lorazepam vs. diazepam in status epilepticus 227

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first benzodiazepine, because lorazepam wassignificantly more likely to achieve seizure control,the cost per successful outcome was no different

between the two drugs (lorazepam 17 doses at£0.78/dose, 9 successes= £1.47/success; diazepam

55 doses at £0.45/dose, 14 successes= £1.46/ success).

DiscussionIn this retrospective study, i.v. lorazepam wasassociated with significantly better seizure outcomethan diazepam, with no associated increase in cost

or adverse events. Both drugs were equally effectiveat terminating seizures, but diazepam was asso-ciated with significantly more seizure recurrencerequiring repeated doses, in keeping with theknown pharmacokinetics. Diazepam is highlylipid-soluble, and rapidly crosses the blood-brainbarrier. However, it is also rapidly redistributedfrom into peripheral stores, with a short distributionhalf-life. Repeated doses may compensate for this,but can lead to saturation of the peripheralcompartments and unpredictable sudden rises inserum levels.8 Lorazepam is less lipid-solublewith a longer duration of action, and less risk of cardiorespiratory depression, although repeatdoses have been associated with tachyphylaxis.However, in practical terms this has little signific-ance, as where two doses of a benzodiazepine havefailed to achieve control in CSE, further dosesare not indicated and second-line therapy (e.g.phenobarbitone, phenytoin) should be instituted.

The definition of eCSE used in this study iswidely accepted. Our definition of premonitorystatus includes the more recently proposed opera-tional definition introduced in order that appro-priate treatment is instituted without delay.11 We

also included patients presenting with an increasedfrequency or severity of habitual seizures in the

Table 1 Clinical details of cases of CSE according to initial benzodiazepine treatment

LZP only DZP only Both

Total number of episodes 17 46 9Number eCSE : pCSE 6 : 11 25 : 21 6 : 3Mean age in years (range) 46.9 (17–84) 51.8 (20–88) 51.8 (25–78)Sex (M : F) 10 : 7 30 : 16 4 : 5Known epileptics (n (%)) 12 (70) 37 (80) 8 (88)Identified aetiology/precipitants* (n (%)) 10 (59) 33 (71) 6 (66)

Alcohol 5 (29) 18 (39) 3 (33)Poor compliance 3 (18) 13 (28) 4 (44)CNS infection 1 (6) 1 (2) 0 (0)Cerebrovascular disease 0 (0) 2 (4) 0 (0)Other** 4 (23) 8 (17) 1 (11)

Mean duration prior to first treatment*** (range) 45 (30–90) 59 (15–315) 45 (10–120)

LZP, lorazepam; DZP, diazepam; *Some patients had more than one identified factor. **Includes systemic infection;subdural haemorrhage; toxic; metabolic; multiple sclerosis. ***eCSE cases only (some DZP patients were treated prior toarrival in A&E).

Table 2 Outcome following initial benzodiazepinetreatment

LZPalone

DZPalone

Both

Number of episodes 17 46 9Treatment success* 11 28 6

Complications **Sedation 5 8 2Hypotension 0 4 0

Other 1 3 1Second-line treatment Phenobarbitone 3 1 1Phenytoin 0 11 3Other 3 6 0

Second-line treatment success 5 11 2Required ITU admission 2 3 1

Other complications Pneumonia 1 2 0Sepsis 0 1 0Other*** 2 2 2

*As defined in the text, seizure cessation withoutrecurrence over 12 h. **Complications/clinical changesas documented in the notes following benzodiazepineadministration. Factors other than the drug (post-icthalchanges, cause of status) may also have contributed.***Included: respiratory arrest (1), respiratory depression(1), atrial fibrillation (1), gastrointestinal haemorrhage (1),raised intracranial pressure (2). Some patients had morethan one complication.


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pCSE group, as urgent intervention in such patientscan prevent the development of eCSE.8

We accept that retrospective case analysisfrom diagnostic codes is liable to inaccuracies,and confounded further by problems withnote retrieval. Of the cases coded as epilepsy,

even after repeated attempts to retrieve notes up to1 year after the data collection period ended, 18%of notes were never examined. This is comparableto retrieval figures in other retrospective studies inthe UK12 and abroad.13 We cannot rule out thepossibility that this has introduced some bias intothe study. However, given that of the 590 notesthat were examined, only 90 (15%) included a CSEepisode, it is likely that the majority of the missingnotes were also not relevant, and missing noteswere equally distributed in the two study periods.In addition, we also independently examined

casualty records in the study period, and notesfor patients identified by this route were allsubsequently retrieved. The annual incidence of SE is estimated to be around 20/100 000/year,including non-convulsive SE, and with the majorityof cases in children.14 We identified 90 episodes of convulsive status in adults over a 3-year period,from a regional population of 500 000, giving anannual adult incidence of 6/100 000, which is inkeeping with the expected incidence. The mortalityrate (11%) amongst eSE cases is also in keepingwith published figures.8 Thus we believe case

identification to be as near complete as possible.Although the lorazepam group included morepatients with pCSE (11/17) than the diazepam group(21/46), and the mean time to first treatment wasshorter (Table 1, last row), these differences werenot significant. The ‘time to first treatment’ datawere also in part skewed by a few cases with veryprolonged delays before treatment (up to 315minutes in the diazepam group), whereas in manyinstances diazepam was actually given earlierthan lorazepam, as it is often administered byparamedics prior to arrival in A&E. Thus thesefactors do not account for the greater success of treatment with lorazepam compared to diazepam,although they may have contributed to it.

There have been three previous prospectivestudies directly comparing lorazepam with dia-zepam as first-line therapy in SE. In the first of these,a randomized double-blind trial in 81 episodes,lorazepam achieved seizure control in 89% of episodes compared to 76% with diazepam.3 Inkeeping with our findings, this was largelyaccounted for by a significant reduction in seizurerecurrence following lorazepam, with both drugsequally effective at initial seizure termination. In

a later open prospective randomized study in102 children with SE, a single dose of lorazepam

controlled convulsions in 76% of cases, comparedto 51% with diazepam.15 This study also docu-mented a significantly lower incidence of respirat-ory depression (3% lorazepam vs. 15% diazepam),and included rectal administration of the solutionlorazepam where venous access was not possible.

Finally, in a randomized double-blind trial in 205episodes, given intravenous therapy out of hospitalby paramedics, seizures had terminated on arrivalto A&E in 59% given lorazepam, 43% givendiazepam and 21% given placebo. After adjust-ment for covariates, the odds ratio for terminationof seizures was 1.9 in the lorazepam groupcompared to the diazepam group, (95%CI 0.8–4.4),with no difference in the rates of circulatory orrespiratory complications (10% both treatments).The authors in all studies concluded that lorazepamwas superior to diazepam with higher rates of

seizure termination. None assessed subsequentseizure recurrence, which as supported by knownpharmacokinetics and our study data, providesfurther evidence in favour of lorazepam. It wasnot possible in our retrospective study to accuratelydocument time from benzodiazepine therapy toinitial seizure termination, but this did not differedsignificantly in the studies described above.

The results from our study support and extendthe findings of previous trials, and demonstrate thatlorazepam is superior to diazepam not only in thetrial setting, but also in routine clinical practice,

and at no added overall cost. Despite the introduc-tion of evidence-based protocols, at least in thishospital, clinicians have been slow to adopt thisdrug and diazepam is still widely used. Therehave been no published studies of guidelineadherence the management of status epilepticus.However, the problems of guideline implementa-tion in medicine are widely recognized anddocumented both within hospital16,17 and com-munity practice.18 In addition, guidelines for themanagement of status epilepticus have been inthe literature for many years, yet other retrospectivestudies have confirmed that management oftenfails to reflect these guidelines. In a study of 26cases transferred to a neurological intensive careunit, 68% had had inadequate loading withphenytoin prior to transfer.19 Similarly, in a recentreport from the USA, 28% of 184 cases hadhad delayed or inappropriate initial drug treatment,and even where an early appropriate antiepilepticwas given, the dose was inadequate in 76%.20

There have been few systematic studies of factorscontributing to poor guideline adherence, but someare recognized. In our study, the fact that diazepam,a more familiar and readily available alternative21

to lorazepam, was always available in Accident &Emergency is a likely contributor, and not one


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that can be overcome given the numerous otherindications for diazepam. Similarly the highturnover of treating (largely junior) medical staff requires very regular reinforcement of guidelines if they are to be maintained. As part of reinforcingadherence, feedback from this audit has already

been presented at the hospital. We are continuingto supply to protocol copies to all new medical staff,and to include teaching on the topic in theireducational programs, but recognize in light of our experience that this alone is insufficient. Theuse of guideline-based ‘care-management teams’has been shown to be more efficient than simpleguideline dissemination in the management of chronic conditions such as heart failure,17 butthis is not practical for emergency situations. Wesuggest in this scenario, regular education andreinforcement must be directed at the Accident &

Emergency staff, and must include the nursingand pharmacy staff, particularly given their lowerturnover compared to junior medical staff. In thisway it is hoped that even if the new junior doctorasks for diazepam, they might be reminded at thetime that there is a more suitable alternative. Werelorazepam to become more routinely used byparamedics prior to arrival in hospital, this mightalso increase familiarity with the drug amongmedical staff.

Whether nationally agreed guidelines (such ashave been published for the management of CSE

in children)

22

would improve adherence, is notknown. It has been suggested that if guidelines aredeveloped nationally, this leaves hospitals to focustheir energies on local adaptation, dissemination,implementation and evaluation.23 We agree thatsuch national guidelines, such have been agreedfor the management of other medical emergencies(e.g. cardiac arrest, myocardial infarction) would bebeneficial, but further study of methods to improveimplementation, and outcome evaluation, is alsoneeded.

We recommend that where venous access ispossible, lorazepam should be the first-line treat-ment for premonitory and established status epi-lepticus in place of diazepam, both in and out of hospital. In patients without venous access, furtherstudy is needed to address the potential role of rectal administration of lorazepam, although altern-atives such as buccal midazolam are also underevaluation and appear promising.24

Acknowledgements

Grateful thanks to the Royal Free Hospital Auditdepartment for assistance with case identification

and notes retrieval. Thanks also to Hilary Watts(Statistician, Institute of Neurology) for advice onstatistical analysis, and Professor Simon Shorvon(Institute of Neurology) for comments on themanuscript.

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