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

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 even after 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

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<0.001 for both noninferiority and superiority). This difference was due to the more rapid administration of the intramuscular medication (1.2 minutes, vs. 4.8 minutes with the intravenous route). This more rapid administration outweighed the faster cessation of seizures with intravenous administration once it was given (1.6 minutes, vs. 3.3 minutes with the intramuscular route). In those for whom seizures ceased prior to arrival in the emergency department, the overall median time to cessation of convulsions was not significantly shorter in the intramuscular-midazolam group (about 5 minutes, vs. 7 minutes with the intravenous route). Intubation was required in 14% of both groups, and other adverse events were also similar. The rate of

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.org February 16, 2012

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 tonicclonic 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 selfsustaining 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. 2012;366:591-600. N Engl J Med

12. Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y. A prospective, randomized study comparing intramuscular

midazolam 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.

Benzodiazepin Intramuscular dibandingkan intravena untuk Perawatan pra-rumah sakit dari status epileptikus
Kejang 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

pengobatan dengan lorazepam, diazepam, atau plasebo intravena ketika mereka sedang dalam perjalanan ke rumah sakit.10 Sukses terminasi jauh lebih umum pada 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 terdiskriminasi 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

pengobatan lini pertama gagal, termasuk mungkin kegunaan dari kombinasi obat dan agen saraf. Akhirnya, kejang antisipasi atau sistem peringatan yang sedang dikembangkan 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.