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Jurnal

Intramuscular versus Intravenous Benzodiazepines for

Prehospital Treatment of Status Epilepticus

Oleh

Rahmat Hidayat

090610047

Pembimbing :

dr. Herlina Sari, Sp.S

BAGIAN/SMF ILMU PENYAKIT SARAF

PROGRAM STUDI PENDIDIKAN DOKTER

UNIVERSITAS MALIKUSSALEH

RSU CUT MEUTIA ACEH UTARA

2013

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Intramuscular versus Intravenous Benzodiazepines for

Prehospital Treatment of Status Epilepticus

Acute seizures account for 1% of adult and 2% of pediatric emergency

department visits, at an annual cost of $1 billion (in U.S. dollars).1 When seizures

are prolonged or repetitive without recovery between episodes, the condition is

termed status epilepticus, and it occurs in approximately 6% of visits to the

emergency department for seizures. The cost for inpatient care of patients in status

epilepticus has been estimated to be $4 billion (in U.S. dollars) annually.2

Although the term prolonged was previously used to refer to seizures lasting 30

minutes or longer, this interval has been shortened to 5 to 10 minutes in recent

studies. This change occurred for several reasons. First, almost all convulsive

seizures in adults cease in less than 5 minutes without treatment; seizures lasting

longer than this are more likely to be self-sustained and to require intervention.3,4

Second, the longer seizures persist, the harder they are to terminate

pharmacologically.

5

Third, outcome tends to correlate with seizure duration evenafter one controls for other factors. Mortality among patients who present in status

epilepticus is 15 to 22%; among those who survive, functional ability will decline

in 25% of cases.6

A little more than half the cases of epilepsy have an acute, symptomatic

cause (e.g., acute brain injury, metabolic dysfunction, or ethanol withdrawal).7

About 25% of patients in status epilepticus will not respond to initial treatments.

After convulsive movements cease, seizure activity will continue to appear on

electroencephalography over the subsequent 24 hours in 48% of patients.8 Thus,

if patients do not wake up shortly after their convulsive movements cease,

nonconvulsive seizures should be considered, and an electroencephalogram

should be obtained as soon as possible.7

The first-line treatment for convulsive status epilepticus is a

benzodiazepine, typically intravenous lorazepam, a choice based largely on the

results of the 1998 Veterans Affairs Cooperative Status Epilepticus Study.9 In

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2001, a landmark study on prehospital treatment of status epilepticus was

published in which patients were randomly assigned to treatment with lorazepam,diazepam, or placebo administered intravenously while they were en route to the

hospital.10 Successful termination was much more common in the two groups that

received benzodiazepines (59% with lorazepam, 43% with diazepam, and 21%

with placebo). Since respiratory distress was twice as common in the group given

placebo as in either of the groups given a benzodiazepine, the best way to avoid

the need for intubation is to stop seizure activity.

In this issue of the Journal, Silbergleit et al. present the results of the

RAMPART (Rapid Anticonvulsant Medications Prior to Arrival Trial).11 This

study involved 79 hospitals and more than 4000 paramedics, as well as the use of

intramuscular autoinjectors and automatic time-stamped voice recorders, and the

subjects were excepted from informed consent. Ultimately, 893 subjects with

convulsive seizures lasting longer than 5 minutes were randomly assigned to

either intravenous lorazepam plus intramuscular placebo or intravenous placebo

plus intramuscular midazolam. Success was defined as cessation of clinical

seizure activity and lack of additional rescue medication before arrival in the

emergency department. The goal was to show oninferiority of intramuscular

midazolam. Results showed that intramuscular midazolam not only was

oninferior but was superior to intravenous lorazepam, with successful ter-mination

of seizures in 73.4% subjects in the intramuscular-midazolam group versus 63.4%

in the intravenous-lorazepam group (P

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hospitalization was lower in the intramuscular-midazolam group, as compared

with the intravenous-lorazepam group (57.6%, vs. 65.6%; relative risk, 0.88).Other trials have shown a more rapid response with nonintravenous

administration of benzodiazepines than with intravenous administration. In a

small trial of children with prolonged motor seizures, cessation was achieved

more quickly with intramuscular midazolam than with intravenous diazepam (8

minutes vs. 11 minutes, P = 0.047).12 Multiple studies have shown that nasal or

buccal midazolam stops seizures faster than rectal or intravenous diazepam13 and

is absorbed faster than intramuscular midazolam.13-15 However, there may be

issues with reliable and consistent delivery or absorption with the buccal and nasal

routes, as compared with the intramuscular route. For this reason the

intramuscular route was chosen for RAMPART, in addition to paramedics

familiarity with the use of intramuscular medication.

Whats next in this field? Home treatment with nasal or buccal

benzodiazepines will soon be widely available and may help prevent status

epilepticus and visits to the emergency department for patients who are at risk for

prolonged or repetitive seizures (clusters). A comparison between the

intramuscular and nasal or buccal routes for administering midazolam is needed,

as is more research to determine the next step when first-line treatment fails,

including the possible usefulness of combinations of medications and

neuroprotective agents. Finally, seizure anticipation or warning systems are under

devel-development that may allow abortive treatment-perhaps in an automated

manner-even before clinical seizure activity occurs. Thus, the future of care for

seizure emergencies is quite bright. The study reported by Silbergleit and

colleagues is an important step in this direction. As soon as a practical

intramuscular autoinjector for midazolam becomes widely available, the findings

in this study should lead to a systematic change in the way patients in status

epilepticus are treated en route to the hospital.

The New England Journal of Medicine N Engl J Med 366;7 nejm.orgFebruary 16, 2012

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DAFTAR PUSTAKA

1. Martindale JL, Goldstein JN, Pallin DJ. Emergency department seizure

epidemiology. Emerg Med Clin North Am 2011; 29:15-27.

2. Penberthy LT, Towne A, Garnett LK, Perlin JB, DeLorenzo RJ. Estimating

the economic burden of status epilepticus to the health care system. Seizure

2005;14:46-51.

3. Jenssen S, Gracely EJ, Sperling MR. How long do most seizures last? A

systematic comparison of seizures recorded in the epilepsy monitoring unit.Epilepsia 2006;47:1499-503.

4. Theodore WH, Porter RJ, Albert P, et al. The secondarily generalized tonic-

clonic seizure: a videotape analysis. Neurology 1994;44:1403-7.

5. Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Timedependent

decrease in the effectiveness of antiepileptic drugs during the course of self-

sustaining status epilepticus. Brain Res 1998;814:179-85.

6. Claassen J, Lokin JK, Fitzsimmons BF, Mendelsohn FA, Mayer SA.

Predictors of functional disability and mortality after status epilepticus.

Neurology 2002;58:139-42.

7. Foreman B, Hirsch LJ. Epilepsy emergencies: diagnosis and management.

Neurol Clin 2012;30:11-41.

8. DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive

status epilepticus after the control of convulsive status epilepticus. Epilepsia

1998;39:833-40.

9. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments

for generalized convulsive status epilepticus. N Engl J Med 1998;339:792-8.

10. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam,

diazepam, and placebo for the treatment of out-ofhospital status epilepticus. N

Engl J Med 2001;345:631-7. [Erratum, N Engl J Med 2001;345:1860.]

11. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus

intravenous therapy for prehospital status epilepticus. N Engl J Med

2012;366:591-600.

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12. Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW,

Waisman Y. A prospective, randomized study comparing intramuscularmidazolam with intravenous diazepam for the treatment of seizures in

children. Pediatr Emerg Care 1997;13:92-4.

13. Wermeling DP. Intranasal delivery of antiepileptic medications for treatment

of seizures. Neurotherapeutics 2009;6:352-8.

14. ORegan ME, Brown JK, Clarke M. Nasal rather than rectal benzodiazepines

in the management of acute childhood seizures? Dev Med Child Neurol

1996;38:1037-45.

15. Reichard DW, Atkinson AJ, Hong SP, Burback BL, Corwin MJ, Johnson JD.

Human safety and pharmacokinetic study of intramuscular midazolam

administered by autoinjector. J Clin Pharmacol 2010;50:1128-35.

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Benzodiazepin Intramuscular dibandingkan intravena

untuk Perawatan pra-rumah sakit dari status epileptikusKejang akut terjadi kira-kira pada 1% orang dewasa dan 2% dari

kunjungan gawat darurat pediatrik, dan menghabiskan biaya sebesar $ 1 milyar

(dolar AS) pertahun.1 Ketika kejang berkepanjangan atau berulang tanpa

pemulihan antara episode, kondisi ini disebut status epileptikus, dan itu terjadi

pada sekitar 6% dari kunjungan ke gawat darurat untuk kejang. Biaya untuk rawat

inap pasien dalam status epileptikus telah diperkirakan $ 4.000.000.000 (dolar

AS) per tahun.2

Meskipun Istilah "berkepanjangan" sebelumnya digunakan untuk

merujuk pada kejang yang berlangsung 30 menit atau lebih, interval ini telah

diperpendek menjadi 5 sampai 10 menit pada penelitian terbaru. Perubahan ini

terjadi karena beberapa

alasan. Pertama, hampir semua kejang pada dewasa berhenti dalam waktu kurang

dari 5 menit tanpa pengobatan; kejang yang berlangsung lebih lama, mungkin

lebih mandiri dan memerlukan intervensi.3,4 Kedua, kejang yang semakin lama

bertahan, sulit untuk mengakhiri pengobatannya.

5

Ketiga, hasilnya cenderung berkorelasi dengan kejang durasi, bahkan setelah

seseorang mengontrol faktor-faktor lain. Kematian di antara pasien yang hadir

dalam status epileptikus adalah 15 sampai 22%, di antara mereka yang bertahan

hidup, kemampuan fungsionalnya akan menurun pada 25% kasus.6

Lebih dari setengah kasus epilepsi memiliki gejala akut, gejala penyebab

(misalnya, cedera otak akut, disfungsi metabolik, atau etanol withdrawal).7 Sekitar

25% dari pasien dalam status epileptikus tidak akan merespon pengobatan awal.

Sekitar 48% dari pasien, setelah gerakan kejang berhenti, aktivitas kejang akan

terus muncul di electroencephalography selama 24 jam berikutnya.8 Jadi, jika

pasien tidak bangun dalam waktu lama setelah kejang gerakan gencatan mereka,

kejang nonconvulsive harus diwaspadai.7

Lini pertama pengobatan status kejang epileptikus adalah benzodiazepin,

biasanya intravena lorazepam.9 Pada tahun 2001, studi tentang pengobatan

prarumah sakit status epileptikus diterbitkan dimana pasien secara acak diberikan

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pengobatan dengan lorazepam, diazepam, atau plasebo intravena ketika mereka

sedang dalam perjalanan ke rumah sakit.

10

Sukses terminasi jauh lebih umumpada kedua kelompok yang menerima benzodiazepin (59% dengan lorazepam,

43% dengan diazepam, dan

21% dengan plasebo). Karena gangguan pernapasan dua kali lebih umum pada

kelompok yang diberikan plasebo sebagai salah satu dari kelompok yang

diberikan benzodiazepin, cara terbaik untuk menghindari kebutuhan untuk

intubasi adalah untuk menghentikan aktivitas kejang.

Dalam edisi Jurnal ini, Silbergleit dkk. mempresentasikan hasil penelitian

tersebut (Obat antikonvulsan prarumah sakit).11 Penelitian ini melibatkan 79

rumah sakit dan lebih dari 4000 paramedis, serta penggunaan intramuskular

autoinjektor dan otomatis waktu dicap perekam suara, dan subjek dikecualikan

dari inform consent. Pada akhirnya, 893 subyek dengan kejang yang berlangsung

lebih dari 5 menit secara acak diberikan intravena lorazepam ditambah plasebo

intramuskular atau plasebo intravena ditambah intramuskular midazolam.

Hasil penelitian menunjukkan bahwa midazolam intramuskular tidak

hanya noninferior tapi unggul untuk lorazepam intravena, dengan sukses ter-

diskriminasi kejang sekitar 73,4% subyek dalam kelompok intramuskular

midazolam dibandingkan 63,4% pada kelompok intravena lorazepam. Intubasi

yang diperlukan dalam 14% kedua kelompok, dan efek samping lainnya juga

serupa. Tingkat rawat inap lebih rendah pada kelompok-intramuskular

midazolam, dibandingkan dengan kelompok intravena-lorazepam.

Percobaan lain telah menunjukkan respon yang lebih cepat dengan

pemberian nonintravena benzodiazepin dibandingkan dengan pemberian secara

intravena. Dalam sebuah percobaan kecil anak-anak dengan ambang kejang yang

berkepanjangan, penghentian dicapai lebih cepat dengan intramuskular

midazolam dibandingkan dengan intravena diazepam

Selanjutnya perawatan di rumah dengan benzodiazepin tersedia secara luas

dan dapat membantu mencegah status epileptikus dan kunjungan ke gawat darurat

untuk pasien yang beresiko kejang berkepanjangan atau kejang berulang

("cluster"). Penelitian lebih lanjut untuk menentukan langkah berikutnya ketika

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pengobatan lini pertama gagal, termasuk mungkin kegunaan dari kombinasi obat

dan agen saraf. Akhirnya, kejang antisipasi atau sistem peringatan yang sedangdikembangkan yang dapat memungkinkan pengobatan gagal, mungkin secara

otomatis bahkan sebelum aktivitas kejang klinis terjadi. Dengan demikian, masa

depan perawatan untuk keadaan kejang darurat cukup cerah.

Penelitian yang dilaporkan oleh Silbergleit dan rekannya merupakan langkah

penting ke arah ini.