Ani Ölüm Olgularında Sildenafil (Viagra) Kullanımı

ÖZET

Giriş ve Amaç: Son yıllarda

er-keklerde seksüel fonksiyonu ar-tırmak için Sildenafil (Viagra vb) içeren ürünlere artan bir ilgi söz konusudur. Sildenafil ağır kar-diyovaskuler sorunlara ve adli olguların oluşumuna yol aça-bilir. Bu nedenle çalışmamız-da travmatik bulgusu olmayan, ani ölüm öykülü erkek olgularda sildenafil düzeyinin araştırılma-sı amaçlanmıştır.

Materyal ve Metot: Bu

çalışma-da Adli Tıp Kurumu Başkanlığı Morg İhtisas Dairesinde 2003-2004 yıllarında gerçekleştirilen

otopsilerden; 45-65 yaş arası, non travmatik, ani ölüm öykü-lü, çürümenin ilerlemediği top-lam 53 erkek olguda; otopside-ki sistematik makroskopik, his-topatolojik, toksikoljik incele-me sonuçlarının yanı sıra , ölüm nedeni, kan ve idrarda “Yüksek Performans Sıvı Kromatografisi (HPLC)” yöntemiyle sildenafil ve nitrat grubu ilaçlar araştırıldı.

Bulgular: Olguların yaş

orta-laması: 54.37±6.77 olarak bu-lundu. İncelenen 53 olgudan 1’i “Akciğer Ca”, 2’si “Subaraknoi-dal Kanama” olmak üzere top-lam 3 olgu dışında kalan 50 ol-gunun (%94.3) ölüm nedeninin

kardiyovasküler kaynaklı oldu-ğu belirlendi.Serimizde sadece 47 yaşında olan ve “Akut Myo-kard Infarktüsü Rüptürüne Bağlı Kalp Tamponadı” nedeniyle ölen bir olguda idrarda sildenafil (+) bulundu.

Tartışma ve Sonuç:

Kardiyovas-küler sisteme ait bulguların varlı-ğında ani ölüm grubundaki erkek olguların otopsilerinde sildena-fil araştırılması, ölüm nedenini ve ölüme etkili faktörleri ortaya koy-mak açısından yararlı olacaktır.

Anahtar kelimeler: Ani ölüm,

sil-denafil, kardiyovasküler hastalık, otopsi.

> Doç.Dr. Erdem Özkara1

> Uzm.Dr. Oya Tanç2 _{> Uz.Dr. Nergis Cantürk}4 _{> Prof.Dr. Zerrin Erkol}5

> Uz.Dr. İbrahim Üzün2 _{> Doç.Dr. Gürol Cantürk}3

SİLDENAFİL

(VİAGRA) KULLANIMI

ANİ ÖLÜM OLGULARINDA

1 Dokuz Eylül Üniversitesi Tıp Fakültesi Adli Tıp AD, İzmir. 2 Adli Tıp Kurumu Başkanlığı, İstanbul.

3 Ankara Üniversitesi Tıp Fakültesi Adli Tıp AD, Ankara. 4 Adli Tıp Kurumu Ankara Grup Başkanlığı, Ankara.

5 Abant İzzet Baysal Üniversitesi Tıp Fakültesi Adli Tıp AD, Bolu.

This article was presented in the “13th National Forensic Medicine Days, 2006” in Antalya TURKEY, as a poster presentation.

Kardiyovasküler sisteme ait bulguların varlığında ani ölüm grubundaki

erkek olguların otopsilerinde sildenafil araştırılması, ölüm nedenini ve

ölüme etkili faktörleri ortaya koymak açısından yararlı olacaktır.

Erdem Özkara, İbrahim Üzün, Gürol Cantürk, Oya Tanç, Nergis Cantürk, Zerrin Erkol

ABSTRACT

Number of sales of sildenafil citrate(Viagra) which used to imp-rove sexual function for man have increased in recent years. Silde-nafil may lead to severe cardio-vascular problems and medico-legal cases. Therefore, we at-tempted to investigate sildena-fil citrate levels in non-traumatic sudden deaths of males.

This study included 53 males’ autopsy in the Morgue Department, State Institute of Forensic Medici-ne, between 2003 and 2004. The inclusion criteria were a history

of non-traumatic- sudden death and lack of advanced putrefac-tion. Data about macroscopic, histopathological and toxicolo-gical findings, the cause of de-ath determined at autopsies and blood and urine sildenafil citrate and nitrate levels measured by High Performance Liquid Chro-matography (HPLC) were collec-ted.

The mean age of the cases was 54.37±6.77 years. Out of 53 ca-ses, a total of 50 cases (94.3%) died from a cardiovascular condition, one had lung cancer and two had subarachnoidal

bleeding. We found a 47-year-old man dying of cardiac tam-ponade caused by acute myo-cardial infarct with ventricular rupture to have sildenafil cit-rate in the urine.

It will be useful to investiga-te whether male cases of sud-den death with cardiovascular signs have taken sildenafil cit-rate since it may reveal the ca-use of death and contributing factors.

Key Words: Sudden death,

Sil-denafil citrate, cardiovascular diseases, autopsy.

SILDENAFIL CITRATE (VIAGRA)

USING IN SUDDEN DEATHS

INTRODUCTION

A large proportion of forensic autopsies are performed to de-termine the causes of sudden deaths. In fact, 80% of all foren-sic autopsies are carried out on cases of sudden deaths in Eng-land and all causes and the exact mechanisms of sudden deaths may not be determined (1-4). Inability to find the causes of deaths has caused a lot of en-vironmental factors and drugs in use to come under suspici-on. Detection of cardiovascular system diseases as the causes of deaths at most of the autopsi-es requirautopsi-es that drugs which af-fect this system should be inves-tigated (1-3).

With technological advance-ments, a lot of new products and drugs have been offered to huma-nity. Although numerous studies on these products and drugs are performed before they are intro-duced, they may have side-effects which have not been shown befo-re (5-7). Side-effects of some wi-dely used preparations which may interact with other drugs are par-ticularly important. In recent ye-ars, there has been an increasing interest in products which con-tain sildenafil citrate frequently used to improve sexual functions in males (5,6,8). It has been re-ported to be prescribed 6 milli-on times in an eight-mmilli-onth peri-od in the United States of Ameri-ca in 1998 (9). It is not known how

much care is taken with the use of sildenafil citrate, which may have side-effects and interact with the drugs used to treat cardiovascu-lar conditions which frequently appear in elderly males. In other words, it is not clear whether pe-ople follow the instructions abo-ut the use of this drug. Actually, sildenafil citrate has been repor-ted to cause dramatic decreases in blood pressure especially when taken with drugs which contain nitroglycerin and nitric oxide (7,9).

Sildenafil citrate is a preparati-on prescribed to improve sexual functions in males with erectile dysfunction. About 80% of erec-tile dysfunction is of organic ori-gins; most causes relate to

vas-cular disorders such as cardio-vascular and cerebro-cardio-vascular di-seases, where the blood flow to the penis is insufficient to develop and maintain a full erection. Sil-denafil citrate is a selective inhi-bitor of cyclic guanosine monop-hosphate (cGMP)-specific phosp-hodiesterase-5 (PDE5), an enz-yme involved in the regulation of blood flow to the penis(7).

When used inappropriately, sil-denafil citrate, like other drugs, may lead to side-effects, ran-ging from cerebro-vascular

ble-eding to sudden cardiac deaths (5,7-10). The aim of this study was to reveal the frequency of silde-nafil citrate use and its mode of action in sudden deaths of males, which mostly require forensic au-topsies. To this aim, we investiga-ted autopsies performed in Istan-bul, the most crowded city of Tur-key, where most of the autopsi-es are carried out, between 2003 and 2004.

According to the statistical data from the State Statistics Institu-te, the population of Turkey was 70.231.000 in 2003 and 71.152.000 in 2004 and the population of Is-tanbul was 10.760.000 in 2003 and 11.045.000 in 2004 (11). This

study was conducted in the Mor-gue Department, State Institute of Forensic Medicine, where all au-topsies requested by health cen-ters in Istanbul and a small pro-portion of autopsies requested by health centers in other cities are performed.

MATERIALS AND

METHODS

This is a prospective and cross-sectional study and included au-topsies of 53 males performed in the Morgue Department, State

Institute of Forensic Medicine, in a 24-month period between 2003 and 2004. The autopsies of 53 out of 6841 males were selected ba-sed on the following inclusion cri-teria: the gender of male, age ranging between 45 years and 65 years, non-traumatic, sudden de-aths and lack of advanced putre-faction. The autopsies done early in the postmortem period were selected because advanced put-refaction might cause macrosco-pic and histopathological features to disappear and sildenafil citra-te might not be decitra-termined. Data about macroscopic and histopat-hological examinations and the causes of deaths were collected. Nitrate containing drugs and

sil-denafil citrate using by High Per-formance Liquid Chromatography was carried out to investigate in blood and urine. For Liquid Chro-matography, first, liquid-liquid ext-raction was carried out and for this phase, chloroform/2-proponol/ n-heptan 60/14/26 as an extracti-on solvent, the devise HPLC-DAD (Agilent 1100 series), the Lichro-sorb RP18-5 colon (Hichrom) were used. Then, the mobile phase was performed with Trietilamin/Meta-nol/Asetonitril 580/250/170 at pH of 3.0 adjusted with phosphoric acid and at the wave length of 290nm.

RESULTS

A total of 53 non-traumatic, sudden deaths without advan-ced putrefaction, were evalua-ted. Three males died outside Istanbul and 50 males died in Istanbul. The mean age of the males was 54.37±6.77 years (range: 45-65). The cause of death was acute myocardial in-farct (AMI) in 46 cases (86.7%), ventricular rupture plus cardi-ac tamponade following previ-ous myocardial infarct (MI) in two cases (3,8%), cardiac tam-ponade due to rupture of aor-tic aneurism in one case (1.9%) and lung cancer in one case (1.9%) (Table 1).

On myocardial sections, there were occasional bleeding points

in the ruptured area 5x8cm in sizes and filthy yellow and

paler in color compared to the adjacent regions ( Fig 1-2).

Abdominal organs were normal.

Erdem Özkara, İbrahim Üzün, Gürol Cantürk, Oya Tanç, Nergis Cantürk, Zerrin Erkol

We investigated whether the ca-ses had previous cardiovascu-lar diseases and found out that two cases –one dying from suba-racnoidal bleeding and the other dying from lung cancer- did not have any pathological conditions in the heart and vessels, but that all the rest had atherosclerosis.

Out of 53 cases, only one (1.9%) aged 47 years and dying from car-diac tamponade due to ventricu-lar rupture caused by AMI based on macroscopic and histopatholo-gical examinations had sildena-fil citrate in his urine specimen. Another case dying from suba-rachnoidal bleeding had 305mg/ dl ethanol in his blood specimen.

Characteristics of the case found to have sildenafil citrate:

He was 47 years old, 176 cm in height and 96 kg in weight. His-tory showed that he was found dead in a hotel room and physical examination revealed that he did not have any traumas.

At autopsy, the scalp and bony structures were normal and the brain was 1380gr and its secti-ons were normal. The right lung was 800gr and the left lung was 690 gr. Both were swollen and bright and had bleeding spots oc-casionally merging on their sur-faces, hyperemia in their sections and hardening in their forms and were discharging copious bloody liquid when squeezed.

Partly clotted blood 600cc was drained through the pericardial space. The heart was 550 gr. The

circumferences of the aortic, mit-ral, tricuspid and pulmonary val-ves were 7.5cm, 9 cm, 12.5 cm and 7.8 cm respectively. The left and right ventricular wall thick-nesses were 1.5 cm and 0.3cm respectively. All valves were dull in color and there were occasi-onal obstructive atheroma pla-ques in the coronary arteries. There were widespread, swol-len atheroma plaques –each was

3x2x0.5cm in size- and a ruptu-re 3cm in size, in the left ventric-le wall, in the border of intervent-ricular wall and neighboring with the ventricular space. On myocar-dial sections, there were occasio-nal bleeding points in the ruptu-red area 5x8cm in sizes and filthy yellow and paler in color compa-red to the adjacent regions ( Fig 1-2). Abdominal organs were nor-mal.

On histopathological examinati-ons of the heart, there was wi-despread necrosis in myocardial fibrils and occasional bleedings

and polymorphonuclear leukocy-tes around necrotic areas. There were also mononuclear inflam-matory cells polymorphonucle-ar leukocytes, vasculpolymorphonucle-ar prolife-ration and new granulation tis-sue made of fibroblastic cells, replacing the muscle fibers. The cells of the surrounding musc-le fibers had larger nucmusc-lei and were hyperchromatic and larger than the cytoplasm. The

diagno-sis was AMI and there was new granulation tissue and hypert-rophy (Fig 3-4).

On histopathological examinati-ons of the lungs, there was seve-re bleeding in some alveoli, seveseve-re hyperemia and increased connec-tive tissue in some alveolar septa.

On histopathological examinati-ons of the liver, there was marked macrovesicular fat in the central vein.

Kidneys, brain and pons were hyperemic.

Causes of Deaths N %

AMI 46 86.7

Ventricular rupture plus cardiac tam-ponade preceded by previous MI

3 5.7

Subarachnoidal bleeding 2 3.8

Lung cancer 1 1.9

Rupture of aortic aneurism+ Cardiac tamponade

1 1.9

Total 53 100

On Toxicological analyses: The urine specimen had sildenafil cit-rate, but blood, urine and internal organ specimens did not contain any other drugs.

We failed to contact with the rela-tives of the case and to ask whet-her he had any known cardiovas-cular diseases and whether he received nitrate containing drugs or any drugs for the treatment of hypertension.

DISCUSSION AND

CONCLUSION

There have been a large number of studies on the causes of sud-den deaths, which play an im-portant part in forensic practi-ces. Sudden deaths account for not only a large proportion of fo-rensic cases but also are respon-sible for a considerable proporti-on of other deaths. In fact, it has been reported from the United States that sudden deaths acco-unt for 32% of all deaths among people aged 20-64 years (12). The most frequent causes of deaths are diseases of the cardiovascu-lar, respiratory, central nervous, gastrointestinal and genitourinary systems (2,12,13). Some authors even claim that almost all sud-den deaths are caused by disea-ses of the cardiovascular system (1). Consistent with the literature, we found that 50 out of 53 deaths (94.3%) were due to diseases of the cardiovascular system.

More and more drugs which af-fect the cardiovascular system are introduced every day.

Silde-nafil citrate, a drug which imp-roves sexual performance but af-fects the cardiovascular system, has been increasingly used in re-cent years. Despite warnings abo-ut its side-effects and interacti-ons with drugs used for the treat-ment of cardiovascular diseases, middle-aged and old-age males may not be very careful with the use of this drug, which poses se-rious risks. In fact, FDA attracts attention to the fact that sildena-fil citrate may lead to serious car-diovascular problems like sudden cardiac deaths (10,14).

In addition, several studies have revealed that sildenafil citrate combined with nitrates may have harmful effects and can even be fatal (5,6,8,9,15). It is recommen-ded that caution should be exer-ted with the use of sildenafil cit-rate in combination with other drugs used for hypertensive treat-ment as well such as ß-blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers due to their in-teractions with each other (10,16). Prescription of nitrates for the tre-atment of hypertension and ische-mic heart disease, both of which are common among the middle-aged and old age men, and con-currently increasing use of silde-nafil citrate pose higher risks for sudden deaths among the middle-aged and old age males (5,7,8,15). In this study, the case found to have sildenafil citrate did not have metabolites of any other drugs. It may suggest that care should be taken with the use of sildenafil cit-rate alone as well as in combinati-on with other drugs.

There are data which draw atten-tion to the associaatten-tion of silden-fail citrate use and MI (7, 10,14). Dumestre et al. reported that a 43-year-old man died in a hotel room when he was making sex with one of his colleagues. At au-topsy, they found severe coronary artery sclerosis, a sign of previ-ous myocardial infarct. They no-ted that he was the first to die from hypotension and cardiac dysrhythmia caused by sildenafil and verapamil in combination (7). In this study, we found out that a 47-year-old man died of cardiac tamponade due to new MI. To our knowledge, this was the first case of death from cardiac tamponade due to MI which may have been triggered by sildenafil citrate. Ac-tually, the data we obtained may not be sufficient to conclude that Sildenafil citrate causes sudden deaths among middle-aged and old age males; however, similar data which are likely to be repor-ted in the future will shed light on the issue.

Cardiovascular deaths have been reported to be responsible for 80% of all sudden deaths (1-3). In a study on autopsy findings of sudden cardiac deaths reported from Greece, of all sudden cardi-ac deaths, 53.6% were due to AMI and 46.4% were due to chronic ischemic heart disease (4). Like-wise, we also found 86.7% of sud-den deaths to be due to AMI.

According to data from FDA, as of February 1999, 401 people presc-ribed sildenafil citrate died in the United States of America during the prior 10 to 11 months. Out

Erdem Özkara, İbrahim Üzün, Gürol Cantürk, Oya Tanç, Nergis Cantürk, Zerrin Erkol

of 401 deaths, 219 were due to cardiovascular accidents (MI, arrhythmia, cardiac arrest, col-lapse), 140 were sudden deaths and 18 were due to cerebrovas-cular diseases. During that pe-riod, 4-5 million males reported to take sildenafil citrate and the risk for death was found to be 8.5 deaths per million men per month (10,14) The present study

included 53 non-traumatic, sud-den deaths without advanced putrefaction of the males aged 45-65 years and one subject (1.9%) was found to have silde-nafil citrate in his urine speci-men. Although there have been occasional reports indicating an association between sildenafil citrate and sudden cardiac de-aths, there is not concrete

evi-dence and reliable data to con-firm it (10, 17).

We think that there will be more data about the issue in the fu-ture. In fact, even one sud-den cardiac death as described here emphasizes investigations for sildenafil citrate in deaths among middle-aged and old age males.

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FIGURES

Fig 1: A rupture 3cm in length, in the left ventric-le wall, in the border of the interventricular wall and neighboring with the ventricular space

Fig 2: A view of the left ventricular rupture from the interior of the ventricle

Erdem Özkara, İbrahim Üzün, Gürol Cantürk, Oya Tanç, Nergis Cantürk, Zerrin Erkol

Corresponding Author:

Fig 4: Mononuclear inflammatory cells and poly-morphonuclear leukocytes replacing the muscle fibers and granulation tissue made of fibroblastic cells surrounded by hypertrophic muscle fibers vas-cular proliferation (HE X 200)

Fig 3: Necrosis, polymorphonuclear leukocytes and pieces of nuclei in the muscle fibers (HE X 400).