emergency treatment of acute seizures and status epilepticus

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CURRENT TOPIC

Emergency treatment of acute seizures and statusepilepticus

Robert C Tasker

This article discusses some of the issues relatedto protocols for emergency anticonvulsanttreatment of acute seizures and status epilepti-cus with particular emphasis on the use of ben-zodiazepines in children presenting to accidentand emergency departments.

DefinitionsInfants and children can have both convulsive

and non-convulsive forms of prolonged sei-zures. This article addresses only convulsiveepisodes of status epilepticus, which is strictlydefined as two or more seizures occurring con-secutively without an intervening period of fullrecovery of consciousness, or as recurrent epi-leptic seizures lasting for more than 30minutes.1 Unfortunately, such a precise defini-tion of status epilepticus, although useful forepidemiological analysis and evaluation oftherapeutic interventions, conceals a some-times frenetic approach to acute care and theurgency experienced by clinicians when con-fronted with a convulsing child, irrespective ofhow long the episode has lasted. It therefore

seems more appropriate to take a pragmaticview and consider status epilepticus as thesevere end of a continuum encountered duringthe progressive evolution of an unrelenting sei-zure, which heralds a potentially life threaten-ing sequence of complications in central, meta-bolic, and systemic physiology (table 1).25 Thissomewhat looser approach is reflected in thepaediatric literature where seizure episodes ofconsiderably less than 30 minutes have beenconsidered as status epilepticus.6 7

Clinical perspectiveBoth the clinical context and natural history ofacute seizures and status epilepticus are very

important considerations when evaluatingchoice of anticonvulsant treatment. In manyparts of the world status epilepticus inchildhood is often associated with fever,although there is wide variation in theproportion of patients who have this symptom(2550%).810

In the UK, status epilepticus (defined as a 30minute episode) is an infrequent occurrence.For example, Verity et alreported in 19939 thatonly 37 of 14 676 children from a long termcohort study had an episode of status epilepti-cus by their 10th birthday. Similarly, Smith et alreported in 199610 only 12 episodes of status

epilepticus (lasting longer than 30 minutes) in254 seizure episodes occurring in children pre-senting to an accident and emergency depart-ment over one year; this was from a surround-ing population of 70 000 children.

Clinical strategySmith et als district general hospital study10

also illustrated another important feature of

acute seizures in children: 80% of them did notrequire any anticonvulsant treatment in theemergency department. Therefore, given thatmost acute seizures in children stop spontane-ously, usually during transit to hospital, weshould assume that if a child is still convulsingon arrival in the emergency department theseizure will continue unless treated. Howrapidly such treatment should be carried outthen becomes an important issue. Statusepilepticus in the 1990s has a relatively lowmorbidity and mortality directly attributable tothe seizure itself,8 9 and an overexuberantapproach with anticonvulsants may exposepatients to the unnecessary iatrogenic risks of

respiratory depression and hypotension. Onecommentator has raised the important ques-tion Does the morbidity of the treatment ofseizures in the emergency room to prevent sta-tus now exceed the morbidity of the status epi-lepticus itself?.11 In the absence of any clearclinical data to answer this question fully, theonus on those involved with acute seizuretreatment is to ensure that it is administeredsafely and in a standardised fashion that isunderstood by all emergency personnel in-volved.

Emergency supportive treatmentAnyone who is still convulsing on arrival in theemergency department should receive immedi-ate, basic, supportive treatment.

AIRWAY AND OXYGENATION

Hypoxaemia can be both the cause and theconsequence of a seizure. In severe episodesbradycardia and hypotension may complicatethe seizure. To begin with, the head and neckshould be positioned to keep the airway openand, if necessary, the airway should besuctioned to ensure patency. If feasible, an oralairway can be insertedalthough this shouldonly be done if there is no likelihood of traumato the mouth and teethand oxygen should be

Arch D is C hild1998;79:788378

Department ofPaediatrics, Universityof Cambridge School

of Clinical Medicine,Cambridge CB2 2QQ,UKR C Tasker


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administered by nasal cannula or mask andbag-valve-mask ventilation. If the need for res-piratory assistance persists after the patient hasbeen supported by bag-valve-mask, endotra-cheal intubation should be considered. How-ever, administering an anticonvulsant is a top

priority because managing the airway andassisting respiration are much easier after theconvulsion has stopped. If persistent convulsiveactivity causes hypoventilation necessitatingendotracheal intubation, seizure activity can bestopped temporarily with a high dose of a shortacting barbiturate or midazolam, and patientventilation dysynchrony can be abolished witha neuromuscular blocking agent.

GLUCOSE

Hypoglycaemia is a rare cause of prolongedseizures in children. However, all patientsshould have prompt measurement of bloodglucose. If hypoglycaemia (blood glucose< 3 mmol/l) is documented or if it is impossi-

ble to obtain the measurement, intravenousglucose (5 ml/kg) should be administered as10% glucose.

BLOOD PRESSURE

Hypotension can potentiate or exacerbate anyderangement in cerebral physiology and func-tion. Systolic blood pressure should be main-tained at normal levels. If there is no evidenceof shock, minimal isotonic fluids of 23 ml/kg/h should be given initially.

Anticonvulsant treatmentIn the convulsing patient, initial supportive,therapeutic, and diagnostic measures need tobe conducted simultaneously. The goal of anti-convulsant treatment is the rapid terminationof clinical and electrical seizure activity by theprompt administration of appropriate drugs inadequate doses,with attention to the possibilityof complicating apnoea, hypoventilation, andother metabolic abnormalities.

PROLONGED SEIZURES AND ANTICONVULSANT

RESPONSIVENESS

The concept of acute seizures and statusepilepticus being on a continuum is useful inregards to administering anticonvulsant treat-

ment. For example, using diazepam in control-led experimental studies of prolonged seizureshas established that the longer the duration of aseizure episode before treatment (ranging from7130 minutes) the more diYcult it is to stop,and the more likely it is that diazepam willconvert an overt motor episode into anothersubtle or electroencephalographic form ofseizure activity.12 As similar findings have beenreported in man,13 the need for rapid, definitive

treatment of acute seizures, irrespective ofwhether 30 minutes has elapsed, is under-scored.

ANTICONVULSANT PROTOCOL

There is a dearth of evidence in children thatone particular anticonvulsant protocol is bestfor treating acute seizures. There is need for aformal systematic review of the literature toidentify what would be the appropriate strategyfor future investigation. A clear path ortreatment plan however is necessary now, andindeed has been recommended for eVectiveand consistent management.14 One such ap-proach is that used by the Advanced Life

Support Group in their recommendations foradvanced paediatric life support (fig 1).15 Whileendorsing wholly this specific approach, notleast because it is taught widely and has beenadopted as a national standard of care, themain problem with this approach is the time itmight take to stop a seizure if oYcialrecommendations are adhered to. For example,25 to 30 minutes of seizure activity may haveelapsed before either phenytoin or phenobarbi-tone is given: five minutes before the first doseof diazepam, then five minutes to see ifdiazepam is eVective, then the second dose ofdiazepam, then five minutes to see if this doseis eVective, then a dose of paraldehyde, then 15to 20 minutes to see if this is eVective, etc. We

shall therefore consider other emergingstrategies using only benzodiazepine agents(figs 1 and 2),16 which may simplify ourapproach to acute emergency seizure treat-ment.

Benzodiazepine agentsPREHOSPITAL TREATMENT

The eYcacy of intravenous diazepam for thetreatment of status epilepticus is well recog-nised with termination of episodes in some80% of cases.17 However, safety is a significantconcern as apnoea and respiratory depressionare common complications.18 Therefore, ex-cept in known cases of recurrent prolonged

seizures, drug treatment in the UK hastraditionally been reserved for administrationafter arriving in hospital. If, as alreadydiscussed, diazepam is not only eVective treat-ment but also better when administered earlier,why not give it before arriving at hospitalproviding it can be carried out safely? Insupport of this argument is a recent Americanretrospective, case-control, study by Alldredgeet al.7 Using a definition of status epilepticus asseizures lasting longer than 15 minutes, theseauthors found (in 45 convulsive episodes) thatprehospital treatment with intravenous di-azepam (0.2 mg/kg) or rectal diazepam

Table 1 Systemic physiology, metabolic, as well as central changes, and derangementsduring prolonged seizures25

< 30 mins(phase I)

> 30 mins( phas e I I) H ou rs ( re fract or y)

Systemic physiologyBlood pressure Increase Decrease HypotensionArterial oxygen Decrease Decrease HypoxaemiaArterial carbon dioxide Increase Variable HypercapniaLung fluid Increase Increase Pulmonary oedemaAutonomic activity Increase Increase ArrhythmiasTemperature Increase by 1C In cre ase by 2C Fever, hyperpyrexia

Metabolic (serum)pH Decrease Variable AcidosisLactate Increase Increase Lactic acidosisGlucose Increase Normal or raised HypoglycaemiaPotassium Increase or normal Increase HyperkalaemiaCreatine phosphokinase Normal Increase Renal failure

CentralCe re bral bl ood fl ow Inc re ase 90 0% In cre ase 2 00% Ce re bra l oe demaCerebral oxygen consumption Increase 300% Increase 300% Cerebral ischaemiaCerebral energy st ate Compensated Failing Deficit, i schaemia

Emergency treatment of acute seizures and status epilepticus 79


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(0.6 mg/kg) by paramedical staV significantly

shortened the duration of status epilepticus(mean for prehospital 32 minutes v mean foremergency department 60 minutes; p = 0.007)

and reduced the likelihood of recurrentseizures in the emergency department (58% v85%; p = 0.045). This study found no diVer-

ence between the eVectiveness of rectal and

intravenous diazepam. This experience seemsto confirm the experimental data already

described,13 but is such an approach safe?

The possible complication of respiratorydepression from rectal diazepam has been con-

sidered in some depth in the treatment of

repeated febrile convulsions.19 Respiratory de-pression from rectal diazepam (0.20.5 mg/kg)

is rare among children studied to date,

probably because of the slower rise in serumdiazepam concentrations compared with that

achieved after intravenous administration. The

clinical eVect from rectal diazepam occurs in

approximately five minutes and peak serumconcentrations are achieved 610 minutes after

administration.20 21 Knudsen22 reported no res-piratory complications in 376 children treated

with rectal diazepam. (The upper limit of the

95% confidence interval for 0/376 is 8 per 1000

cases.) A literature review of 13 papers on rec-tal diazepam by Siegler in 199023 identifiedonly three cases of reversible respiratorydepression in 843 cases. Some patients, how-ever, may be at more risk of respiratorydepressionfor example, those with seriouscomorbidity and those on regular anticonvul-

sants or with chronic central nervous systemabnormalities.23 In these patients a lower rectaldose of 0.25 mg/kg is advised.

Therefore, the literature supports the use ofa single prehospital dose of rectal diazepam,although attendants should be aware of thepossibility of respiratory depression and be ableto support breathing if necessary.

FIRST LINE HOSPITAL TREATMENT

A child who is still convulsing on arrival inhospital can be assumed to have had a seizurelasting at least 10 minutes and therefore willrequire emergency treatment. Some childrenmay have already received rectal diazepam. Inthis phase of management the issues arewhether diazepam is the treatment of choiceand, if it is, should it be used more than once.Although the precise serum diazepam concen-tration required for a therapeutic eVect is notknown, concentrations of 150336 ng/ml areassociated with arrest of seizure activity.24

These are achieved with a single dose of rectaldiazepam,20 22 which questions the notion thatfurther doses would be of benefit in those

whose seizure has not come under controlunless of course administration of the first dosehas been unreliable or if a second episode hasoccurred. Few studies in children have lookedspecifically at the eVectiveness of serial doses ofdiazepam when the first dose has failed to con-trol the seizure. However, some information onthis question can be learnt indirectly from arecent prospective study reported by Appletonet al.25 Of 53 patients presenting with acute sei-zures to an emergency department, 28 re-sponded to a single dose of rectal orintravenous diazepam (0.30.4 mg/kg). In the25 who required a second dose, 17 also neededadditional anticonvulsant drugs.This may havebeen because of the local protocol, but it does

suggest that in those who do not respond to aninitial dose of diazepam, the second dose is alsolikely to be ineVective. Therefore, if givingdiazepam twice is questionable, is there a betteralternative?

Choices from phenobarbitone, phenytoin,and lorazepam as candidate alternative drugsfor status epilepticus have been debated in theliterature.16 26 27 Lorazepam, a hydroxylatedbenzodiazepine (fig 2), is an eVective anticon-vulsant with a response latency comparable tothat of diazepam, and it has the advantage of alonger duration of anticonvulsant eVect thandiazepam.27 Although there are few studiescomparing lorazepam with established stand-

ards, it has been recommended as one of thefirst line agents for status epilepticus for theabove reasons.27 One preliminary study25 com-pared lorazepam with diazepam for the treat-ment of acute convulsions and status epilepti-cus in 102 children in a prospective, open (oddand even dates) trial. Sixteen children had to beexcluded and of the remaining 86, convulsionswere controlled in 76% of patients treated witha single dose of lorazepam (0.050.1 mg/kg)and 51% of patients treated with a single doseof diazepam. Significantly fewer patientstreated with lorazepam required additionalanticonvulsants to terminate the seizure.

Figure 1 Timing for the Advanced Paediatric Life Suppor t (APLS) standardanticonvulsant protocol for status epilepticus15 alongside a potentially challenging approachusing only benzodiazepines.The time line highlights a problem with the APLS approach:it may be 25 minutes before progressing to phenytoin or phenobarbitone. *Do not use if thechild is known to be on regular phenytoin.

Standard protocol Benzodiazepines

Diazepam0.4 mg/kg iv or rectal

Prehospital(0 to 10 minutes)Diazepam rectal

Diazepam

0.4 mg/kg iv or rectal

Paraldehyde0.2 ml/kg rectal

Paralyse and ventilateThiopentone infusion

Midazolamup to 18 g/kg/min

ORThiopentone infusion

Phenytoin*

18 mg/kg iv

Phenobarbitone

15 mg/kg iv

< 1year 25 minutes

60 minutes

10 minutes

> 1year

First line

(10 to 25 minutes)Lorazepam0.050.1 mg/kg 2

iv or rectal? Midazolam

Refractory(> 30 minutes)

Midazolam0.15 mg/kg iv bolus

Then infusion: 1 g/kg/minincreasing to 4 g/kg/min

over 60 minutes if necessary

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Respiratory depression occurred in 3% oflorazepam treated patients and 15% of di-azepam treated patients. No patient whoreceived lorazepam required admission to theintensive care unit for either respiratorydepression or refractory status epilepticus,whereas all eight of the patients with diazepamrelated respiratory depression were admittedfor intensive care. Importantly, rectal andparenteral lorazepam were equally eYcacious.

Despite these favourable aspects oflorazepam, there are still indications for theother agents. Lorazepam appears to be lesseVective in patients chronically treated withother benzodiazepine anticonvulsants and inthose who will need the drug more than once.27

In both of these instances phenobarbitoneappears to be superior,26 28 although there islittle comparative clinical data for these agentsand phenytoin. In practice, choice betweenanticonvulsants appears to relate to age andaetiology. In infants, the metabolism ofphenobarbitone is more predictable than themetabolism of phenytoin. Phenytoin has a rolewhen there is concern about impaired cerebralfunction and the need for clinical assessment ofneurology.

REFRACTORY SEIZURES

Refractory status epilepticus has been defined

as a seizure that is unresponsive to an adequatedose of a first line parenteral anticonvulsant28;or a seizure that is unresponsive to at least twodoses of diazepam intravenously or rectally insuccession followed by phenytoin/phenobarbitone or both (20 mg/kg) given over30 minutes as an infusion, or failure to respondto the latter alone or in combination15 2830; or aseizure that continues for 60 to 90 minutesafter the initiation of treatment.1 This lack ofconsistency in definition is important when oneconsiders the treatment and its consequences.Traditionally, for the most severe cases of statusepilepticus induction of general anaesthesia has

been recommended using a short actingbarbiturate such as thiopentone (48 mg/kgbolus followed by infusion of up to 10 mg/kg/h)along with supportive endotracheal intubationand mechanical ventilation.15 29 An alternative,eVective approach has been to use, if necessary,repeated bolus doses of intravenous phenobar-bitone (10 mg/kg) every 30 minutes, withoutreference to a predetermined maximum levelor dose, after one dose of intravenous diazepamhas failed to control a seizure.28 A number ofquestions arisefor example, at what point isinduction of anaesthesia overexuberant? Is itreally necessary to wait 60 to 90 minutes beforedeciding that standard anticonvulsants are

ineVective? When is it inevitable that standardanticonvulsants are unlikely to workafter thesecond dose of diazepam, after the seconddrug, or after the third drug? Some of theseissues have been addressed already. The maindisadvantage of thiopentone relates to its highlipid solubility and slow metabolism, whichresults in a prolonged period of intensive caresupport before a child is completely awake andcooperative once treatment has been stopped.29

Similarly, prolonged intensive care will be nec-essary when using the very high dose pheno-barbitone strategy.28

A newer approach, recently delineated inchildren, has been to use midazolam,30 31 animidazobenzodiazepine (fig 2). This drug has arelatively short elimination half life of 1.5 to 3.5hours, and preclinical and clinical analysesindicate that it shares anxiolytic, muscle relax-ant, hypnotic, and anticonvulsant actions withother benzodiazepines. Rivera et alreported theuse of midazolam in 24 children (aged 2months to 2 years) with status epilepticus fail-ing to respond to three repeated doses of0.3 mg/kg diazepam, 20 mg/kg of phenobarbi-tone, and 20 mg/kg phenytoin.30 Intravenousmidazolam given as a bolus of 0.15 mg/kg fol-lowed by continuous infusion of 1 g/kg/min(with increasing increments of 1 g/kg/min

Figure 2 Chemical structure and pharmacokinetic properties of diazepam, lorazepam, and midazolam illustrating some of the s imilarities between thesebenzodiazepine GABA

Aagonists. Adult pharmacokinetics16: V

d, volume of distribution; T12, distribution half life; T12, elimination half life; Cl, clearance.

All three drugs are metabolised in t he liver and exc reted via the kidney. All three have significant protein binding (> 88%).

CH3

ON

NCl

Diazepam

LipophilicRelatively insoluble in waterpKa 3.4 (basic)

Vd 0.82.6 l/kgT1/2 20240 minutesT1/2 2448 hoursCl 0.020.03 ml/kg/h

Active metabolite: nordiazepam

H3C

CH3

N

CCH

N

N

F

Cl

Lorazepam

Moderately lipid solubleInsoluble in water (unionised at pH 7.4)pKa 1.3/11.5 (amphoteric)

Vd 12 I/kgT1/2 23 hoursT1/2 824 hoursCl 0.010.1 ml/kg/h

Active metabolite: none

H

O

OH

HN

NCl

Midazolam

Lipid solubleWater solublepKa 6.2 (basic)

Vd 0.61.7 l/kgT1/2 15 minutesT1/2 1.53.5 hoursCl 0.40.7 ml/kg/h

Active metabolite: hydroxymidazolam

Cl



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every 15 minutes until seizure control) wassuccessful in all cases. The average time toachieve seizure control was 47 minutes (range15 minutes to 4.5 hours) with a mean infusiondose of 2.3 g/kg/min (range 1 to 18). Afterstopping the infusion, the average time to fullconsciousness was just over four hours (range 2to 8.5). Lal Koul et alrecently reported similarfindings in a further 20 children.31

Given the structural and pharmacokinetic

similarities between diazepam and midazolam(fig 2) and their similar mechanism of actionvia binding to the -aminobutyric acid A(GABAA) receptor, it is pertinent to questionWhy should midazolam be eVective whenother GABAA agonists including phenobarbi-tone and benzodiazepines have failed? As yetthis cannot be answered from the availabledata, but it may relate to actions andinteractions distant to the benzodiazepinebinding site on the GABAA receptor.

32 Thistherapeutic conundrum does however raiseanother important considerationif mida-zolam is eVective when all drugs have f ailed,would it be a better option earlier in acute sei-

zure care? Lal Koul et al addressed thisquestion in their report31 by using a midazolaminfusion as their only treatment in eightpatients who had seizure activity for at least 30minutes. Once this treatment was started, con-trol of the seizure was achieved within 10 to 60minutes (mean 34). None of their patientsrequired mechanical ventilation or endotra-cheal intubation.

What about the potential use of midazolamas a first line anticonvulsant for all acuteseizures? In the accident and emergencydepartment in predominantly adult series,intravenous33 and intramuscular34 midazolamas first line treatment for seizures have beenused eVectively and safely. Galvin and Jelinek33

reported that intravenous midazolam alone wassuccessful in stopping seizures in all 75 patientsthey treated. Intramuscular midazolam is alsorapidly eVective: in 36 of 38 patients undergo-ing seizures, seven of whom were children, sei-zures were controlled with a mean of 1 minuteand 53 seconds.34 The two patients whose sei-zures continued despite intramuscular mida-zolam responded to another benzodiazepinegiven intravenously.

ConclusionDevising a protocol for the management of sta-tus epilepticus with the optimal selection ofanticonvulsant drugs is fraught with problems

given the reality of clinical duty rotations andvaried expertise of frontline staV. Introducingrelatively new agents such as midazolam andlorazepam into an established pattern of prac-tice will need to be justified. Inevitably, factorsother than pharmacology and therapeutics willinfluence the specific approach adopted. Whatis right for a practice seeing head injury as themajor cause of status epilepticus may not beappropriate for those dealing with centralnervous system infection as the leading cause.The clinical context, cost, and logistics ofdelivering eVective treatment and care are alsoimportant. Finally, diagnostic studies and the

type and timing of investigation are a concern.Some of these aspects are well summarisedelsewhere.35 36 However, irrespective of regionalvariance in practice, it is clear that muchthought should be given to these issues at alocal level. In a recent UK intensive care ques-tionnaire study reported by Walker et al,14 only12% of the respondents were aware of a localprotocol for status epilepticus.

Future directionPerhaps not surprisingly there is a paucity ofclinical data comparing drug regimens for sta-tus epilepticus, which means that there is stillmuch to learn about this emergency. Asalluded to already, there is a need to formaliseand confirm our current ignorance in asystematic review. Building on this knowledgewill inevitably require a number of specificstudies concentrating on prehospital, first line,and refractory phases of drug treatment. Forexample: Is prehospital administration ofrectal lorazepam by paramedical staV ofbenefit? Can midazolam be used as mono-therapy, intranasal or rectal in the prehospital

setting and then parenterally thereafter? Canwe predict better those patients who will even-tually prove to be refractory to treatment? Forthe present, standards such as that recom-mended by the Advanced Paediatric Life Sup-port Group15 have been rightly adopted on anational level, but that should not detract froma constructive, investigational questioning ofalternative or even better, more timely ap-proaches, which have as their goal improvedemergency care.

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emergency treatment of acute seizures and status epilepticus

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