DRUG-RELATED FATAL ANAPHYLACTIC SHOCK IN DENMARK 1968-1990.

A
STUDY BASED ON NOTIFICATIONS TO THE COMMITTEE ON ADVERSE DRUG
REACTIONS

OBAT-TERKAIT FATAL anafilaksis SHOCK DI DENMARK 1968-1990. STUDI

BERDASARKAN PEMBERITAHUAN ATAS KOMITE efek samping obat

Abstrak

Based on notifications to the Danish Committee on Adverse Drug Reactions and to the Central
Death Register

Berdasarkan pemberitahuan kepada Komite Denmark pada Reaksi efek samping obat dan
ke Central Death Register

, 30 cases of fatal drug-induced anaphylactic shock were identified during the period 1968-1990

30 kasus yang fatal akibat obat syok anafilaksis diidentifikasi selama periode 1968-1990

. The most frequent causes were contrast media for X-ray examinations, antibiotics, and extracts
of allergens

Penyebab paling sering adalah media kontras untuk pemeriksaan X-ray, antibiotik, dan
ekstrak alergen

Nine cases occurred outside hospital; they were mainly caused by the use of allergen extracts of
moulds for desensitization in general practice. Fatal drug-induced anaphylactic shock is rare,
estimated in the present study at 0.3 case per million inhabitants per year.

Sembilan kasus terjadi di luar rumah sakit; mereka terutama disebabkan oleh penggunaan
ekstrak alergen dari cetakan untuk desensitisasi dalam praktek umum. Fatal akibat obat
shock anafilaksis jarang terjadi, diperkirakan dalam penelitian ini sebesar 0,3 kasus per
juta penduduk per tahun.

PENGANTAR/ INTRODUCTION

Anaphylactic shock (AS) is caused either by an The study included all patients with fatal acute
hypersensitivity reaction or by non-Ig E drug-induced AS from 1 January 1968 to 3 1 mediated
mast cell mediator liberation[ 11. Both March 1990. They were identified from the mechanisms
give the same clinical picture of following data sources: anxiety, palpitations, urticaria, difficult
respir- ation, and circulatory collapse[2, 31. This type of reaction is one of the most serious acute
adverse drug reactions, with the risk of a fatal outcome. Understanding of the epidemiology of
drug-in- duced AS is limited[2,4, 51. The purpose of the present study was to investigate fatal
AS in Denmark, its occurrence and precipitating factors, and the method of administration of the
drugs involved. We also investigated the completeness of the Central Death Register regarding
AS as a cause of death[6].

Shock anafilaksis (AS) disebabkan baik oleh Penelitian ini melibatkan semua pasien
dengan reaksi hipersensitivitas yang fatal akut atau dengan non-Ig E yang diinduksi obat
AS dari 1 Januari 1968-3 1 dimediasi mediator sel mast pembebasan [11. Kedua Maret
1990. Mereka diidentifikasi dari mekanisme memberikan gambaran klinis yang sama dari
sumber data berikut: kecemasan, palpitasi, urtikaria, sulit asi respir-, dan kolaps sirkulasi
[2, 31. Jenis reaksi adalah salah satu efek samping obat akut yang paling serius, dengan
risiko hasil yang fatal. Pemahaman tentang epidemiologi obat-in yang diinduksi AS
terbatas [2,4, 51. Tujuan dari penelitian ini adalah untuk menyelidiki berakibat fatal AS di
Denmark, kejadian dan faktor pencetus, dan metode pemberian obat yang terlibat. Kami
juga meneliti kelengkapan Central Death Register mengenai AS sebagai penyebab
kematian [6].

BAHAN DAN METODE/ MATERIAL AND METHODS

The study included all patients with fatal acute hypersensitivity reaction or by non-Ig E drug-
induced AS from 1 January 1968 to 3 1 mediated mast cell mediator liberation[ 11. Both March
1990. They were identified from the mechanisms give the same clinical picture of following data
sources

Penelitian ini melibatkan semua pasien dengan reaksi hipersensitivitas yang fatal akut atau
dengan non-Ig E yang diinduksi obat AS dari 1 Januari 1968-3 1 dimediasi mediator sel
mast pembebasan [11. Kedua Maret 1990. Mereka diidentifikasi dari mekanisme
memberikan gambaran klinis yang sama berikut sumber data

1. The Committee on Adverse Drug Reactions. All cases, a total of 1252 reports, with diagnoses
of AS, anaphylactic reaction and allergic reaction were analysed. Fatal reactions were registered
if it was found probable that death was caused by AS, i.e. the notification should (a) have clinical
details compatible with AS, or (b) have AS as the diagnosis, without clinical descrip- tion.The
Danish Committee on Adverse Drug Reactions is operated under the National Board of Health
and has covered the whole country with respect to the reporting of drug-induced

*All correspondence should be addressed to: Dr P.

adverse reactions since 1 May 1968[7]. The most Lenler-Petersen. Topasdalen 8, DK-8900
Randers, important data collected by the reporting system Denmark. are: personal registration
number (CPR-num-

1185-1186 Pod Lenler-Petersen elalber), name of drug and manufacturer, daily dose and method
of drug administration, concomi- tant intake of other drugs, description of the adverse reaction
and its consequences. The Committee on Adverse Drug Reactions regularly requests doctors
through the Journal of the Danish Medical Association to notify adverse drug reactions.

1. Komite Reaksi efek samping obat. Semua kasus, total 1.252 laporan, dengan diagnosa
AS, reaksi anafilaksis dan reaksi alergi dianalisis. Reaksi yang fatal yang terdaftar jika
ditemukan kemungkinan bahwa kematian disebabkan oleh AS, yaitu pemberitahuan harus
(a) memiliki rincian klinis kompatibel dengan AS, atau (b) memiliki AS sebagai diagnosis,
tanpa deskripsi klinis tion.The Komite Denmark di Reaksi obat yang merugikan
dioperasikan di bawah Dewan Nasional Kesehatan dan telah mencakup seluruh negeri
sehubungan dengan pelaporan obat-induced
* Semua korespondensi harus ditujukan kepada: Dr P.
reaksi merugikan sejak 1 Mei 1968 [7]. Yang paling Lenler-Petersen. Topasdalen 8, DK-
8900 Randers, data penting yang dikumpulkan oleh sistem pelaporan Denmark. adalah:
nomor registrasi pribadi (CPR-num 1185-1186 Pod Lenler-Petersen el alber), nama obat
dan produsen, dosis harian dan metode pemberian obat, asupan tant concomi- obat lain,
deskripsi reaksi yang merugikan dan konsekuensinya. Komite Reaksi efek samping obat
secara teratur meminta dokter melalui Journal of Medical Association Denmark untuk
memberitahu reaksi obat yang merugikan

2. The Central Death Register. All deaths registered according to the WHO code (ICD) 999.49
(Collapsus Anafylacticus) from 1 January 1977 to 31 March 1990 were identified. Death
certificates for patients identified under point (l), and not found under code 999.49, were also
obtained.The Central Death Register is also administered by the Danish National Board of
Health; it contains data on all deaths in Denmark since 1970. These data reach the register via the
death certificates, which in Denmark always are completed by a doctor.

2. Central Death Register. Semua kematian terdaftar sesuai dengan kode WHO (ICD)
999,49 (Collapsus Anafylacticus) dari 1 Januari 1977 sampai 31 Maret 1990 diidentifikasi.
Sertifikat kematian untuk pasien diidentifikasi di bawah titik (l), dan tidak ditemukan di
bawah kode 999,49, juga obtained.The Central kematian Pendaftaran juga diberikan oleh
National Dewan Denmark Kesehatan; itu berisi data pada semua kematian di Denmark
sejak 1970. Data ini mencapai register melalui sertifikat kematian, yang di Denmark selalu
diselesaikan oleh dokter.

Link between the data systems/ Hubungan antara sistem data

Everyone in the Danish population is identified by a unique lo-digit personal regis- tration
number (CPR-number), and linkage of data with time, as well as between different data sources,
is highly accurate.

Semua orang dalam populasi Denmark diidentifikasi oleh lo-digit pribadi nomor unik nal
trasi (CPR-nomor), dan hubungan data dengan waktu, serta antara sumber data yang
berbeda, sangat akurat.
Demography

Denmark has 5.1 million inhabitants and covers about 44,000 sq.km. There are some 3400
general practitioners, all of whom have a contract with the Danish National Health System. Their
patients belong either to group 1 (96%) or group 2 (4%)[8]. Group 1 patients have the right to
free medical care from the general practitioner with whom they are registered, while group 2
patients have free choice of general practitioner but must pay part of the fee. With very few
exceptions, all Danish hospitals are owned by the Danish counties, and all patients receive free
medical care there. In all cases the adverse drug reaction notifications and death certificates were
studied and, if relevant, hospital records or discharge summaries as well. The following data
were extracted: sex, age, drug, method of adminis- tration, place of reaction and treatment, and
previous episodes of anaphylaxis or exposure. The completeness of the Central Death Register
regarding AS was estimated by comparing the Central Death Register with the Committee on
Adverse Drug Reactions file[6].

Demografi
Denmark memiliki 5,1 juta penduduk dan mencakup sekitar 44.000 sq.km. Ada beberapa
dokter umum 3400, yang semuanya memiliki kontrak dengan Sistem Kesehatan Nasional
Denmark. Pasien mereka bisa milik kelompok 1 (96%) atau kelompok 2 (4%) [8].
Kelompok 1 pasien memiliki hak untuk membebaskan perawatan medis dari dokter umum
dengan siapa mereka terdaftar, sedangkan kelompok 2 pasien memiliki pilihan bebas dari
dokter umum tetapi harus membayar sebagian dari biaya. Dengan beberapa pengecualian,
semua rumah sakit Denmark dimiliki oleh kabupaten Denmark, dan semua pasien
menerima perawatan medis gratis di sana. Dalam semua kasus pemberitahuan reaksi obat
yang merugikan dan sertifikat kematian dipelajari dan, jika relevan, catatan rumah sakit
atau ringkasan debit juga. Berikut ini data yang diambil: jenis kelamin, usia, obat, metode
administrasi, tempat reaksi dan pengobatan, dan episode sebelumnya anafilaksis atau
paparan. Kelengkapan Central Death Daftar Mengenai AS diperkirakan dengan
membandingkan Central Death Register dengan Komite Reaksi efek samping obat
mengajukan [6].

The study was approved by the scientific ethics committee, the Board of Registers, and the
National Board of Health.

Studi ini disetujui oleh komite ilmiah etika, Dewan Register, dan Dewan Nasional
Kesehatan.

RESULTS/ HASIL

Drug-induced fatal AS was found in 30 persons, 11 females (median age 45 years, range 14-90
years) and 19 males (median age 65 years, range l&87 years).
Diinduksi obat yang fatal AS ditemukan di 30 orang, 11 wanita (usia rata-rata 45 tahun,
kisaran 14-90 tahun) dan 19 laki-laki (usia rata-rata 65 tahun, kisaran l & 87 tahun).

All 30 cases except one were identified from notifications to the Committee on Adverse Drug
Reaction. Only 6 of the 30 cases (20%) were in the Central Death Register under the diagnosis
AS. The death certificates of the remaining 24 cases did not suggest other causes of death; just
the main underlying disease had been registered. The Central Death Register did contain one
case of drug-induced AS which had been registered at the Committee on Adverse Drug Reaction
under the diagnosis Cardiac arrest.

Semua 30 kasus kecuali satu diidentifikasi dari pemberitahuan kepada Komite Merugikan
Reaksi Obat. Hanya 6 dari 30 kasus (20%) berada di Central Death Daftar di bawah
diagnosis AS. Sertifikat kematian sisanya 24 kasus tidak menyarankan penyebab lain
kematian; hanya penyakit yang mendasari utama telah terdaftar. The Central Kematian
Register lakukan mengandung satu kasus obat-induced AS yang telah terdaftar di Komite
Merugikan Obat Reaksi bawah diagnosis Henti jantung.

Table 1 lists the drugs concerned, patients’ sex and age, the method of drug administration, and
where the AS occurred. The commonest drugs were contrast media for X-ray examinations,
antibiotics, and extracts of allergens, of which 4 were moulds used for desensitization in general
practice. The reactions were evenly distributed across the observation period except for 3 cases
of allergen extracts occuring in 1973. These allergen extracts were moulds. The reactions
occurred in a hospital in 21 cases (70.0%; 95% CL, 50.685.3%). The drugs were taken orally in
only 3 cases. Definite evidence that the patient had reacted to the same drug previously was
found in 4 cases (13.3%; 95% CL, 3.8-30.7%).

Tabel 1 daftar obat yang bersangkutan, jenis kelamin pasien dan usia, metode pemberian
obat, dan di mana AS terjadi. Obat-obatan yang paling umum adalah media kontras untuk
pemeriksaan X-ray, antibiotik, dan ekstrak alergen, yang 4 adalah cetakan yang
digunakan untuk desensitisasi dalam praktek umum. Reaksi yang merata di seluruh
periode pengamatan kecuali untuk 3 kasus ekstrak alergen yang terjadi pada tahun 1973.
ekstrak alergen ini adalah cetakan. Reaksi terjadi di sebuah rumah sakit di 21 kasus
(70,0%; 95% CL, 50.685.3%). Obat yang diminum hanya 3 kasus. Bukti yang pasti bahwa
pasien bereaksi terhadap obat yang sama sebelumnya ditemukan pada 4 kasus (13,3%;
95% CL, 3,8-30,7%).

DISKUSI/DISCUSSION

The present study was based on voluntary notifications of adverse drug reactions. It is well
known that this type of study entails methodo- logical problems, especially concerning under-re-
porting. Such under-reporting probably decreases with increasing severity of the adverse
reactions. A previous study demonstrated an under-reporting of non-fatal AS to the Commit- tee
on Adverse Drug Reactions[2]. In the present study the number of notified fatal cases of AS
corresponded to figures in Sweden (22 cases during 196&75)[5].

Penelitian ini didasarkan pada pemberitahuan sukarela reaksi obat yang merugikan. Hal
ini juga diketahui bahwa jenis penelitian memerlukan masalah logis methodo-, terutama
menyangkut bawah-ulang porting. Seperti di bawah-pelaporan mungkin menurun dengan
meningkatnya keparahan reaksi yang merugikan. Penelitian sebelumnya menunjukkan
sebuah bawah-pelaporan non-fatal AS ke tee Committee on Reaksi efek samping obat [2].
Dalam penelitian ini jumlah kasus yang fatal diberitahu AS berhubungan dengan angka di
Swedia (22 kasus selama 196 & 75) [5].

Population based morbidity and mortality registers, such as the Scandinavian, are usually
considered of high validity, because of the equal access by all to the National Health Service, and
because of the use of CPR-numbers. The study was aimed to investigate the completeness of the
Central Death Register regarding drug-induced AS. We used the “independent case ascertain-
ment method” as described by Goldberg et a1.[6], where the Death Register was compared with
an independent data source, namely the Committee on Adverse Drug Reactions file. Our study
showed, if the frequency had been based on the statistics of causes of death alone, it would have
been considerably underestimated, because this register often gives the disease for which the
drug was given as the main cause of death. This also applies to data taken from hospital
discharge notes[2]. Unfortunately, it was only possible to compare the data sources in part of the
period because of changes in the data system of the Central Death Register in 1977.

Morbiditas dan mortalitas penduduk berdasarkan register, seperti Skandinavia, biasanya

dianggap validitas tinggi, karena akses yang sama oleh semua untuk National Health
Service, dan karena penggunaan CPR-angka. Penelitian ini bertujuan untuk mengetahui
kelengkapan Central Death Register mengenai obat-induced AS. Kami menggunakan
"metode ment kasus ascertain- independen" seperti yang dijelaskan oleh Goldberg et a1.
[6], di mana Death Daftar dibandingkan dengan sumber data independen, yaitu Komite
Merugikan Reaksi Obat berkas. Studi kami menunjukkan, jika frekuensi telah
berdasarkan statistik dari penyebab kematian saja, itu akan telah jauh diremehkan,
karena register ini sering memberikan penyakit yang obat itu diberikan sebagai penyebab
utama kematian. Hal ini juga berlaku untuk data yang diambil dari catatan dari rumah
sakit [2]. Sayangnya, itu hanya mungkin untuk membandingkan sumber data di bagian
periode karena perubahan dalam sistem data dari Central Death Register pada tahun
1977.

Even taking into account the possible under-reporting, the present study indicates that fatal AS is
rare. This is also supported by the fact that only 5% of all fatal reactions reported to the
Committee are caused by anaphylaxis[9]. Most cases occurred in hospital and were related to
anesthesia and the administration of contrast media from radiological examinations. Another
cause in hospitals was the intake of antibiotics, but considering the number of exposed people,
the risk is probably highest with respect to the two first groups. The study also showed that in
most cases, drugs were administrated parenterally.

Bahkan dengan mempertimbangkan kemungkinan kurangnya pelaporan, penelitian ini

menunjukkan bahwa yang fatal AS jarang. Hal ini juga didukung oleh fakta bahwa hanya
5% dari semua reaksi fatal yang dilaporkan kepada Komite disebabkan oleh anafilaksis
[9]. Sebagian besar kasus terjadi di rumah sakit dan terkait dengan anestesi dan
administrasi media kontras dari pemeriksaan radiologi. Penyebab lain di rumah sakit
adalah asupan antibiotik, tetapi mengingat jumlah orang yang terkena, risiko tersebut
mungkin tertinggi sehubungan dengan dua kelompok pertama. Penelitian ini juga
menunjukkan bahwa dalam kebanyakan kasus, obat yang diadministrasikan secara
parenteral.

Another important finding was the five deaths caused by extracts of allergens, since they all
occurred under a general practitioner’s care. It emphasizes that this treatment, which is often
given to younger people, entails a certain risk, and that appropriate treatment for AS should be at
hand. The four cases of previous reactions all belonged to this group. Other studies have not
described extracts of allergens as a cause of drug-induced AS outside hospital[2, 10, 11

Temuan penting lainnya adalah lima kematian yang disebabkan oleh ekstrak alergen,
karena mereka semua terjadi di bawah perawatan dokter umum itu. Ini menekankan
bahwa pengobatan ini, yang sering diberikan kepada orang-orang muda, memerlukan
risiko tertentu, dan bahwa pengobatan yang tepat untuk AS harus di tangan. Empat kasus
reaksi sebelumnya semua milik kelompok ini. Penelitian lain yang tidak dijelaskan ekstrak
alergen sebagai penyebab akibat obat sakit AS di luar [2, 10, 11

Drug reactions should be expressed ideally as the number of adverse drug reactions in relation to
the number of exposed persons. It is often impossible to obtain information on the number of
individuals exposed. Often, only information about aggregated data of the amounts used are
available, therefore the population based studies are important. Data- base studies are often used
in the analytical epidemiological surveillance of adverse reactions of drugs based on
prescriptions, but they cannot identify cases caused by diagnostic or therapeutic procedures in
hospitals. The present study estimated the incidence of fatal AS at about 0.3 case per million
inhabitants per year. Consider- ing the enormous numbers of drugs in use, the cases of fatal AS
are related to very few groups of drugs.

Reaksi obat harus dinyatakan idealnya sebagai jumlah reaksi obat yang merugikan dalam
kaitannya dengan jumlah orang yang terkena. Hal ini sering tidak mungkin untuk
mendapatkan informasi tentang jumlah individu yang terkena. Seringkali, hanya
informasi tentang data dikumpulkan dari jumlah yang digunakan tersedia, maka studi
populasi berdasarkan penting. Data- studi dasar yang sering digunakan dalam surveilans
epidemiologi analitik reaksi merugikan dari obat berdasarkan resep, tetapi mereka tidak
dapat mengidentifikasi kasus disebabkan oleh prosedur diagnostik atau terapeutik di
rumah sakit. Penelitian ini memperkirakan kejadian fatal AS sekitar 0,3 kasus per juta
penduduk per tahun. -Pertimbangan ing angka besar obat yang digunakan, kasus yang
fatal AS terkait dengan sangat sedikit kelompok obat.