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HIPERTERMIA MALIGNA MALIGNANT HYPERTHERMIA (MH)

R.F. Soenarto

Istilah Malignant Hyperthermia pertama kali diperkenalkan oleh Denborough & Lovell dalam sebuah artikel (Anaesthetic Deaths in a Family, Lancet 1960). Diagnosis MH pada waktu itu didasarkan atas observasi seksama tanda-tanda klinis, tanpa peralatan pemantau canggih. Saat ini ketika MH sudah lebih dikenal, istilah hipertermia menjadi kurang relevan karena seringkali peningkatan suhu timbul lambat. Hipertermia Maligna (MH) merupakan salah satu mimpi buruk para pelaku anestesia yang jarang terjadi namun fatal. Namun ini bukanlah kesalahan prosedur anestesia atau alergi obat anestetik. Kumpulan gejala klinis yang diakibatkan oleh peningkatan tonus dan metabolisme otot rangka terjadi sangat cepat dan hebat, oleh karena itu sering mengakibatkan mortalitas. Dantrolen (dantrolene) disebut telah menurunkan mortalitas akibat MH dari 80% menjadi 5% saja. Sejak pertama kali kejadian MH dilaporkan th 1960 hingga kini, belum ada alternatif terapi selain dantrolen. Oleh karena itu, sangat beralasan jika ketersediaan dantrolen di semua negara adalah krusial, hingga nanti jika ditemukan alternatif lain. EPIDEMIOLOGI Insiden terjadinya MH berkisar antara 1: 5000 hingga 1:50.000-100.000 kasus dewasa dan 1:3000-1:5000 pada kasus pediatrik. Prevalensi kelainan ini mungkin 1 dalam 3000 4000 individu, mengenai semua kelompok etnik dan golongan umur, terbanyak adalah dewasa muda dengan kekerapan 2:1 untuk pria dibandingkan wanita. Angka kejadian MH di Indonesia tidak diketahui karena belum ada sistem pencatatan dan pelaporan. Hal yang sama tampaknya terjadi juga di negara-negara Asia yang lain, dengan perkecualian di Jepang dan Taiwan. Diketahui berbagai laporan kasus anekdotal tentang kejadian yang sangat dicurigai MH di Indonesia. Kasus-kasus tersebut banyak di antaranya fatal, terutama karena tidak tersedianya dantrolen di Indonesia. PATOFISIOLOGI MH bukan merupakan penyakit alergi terhadap zat anestetik atau zat lainnya. MH adalah kelainan genetik autosomal dominan. Jadi MH bukan penyakit akibat anestesia. Meskipun tidak mengalami krisis MH, penyandangnya tetaplah penyandang MH. Autosomal dominan berarti cukup satu orangtua yang menyandangnya, maka kemungkinan besar anak-anak mereka juga menyandang MH. Penyandang MH sebagian terbukti mengalami mutasi kromosom no.19q 12.1-13.2. Mutasi ini menyebabkan perilaku menyimpang pada reseptor ryanodin (RyR) di dalam sel otot skeletal. Pada setiap manusia normal, RyR menempel pada retikulum sarkoplasmik dalam sel, yang merupakan gudang penyimpanan terbesar Ca2+ intraselular. Aktivasi RyR akan menyebabkan penglepasan Ca2+ ke sitosol. Apa yang mengaktivasi RyR? Potensial aksi. Potensial aksi akan mengaktivasi RyR, membuka retikulum sarkoplasmik sehingga memungkinkan Ca2+ yang tersimpan keluar ke sitoplasma. Ca2+ inilah yang memicu eksitasi sel dengan hasil kontraksi sel otot. Jadi, yang berperan besar dalam eksitasi sel adalah Ca2+ intraselular yang tersimpan di retikulum sarkoplasmik, bukan arus masuk Ca2+ dari ekstrasel ke intrasel. (Karena itu tidak ada gunanya memberikan obat penghambat kanal Ca ketika serangan MH terjadi.) Pada penyandang MH, mekanisme di atas terjadi berlebihan. Aktivasi RyR yang tidak lazim menyebabkan penglepasan berlebihan dan akumulasi Ca2+ di sitosol, yang berakibat hiperkontraktur sel otot rangka. RyR yang abnormali ini bertingkah setiap kali terpajan dengan zat pemicunya. Apa saja? Yang paling terkenal adalah anestetika volatil. Pemicu lain yang juga terkenal adalah kafein,

suksinilkolin dan suatu zat kimia bernama klorokresol. Ketika penyandang MH terpajan dengan zat pemicunya, terjadilah reaksi malapetaka ini. Otot skeletal pasien akan mengalami hiperkontraktur dengan segala akibatnya. GAMBARAN KLINIS Sehari-hari, penyandang MH tidak berbeda sama sekali dengan manusia normal lain. Itulah sebabnya tidak ada penyandang MH yang didiagnosis MH, sebelum terjadinya kejadian malapetaka tadi. Kejadian itu, yang dikenal dengan MH crisis, paling sering terjadi ketika pasien menjalani anestesia inhalasi. Sebelum patofisiologi MH ini terkuak, orang akan dengan mudah menyatakan kondisi ini sebagai komplikasi anestesia. Pernyataan ini tidak benar. Krisis MH bukan komplikasi anestesia. Terbukti kemudian, ada juga dilaporkan kematian penyandang MH di luar kamar bedah, yaitu ketika sedang bermain bola. Pajanan dengan panas (heat) dan aktivitas skeletal yang tinggi merupakan salah satu yang dapat pula memicu krisis MH. Ketika terjadi krisis MH, inilah sekuens yang sebenarnya. Hiperkontraktur otot-otot skeletal terjadi menyeluruh. Sebagian besar dimulai dari otot masseter (masseter spasm), tapi segera diikuti otot skeletal yang lain. Pasien akan tampak kaku. Hasil kontraksi berlebihan ini adalah peningkatan produksi panas, CO2 dan asam laktat. Selanjutnya, akan terjadi kerusakan sel otot skeletal dengan hasil peningkatan kreatinin kinase (CK) dan myoglobinuria serta peningkatan kalium darah. Peningkatan aktivitas simpatis dapat bermanifestasi sebagai gangguan hiperdinamik kardiovaskular (takikardia/aritmia, hipertensi dsb). Secara klinis, selain masseter spasm, tanda yang paling dini dapat terdeteksi adalah peningkatan ETCO2. Sedangkan panas yang meningkat tidak selalu langsung terdeteksi. Itulah sebabnya, istilah yang tepat sebenarnya bukan hipertermia tetapi hipermetabolisme. DIAGNOSIS Gejala klinis krisis MH tidak sepenting diagnosisnya. Proses ini berlangsung sangat cepat dan tentu lebih penting menyelamatkan pasien daripada berpikir mengenai diagnosis pasti. Baku emas diagnosis pasti MH hingga saat ini masih CHCT (Caffeine-Halothane Contracture Test). Otot tersangka penyandang MH dipajankan dengan halotan dan kafein, kemudian dilihat adakah hiperkontraksi akibat pajanan ini. Sayangnya di dunia baru ada sedikit sekali laboratorium yang melakukan tes ini, sebagian besar di USA. Terlebih lagi, spesimen otot harus segar. Artinya, tersangka penyandang MH harus pergi ke pusat tersebut. Sekali hasil CHCT positif MH, semua saudara kandung dan orangtuanya harus diperiksa kromosomnya, untuk mengetahui dari garis mana MH ini didapat. Karena CHCT sangat terbatas, saat ini mulai digalakkan pemeriksaan alternatif, yaitu langsung dilakukan pemeriksaan kromosom untuk melihat mutasi yang sesuai. Namun dikatakan, hanya sekitar 30% pasien yang positif CHCT juga terbukti mengalami mutasi genetik sesuai MH. DIAGNOSIS DIFERENSIAL Beberapa kondisi menunjukkan gambaran klinis mirip dengan krisis MH. Di antaranya adalah: 1. Neuroleptic Malignant Syndrome (NMS). Ini adalah reaksi sebagian pasien yang mendapat antipsikosis tertentu. Terjadi penurunan aktivitas dopamin, baik akibat blokade maupun akibat withdrawal terapi dengan obat dopaminergik. Selain suhu yang meningkat, pasien akan menunjukkan agitasi atau penurunan kesadaran, rigiditas otot, diaforesis dan disfungsi otonom. Terapinya simtomatik, namun dantrolen dan bromokriptin dapat meredakan dengan cepat. 2. Serotonin Syndrome atau tepatnya toksisitas serotonin. Banyak obat dapat memicu reaksi ini, terutama jika digunakan bersama-sama. Agonis 5HT (golongan triptan), antagonis 5HT (ondansetron, granisetron), obat antikolinergik (metoklopramid), antidepresan (misalnya inhibitor MAO), opioid, stimulan otak (amfetamin, metamfetamin, kokain), bahkan obat-obat herbal (misalnya ginseng) dilaporkan dapat memicu toksisitas serotonin. Hipermetabolisme yang terjadi di

sini tidak disertai rigiditas otot. Biasanya yang terjadi adalah tremor, hiperefleksia atau twitching. Terapinya adalah antagonis serotonin (siproheptadin atau klorpromazin) dan simtomatik. 3. MH-like Syndrome. Kondisi mirip dengan krisis MH juga dapat terjadi pada pasien dengan kelainan muskuloskeletal yang dibius dengan anestetika inhalasi, terutama jika prosedurnya melibatkan manipulasi otot (misalnya operasi koreksi strabismus). Gejala klinis yang timbul tidak sehebat krisis MH dan diterapi simtomatik. Pasien yang mengalami kondisi ini bukan penyandang MH. PANDUAN TATALAKSANA KRISIS HIPERTERMIA MALIGNA INTRA-ANESTESIA (dimodifikasi dari berbagai panduan di dunia) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Segera hentikan semua zat anestetik volatil. Aktifkan situasi kegawatdaruratan. Naikkan ventilasi semenit untuk menurunkan ETCO2. Gunakan oksigen tinggi dengan melihat SpO2. Berikan dantrolen sodium. Dosis inisial 2,5 mg/kg BB, dilakukan secara bolus intravena. Dinginkan pasien. Gunakan ice packs di inguinal, aksila dan leher. Lavase lambung dengan cairan dingin. Hentikan pendinginan jika suhu badan telah mencapai 38,5 C. Ganti CO2 absorber tiap kali telah jenuh. Atasi aritmia sesuai algoritma. Jangan gunakan Ca channel blocker Dosis lanjutan dantrolen dititrasi sesuai perubahan ETCO2 dan laju jantung. Batas dosis total (bolus dan rumatan) dantrolen adalah 10 mg/kg BB, namun boleh ditambah bilamana sangat perlu. Periksa AGD, elektrolit, kreatinin kinase urin. Hiperkalemia diatasi dengan insulin dan glukosa, ditambah hiperventilasi. Periksa koagulasi lengkap setelah 6-12 jam. Pastikan semua proses tercatat dan segera dilaporkan ke Indonesian MH Registry.

Neuroleptic malignant syndrome


From Wikipedia, the free encyclopedia

Neuroleptic malignant syndrome

Classification and external resources

ICD-10

G21.0

ICD-9

333.92

DiseasesDB

8968

eMedicine

emerg/339med/2614ped/1581

MeSH

D009459

Neuroleptic malignant syndrome (NMS) is a life-threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. NMS typically consists of muscle rigidity, fever, autonomic instability,[1]and cognitive changes such as delirium, and is associated with elevated plasma creatine phosphokinase.[2] Theincidence of neuroleptic malignant syndrome has decreased since it was first described, due to changes in prescribing habits, but NMS is still a potential danger to patients being treated with antipsychotic medication. Because of the unpredictability of NMS, treatment may vary substantially but is generally based on supportive care and removal of the offending antipsychotic drug.
Contents [hide]

1 Signs and symptoms

1.1 Differential diagnosis

2 Causes

2.1 Risk factors

3 Pathophysiology 4 Treatment 5 Prognosis 6 Epidemiology 7 History 8 Research 9 References

10 External links

Signs and symptoms[edit]


The first symptoms of neuroleptic malignant syndrome are usually muscle cramps and tremors, fever, symptoms of autonomic nervous system instability such as unstable blood pressure, and alterations in mental status (agitation, delirium, or coma). Once symptoms appear, they may progress rapidly and reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.[2] The muscular symptoms are most likely caused by blockade of thedopamine receptor D2, leading to abnormal function of the basal ganglia similar to that seen in Parkinson's disease.[3] A raised white blood cell count and creatine phosphokinase (CPK) plasma concentration will be reported due to increased muscular activity and rhabdomyolysis(destruction of muscle tissue).[4] The patient may suffer hypertensive crisis and metabolic acidosis. A non-generalized slowing on an EEG is reported in around 50% of cases. The fever is believed to be caused by hypothalamic dopamine receptor blockade. The peripheral problems (the white blood cell and CPK count) are caused by the antipsychotic drugs. They cause an increased calcium release from the sarcoplasmic reticulum of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal EEG, but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.[5] Unfortunately, symptoms are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment.[6] NMS is less likely if a person has previously been stable for a period of time on antipsychotics, especially in situations where the dose has not been changed and there are no issues of noncompliance or consumption of psychoactive substances known to worsen psychosis.

Increased body temperature >38C (>100.4F), or Confused or altered consciousness Diaphoresis "sweat shock" Rigid muscles Autonomic imbalance

Differential diagnosis[edit]
Differentiating NMS from other neurological disorders can be very difficult. It requires expert judgement to separate symptoms of NMS from other diseases. Some of the most commonly mistaken diseases are: encephalitis, toxic encephalopathy, status epilepticus, heat stroke, and malignant hyperthermia. Due to the comparative rarity of NMS, it is often overlooked and immediate treatment for the syndrome is delayed. Drugs such as cocaine and amphetamine may also produce similar symptoms.[2][2][7] The differential diagnosis is similar to that of hyperthermia, and includes serotonin syndrome.[8] Features which distinguish NMS from serotonin syndrome includebradykinesia, muscle rigidity, and elevated white blood cell count and plasma creatine kinase level.[9]

Causes[edit]

NMS is usually caused by neuroleptic drug use, and a wide range of drugs can result in NMS.[1] Individuals using haloperidol or chlorpromazine are reported to be at greatest risk. NMS may also occur in people taking dopaminergic drugs (such as levodopa) for Parkinson's disease, most often when the drug dosage is abruptly reduced.[10] In addition, other drugs with anti-dopaminergic activity, such as the antiemetic metoclopramide, can induce NMS.[11] Even drugs without known antidopaminergic activity have been associated with NMS; examples include amoxapines and lithium. Also, desipramine, dothiepin, phenelzine, tetrabenazine, andreserpine have been known to trigger NMS.[12] At the molecular level, NMS is caused by a sudden, marked reduction in dopamine activity, either from withdrawal of dopaminergic agents or from blockade of dopamine receptors.

Risk factors[edit]
One of the clearest risk factors in the development of NMS is the course of drug therapy chosen to treat a condition. Use of high-potency neuroleptics, rapid increase in dosage of neuroleptics, and use of long-acting forms of neuroleptics are all known to increase the risk of developing NMS.[13] It has been purported that there is a genetic risk factor for NMS, since identical twins have both presented with NMS in one case, and a mother and two of her daughters have presented with NMS in another case.[14] Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater neuroleptic use in men under forty.[1] It has also been suggested that postpartum women may be at a greater risk for NMS.[15] An important risk factor for this condition is Lewy body dementia. These patients are extremely sensitive to neuroleptics. As a result, neuroleptics should be used cautiously in all cases of dementia.[citation needed]

Pathophysiology[edit]
The mechanism is thought to depend on decreased levels of dopamine activity due to:

Dopamine receptor blockade Genetically reduced function of dopamine receptor D2[16]

However, the failure of D2 dopamine receptor antagonism or dopamine receptor dysfunction does not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with atypical antipsychotic drugs with lower D2 dopamine activity.[17] This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as an etiological mechanism for NMS.[18] Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as typical neuroleptics, are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.[2]

There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.[19]

Treatment[edit]
NMS is a medical emergency, and can lead to death if untreated. The first step is to stop neuroleptic drugs and treat the hyperthermia aggressively, such as with cooling blankets or ice packs to the axillae and groin. Supportive care in an intensive care unit capable of circulatory and ventilatory support is crucial. The correct pharmacological treatment is still unclear. Dantrolene has been used when needed to reduce muscle rigidity, and more recently dopamine pathway medications such as bromocriptine have shown benefit.[20] Amantadine is another treatment option due to its dopaminergic and anticholinergic effects. Apomorphine may be used however its use is supported by little evidence.[3] Benzodiazepines may be used to control agitation. Highly elevated blood myoglobin levels can result in kidneydamage, therefore aggressive intravenous hydration with diuresis may be required. When recognized early NMS can be successfully managed, however up to 10% of cases can be fatal.[2]

Prognosis[edit]
The prognosis is best when identified early and treated aggressively. In these cases NMS is not usually fatal. In previous studies the mortality rates from NMS have ranged from 20%38%, however in the last two decades[when?] mortality rates have fallen below 10% due to early recognition and improved management.[21] Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not. Memory impairment is a consistent feature of recovery from NMS, and usually temporary, though in some cases, may become persistent.[22]

Epidemiology[edit]
Pooled data suggests the incidence of NMS is between 0.2%3.23%.[23] However, more physician awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS.[1] Additionally, young males are particularly susceptible and the male:female ratio has been reported to be as high as 2:1.[1][23][24]

History[edit]
NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines.[25] NMS was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterized the condition that was associated with the side effects of haloperidol "syndrome malin des neuroleptiques", which was translated to neuroleptic malignant syndrome.[12]

Research[edit]

While the pathophysiology of NMS remains unclear, the two most prevalent theories are:

Reduced dopamine activity due to receptor blockade Sympathodrenal hyperactivity and autonomic dysfunction

In the past, research and clinical studies seemed to corroborate the D2 receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D2 receptors associated with this neurotransmitter. However, recent studies indicate a genetic component to the condition.[26] In support of the Sympathoadrenal Hyperactivity model proposed, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS.[27] This model of NMS strengthens its suspected association with malignant hyperthermia in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins. The introduction of atypical antipsychotic drugs, with lower affinity to the D2 dopamine receptors, were thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves.[17] NMS induced by atypical drugs also resembles "classical" NMS (induced by "typical" antipsychotic drugs), further casting doubt on the overall superiority of these drugs.[28]

References[edit]
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28. Jump up^ Hasan S, Buckley P (August 1998). "Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique". Am J Psychiatry 155 (8): 11136.PMID 9699705.