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1 음경복합초음파검사의발기유발제로서복용약이주사제를대체할수있는가? Can the PDE5 Inhibitor Replace Intracavernosal Injection as a Method for Inducing a Penile Erection during the Evaluation of Erectile Dysfunction Using Penile Duplex Ultrasonography? 대한비뇨기과학회지제 49 권제 7 호 2008 In Wook Ryu, Hana Yoon, Bong Suk Shim, Young Yo Park, Woo Sik Chung From the Department of the Urology, Ewha Womans University School of Medicine, Seoul, Korea Purpose: To clarify whether vardenafil can be used as a substitute for intracavernosal injection as a method of induction of penile erection, we compared the outcome of penile duplex Doppler ultrasonography using both methods in the same patient with erectile dysfunction. Materials and Methods: A total of 23 patients underwent penile duplex ultrasonography twice with a one week interval between procedures. Twelve were randomly selected for intracavernosal injection first with prostaglandin E1 (PGE1) 20μg and the remaining 11 were initially treated with oral vardenafil 20mg 1 hour before the Doppler study and in addition had visual sexual stimulation using a head-mounted display during the study. The peak systolic velocity (PSV), end diastolic velocity (EDV) and the degree of maximum erectile response were measured and compared between the two groups. Results: Measurements from the PGE1 treatment were not significantly different from those with the vardenafil treatment. The percentage of compatibility between the two methods with regard to hemodynamic diagnosis and pharmaceutical erectile response was as high as 83% (19 of 23) and 91% (21 of 23), respectively. Both methods were tolerable and safe without severe complications. However, in 4 patients where the diagnosis was uncertain, the injection method provided a more accurate interpretation of the penile vascular status with duplex ultrasonography. Conclusions: These results suggest that oral vardenafil can be used as an initial method for inducing penile erection when assessing erectile dysfunction with penile duplex Doppler ultrasonography in selected patients with erectile dysfunction. (Korean J Urol 2008;49: ) Key Words: Erectile dysfunction, Phosphodiesterase inhibitors, Ultrasonography, Doppler 이화여자대학교의학전문대학원비뇨기과학교실 류인욱ㆍ윤하나ㆍ심봉석박영요ㆍ정우식 접수일자 :2008년 4월 4일채택일자 :2008년 6월 12일 교신저자 : 정우식이화의대목동병원비뇨기과서울시양천구목동 TEL: FAX: woochung@ ewha.ac.kr 서론발기부전은질내삽입이가능한발기를얻거나유지하기가어려운경우를일컫는질환으로, 1 기질성원인이 80-90% 를차지하고있는바, 그중에서도혈관성발기부전 이가장흔한원인으로알려져있으며 2 이는해면체로유입되는동맥의혈류가감소하거나정맥폐쇄기능의장애로인해해면체라는공간내에혈액이충만하지못함으로발생하게된다. 3 음경의혈류역동학과발기의기전에대한이해가높아지면서발기부전의진단방법에많은발전이이루어져왔고, 4 다양한진단방법중에음경복합도플러초음파는 641

2 642 대한비뇨기과학회지 : 제 49 권제 7 호 2008 혈관성발기부전을비교적정확하게평가할수있는검사방법으로인정받고있다. 5,6 발기부전의진단에있어대부분의진단방법이그러하듯이발기를유발하는과정이필요한데, 현재까지주로혈관확장제를이용한해면체내주사방법을이용해왔다. 그러나이방법의단점으로주사라는침습적인점외에도, 주사시동통, 주사부위의반상출혈등의경미한합병증은물론, 음경지속발기증이나해면체섬유화등의치명적인합병증을일으킬수있다. 7 한편 1998년경구용발기부전치료제로 sildenafil이처음소개된후현재여러가지다양한제 5형 phosphodiesterase (PDE5) 억제제가발기부전의 1차치료에널리이용되고있다. 8,9 이에저자들은발기를유도하는방법으로비교적작용시간이빠른것으로알려진 vardenafil을이용하여, 10,11 이를복용한후시청각성적자극하에서시행한음경복합초음파검사법의유용성을기존의음경해면체내주사법을이용한결과와비교하여알아보고자하였다. 대상및방법최근 6개월간발기부전을주소로본원외래를방문한환자중신경인성및내분비성원인이아닌발기부전환자 23명을대상으로하였다. 대상자들은모두병력채취, 신체및신경학적검사를시행하였고검사시행전환자에게검사의내용을설명하고동의를구하였다. 대상환자에대한음경복합초음파검사는 1주일간격으로 2차례시행하였는데, 한번은음경해면체내주사제를이용하였고, 다른한번은 PDE5 억제제복용약을이용하였다. 시행순서는무작위로 12명에서는주사약을먼저, 11명에서는복용약을먼저사용하였다. 음경해면체내주사제로는 alprostadil (Caverject R, Pfizer, Bruxelles, Belgium) 20μg 을이용하였고경구용발기부전치료제는 vardenafil (Levitra R, Bayer AG, Leverkusen, Germany) 20mg을이용하였다. 음경복합초음파검사는 B&K-medical사의컬러도플러초음파 7.5MHz 탐침자를이용하여환자가약물에의해음경발기가유도된상태에서초음파탐침자를음경의배부에위치시키고음경해면체동맥의혈류를측정하였다. 탐침자의도플러입사각도는 60도미만을유지한상태에서최고수축기유속 (peak systolic velocity; PSV) 과확장말기유속 (end diastolic velocity; EDV) 을최대발기가유도될때까지 20-60분에걸쳐 3-4차례측정하였고, 아울러최대약물발기반응의정도도함께측정하였다. 대상환자들은조용하고어두운방에서안정된상태를유지하며검사를시행받았고, 복용약을이용하는경우에는검사 1시간전에복용하고검사시에는안경형태의모니터를착용하고성적흥분을야 기할수있는시청각성자극동영상을최소 10분이상시청하게하였으며주사제를사용한경우에는시청각자극없이시행하였다. 음경해면체동맥의 PSV가 30cm/sec 이상이면서 EDV가 5cm/sec 미만이면정상, EDV값에상관없이 PSV가 30cm/sec 이하인경우는동맥부전 (arterial insufficiency; AI) 으로, PSV가 30cm/sec 이상이면서 EDV가 5cm/ sec 이상인경우에는정맥폐쇄기능부전 (venous incompetency; VI) 으로분류하였다. 약물발기의반응은반응의정도를 4단계로나누어전혀발기가되지않거나음경팽대만있는경우를 1, 팽대와함께음경강직이있으나삽입에충분치못한경우를 2, 삽입에충분한정도의음경강직이있으나완전하지않은경우를 3, 팽대와강직도가완전한경우를 4로하여초음파검사를시행하는동안보여준가장높은발기반응의정도를택하였다. 통계학적검증방법으로음경해면체내주사법과 vardenafil 복용법의결과차이를 SPSS (Ver.12, SPSS Inc.) 를이용하여 Student's t-test (paired) 를시행하였으며 p값이 0.05 미만인경우를유의한것으로판단하였다. Table 1. Characteristics of patients (n=23) Characteristics 결 연구에포함된환자들의특성을살펴보면평균연령은 45.3세 (28-62) 이었고, 발기부전의평균유병기간은 23.4개월 (3-72) 이었다. 동반질환으로는당뇨와고혈압을앓고있는경우가각각 5례 (21.7%), 고지혈증과기타심장혈관질환이각각 2례였다 (Table 1). 음경복합초음파를통한각환자의혈류역동학적지표와진단을발기를유도한방법에따라비교해본결과는 Table 2와같다. 방법에따른 PSV 및 EDV의차이검정에있어서는통계적으로의미있는변화를발견할수없었으나 (p> 0.05) 발기부전의혈류역동학적진단은 alprostadil 을이용한 Values (range) or No. of patients (%) Mean age (years) 45.3 (28-62) ED periods (months) 23.4 (3-72) Risk factors Diabetics 5 (21.7%) Hypertension 5 (21.7%) Hyperlipidemia 2 (8.6%) CHD 2 (8.6%) ED: erectile dysfunction, CHD: coronary heart disease 과

3 류인욱외 : 음경복합초음파검사발기유발제로서의복용약 643 Table 2. Comparison of PSV, EDV, erection grade and diagnosis between the group with intracavernosal injection and oral vardenafil with sexual stimulation PSV* (cm/sec) EDV* (cm/sec) Erection grade Diagnosis 1st No. study ICI Vardenafil ICI Vardenafil ICI Vardenafil ICI Vardenafil 1 I VI VI 2 O N AI 3 I VI VI 4 O AI AI 5 I VI VI 6 O AI AI 7 I AI AI 8 O VI AI 9 I VI VI 10 O VI VI 11 I N AI 12 O N N 13 I AI AI 14 O N AI 15 I VI VI 16 O AI AI 17 I AI AI 18 O N N 19 I AI AI 20 O AI AI 21 I AI AI 22 O AI AI 23 I N N PSV: peak systolic velocity, EDV: end-diastolic velocity, ICI: intracavernosal injection of PGE1, I: injection, O: oral administration, AI: arterial insufficiency, VI: venous incompetency, N: non-vasculogenic, *: p>0.05 Student's t-test (paired) 음경해면체내주사군에서정상 6명, 동맥부전 10명, 정맥폐쇄기능부전 7명으로나타났고 vardenafil 20mg을복용한군에서는정상 3명, 동맥부전 14명, 정맥폐쇄기능부전 6명으로나타나 4명의환자에서 ( 환자 2, 8, 11, 14) 진단의차이를보였다. 발기반응의정도에있어서는 6명이차이를보인바, 5명은주사제에, 1명은복용약에더높은발기반응을보였다. 그러나삽입이가능한경우 ( 정도 3, 4) 와그렇지못한경우 ( 정도 1, 2) 로나누어비교하면주사제에삽입이가능한정도 3을보인두명에서 ( 환자 2, 11) vardenafil 복용시비정상반응인정도 2와정도 1로관찰되어극히일부인 2명에서만차이를보였다 (Table 2, 3). 두방법간의혈류역동학적진단의분포에있어차이를보면, 주사군의경우정상혈류를보인경우가복용약군에비해 2배많았으며 ( 각각 6명, 3명 ), 동맥부전은복용약군에서, 정맥폐쇄기능부전은주사군에서더많이발견되었다 (Table 3). 치료방침결정에도움이되는발기반응의정도는 Table 3. Distribution of diagnosis and grade of pharmacological erection between the group with intracavernosal injection and the oral vardenafil with sexual stimulation group Intracavernosal injection (%) Vardenafil with sexual stimulation (%) Diagnoses Arterial insufficiency 10 (43.5) 14 (60.9) Venous incompetency 7 (30.4) 6 (26.1) Non-vasculogenic 6 (26.1) 3 (13.0) Erection response Abnormal (Grade 1, 2) 17 (73.9) 19 (82.6) Normal (Grade 3, 4) 6 (26.1) 4 (17.4) 주사군에서복용약군보다정상반응의정도가많았다 ( 각각 6명, 4명 ). 혈류역동학적진단과발기반응에있어각각 19명과 21명에서일치하여두방법간의일치도는 83% 및 91% 로비교적높았다.

4 644 대한비뇨기과학회지 : 제 49 권제 7 호 2008 Table 4. Complications occurred according to methods Complications No. of patients (%) Intracavernosal injection Penile pain 6 (26.1) Ecchymosis 2 (8.7) Vardenafil with sexual stimulation Headache 4 (17.3) Nasal congestion 2 (8.7) Facial flushing 1 (4.3) 검사시나타난부작용으로는음경해면체내주사법을시행한경우주사시음경통증 6례 (26.1%), 반상출혈이 2례 (8.7%) 에서나타났고, vardenafil 복용군에서는두통 4례 (17.3%), 코막힘 2례 (8.7%), 안면홍조 1례 (4.3%) 가있었다 (Table 4). 그러나음경해면체내주사제와경구용발기부전치료제사용시검사를중단할만큼심각한부작용은없었다. 고 발기부전의원인중음경의혈류역동학적기전의이상에의해발생하는혈관인성발기부전이가장흔히발견되며, 2 이는음경복합초음파를이용하여비침습적으로비교적포괄적으로평가할수있으므로음경의동맥부전및정맥폐쇄기능부전을진단하기위한검사방법으로이용되고있다. 12 음경복합초음파는음경해면체동맥의유속 (flow velocity), 직경, 가속시간 (acceleration time) 등여러가지변수를측정할수있으나이중 PSV와 EDV가혈관성발기부전을진단하는데유용한지표로이용되고있다. 13,14 PSV와 EDV 를측정하기위해서는발기유발이필요하며이를위해음경해면체에주사하는약물로 papaverine, phentolamine 그리고 prostaglandin E1 (PGE1) 의단독또는병합약제가사용되어왔다. 15 그러나이약물들을이용한음경해면체내주사법은음경지속발기증등의합병증이많게는 9.5% 까지보고되었고 16 초기합병증으로음경통증, 반상출혈등이생길수있으며지속적사용시해면체섬유화가생길수있다. 17 또한음경해면체내주사법은주사에대한두려움과주사시통증으로인해환자에게불안감을주는데이로인한교감신경의자극으로발기를억제하여동맥부전의진단에위양성률을높일수있다. 7 따라서검사의민감도를높이기위한방법으로음경복합초음파를시행하는동안교감신경의자극을최소화하기위해시청각자료를통한자극, 혹은직접성기를자극하거나발기유발제의반복주사를통하여정확한진단을얻으려는노력을해왔다. 12 음경해면체내주 찰 사법과달리경구용발기부전치료제인 vardenafil에의한음경의발기기전은성적자극에의해산화질소 (nitric oxide; NO) 가혈관내피세포에서생성되어유리되면 NO가 guanylate cyclase를활성화하여 cgmp를생성시키고이 cgmp는평활근세포내칼슘농도를감소시키며 PDE5에의해 GMP 로분해되어비활성화된다. 이때 vardenafil은 PDE5를선택적으로억제하여 cgmp가분해되는것을억제함으로써발기의강도및시간을유지시키는작용을한다. 따라서 vardenafil에의한발기유도에는성적흥분에의한 NO와 cgmp 가먼저생성되어야한다. 10,11,18 본연구에서는평소시행해왔던방법을적용했을때를기준으로두방법간의차이를보기위하여약물주사시에는따로시청각자극을사용하지않고최대용량의주사를준후최대발기를얻을때까지충분히기다리며측정하였고, 약물복용시에는 vardenafil 투약 60분후시청각성적자극에 10분간노출한후검사를시작하였으며검사중에도시청각적자극을유지하여발기반응의유도는물론환자의심리적부담을줄이려는노력을하였다. 또한일반적으로검사에처음으로노출시심리적부담이클수있고, 두번째노출시부담이감소하는경향이있으므로이런검사순서에따른결과의차이를보정하기위하여교대로서로다른검사를첫검사로시행하였다. 본연구의결과음경복합초음파검사에서음경해면체내주사법과경구용약물복용을비교하였을때혈관인성발기부전을진단하는척도인 PSV와 EDV의전반적인비교에서통계학적으로유의한차이를나타내지않았다. 최근에혈관인성발기부전환자를대상으로 sildenafil을이용하여주사제와비교한연구에서도 PSV, EDV, RI 등의혈류지표들에있어두방법간에통계적인의미가없다고보고하였고, 19 주사제로는 3중복합제를이용하였지만복용제는본연구와같이 vardenafil을이용한경우에도두군간에 75% 이상에서동일한소견을보였다. 20 그러나본연구에서는혈류역동학적진단에차이를보인경우가 4례있었다. 이중 3명은음경해면체내주사시정상혈류를보인반면, vardenafil 복용시동맥부전으로진단되었는데, 환자 2의경우는복용약에의한검사를먼저시행했던환자로첫번째검사에서낮은 PSV 수치를보이다가주사제를이용한 2차검사에서정상소견을보인점으로미루어초기검사시심리적부담에의한발기억제가일어나발생한위음성소견으로추정되고, 환자 11의경우는첫번째로주사제를이용한경우정상반응을보이다가복용약에는미약한발기반응을보인경우로주사제를사용하지않으면정확한검사가이루어지지않을정도의중증의발기부전환자이거나오히려시청각자극으로인한심리적부담으로인해반응이억

5 류인욱외 : 음경복합초음파검사발기유발제로서의복용약 645 제된정상환자로추정된다. 또한사용된약물의작용특성상복용약인 PDE5 억제제는 cgmp 경로에만작용하는반면 PGE1은 camp 경로에작용하므로병인에있어세부적인차이에의해서도반응의결과가달리나타날수있겠다. 이외에도검사실에서의시청각성적자극에일부거부감혹은수치심을느꼈을경우혹은 PDE5 억제제가성적자극에의해발기반응을일으키기때문에비디오를통한시청각성적자극의종류나강도가검사결과에영향을주었을경우를생각해볼수있겠다. 나머지진단이불일치한환자 8과 14는진단기준에있어경계점에위치한이유로차이가났던환자로실제발기반응에있어서는차이를보이지않아특별한의미를갖기에는부족하다. 약물에의한발기반응의정도에있어서도전반적으로주사제에높은반응을보인것은일반적으로알려진바대로주사제가복용약에비해발기개선의정도가높다는것을반영한다. 21,22 그러나실제치료방침에도움이되는삽입가능유무에따른차이는 2명에서만나타나므로진단적가치에있어서는복용약이크게떨어지지않으며, 더나아가서최근에는일차치료방법으로주사제보다는당연히복용약이우선하므로복용약에대한반응정도를직접평가할수있다는장점을가질수있겠다. 그러나음경해면체내약물주사는초기용량에의해충분한발기가이루어지지않을경우추가로 2차주사후즉시검사가가능하지만 vardenafil 등의경구용발기부전치료제는복용후발기를유발하기까지의시간이걸리며전신적부작용때문에최대용량에효과가없는경우용량증량에제한이따르는단점이있다. 합병증이나부작용에있어서는역시주사제의경우음경동통과반상출혈이문제가되었고, 복용약의경우두통, 홍조및코막힘정도가나타났으나빈도에있어기존보고와큰차이가없었다 결론경구용발기부전치료제인 vardenafil의복용후시청각성적자극에의한음경복합초음파검사는주사제를이용한검사와비교하여혈류역동학적진단이나혈류지표의측정값에있어통계적으로의미있는차이를발견할수없었다. 그러나심리적부담이있거나증세가심한일부환자에서는복용약보다주사제가환자의혈류상태를보다정확히평가하는데에도움이되었다. 따라서사전에 PDE5 억제제에반응이없었던환자이거나, 발기부전의증세가심한경우등의환자에서는기존의주사제를이용하여시행되어야하겠으나, 주사제에두려움이있거나약물치료경험이없는환자의경우주사제이용에따른합병증을피할수있는 덜침습적인검사방법으로서의사용을고려해볼수있을것이라생각한다. REFERENCES 1. Carrier S, Brock G, Kour NW, Lue TF. Pathophysiology of erectile dysfunction. Urology 1993;42: Quam JP, King BF, James EM, Lewis RW, Brakke DM, Ilstrup DM, et al. Duplex and color Doppler sonographic evaluation of vasculogenic impotence. AJR Am J Roentgenol 1989;153: Sattar AA, Wery D, Golzarian J, Raviv G, Schulman CC, Wespes E. Correlation of nocturnal penile tumescence monitoring duplex ultrasonography and infusion cavernosometry for the diagnosis of erectile dysfunction. J Urol 1996;155: Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999;161: Meuleman EJ, Bemelmans BL, van Asten WN, Doesburg WH, Skotnicki SH, Debruyne FM. Assessment of penile blood flow by duplex ultrasonography in 44 men with normal erectile potency in different phases of erection. J Urol 1992;147: Junuzovic D. Mehmedbasic S, Smajlovic F. Color-Doppler ultrasonography in the diagnostic evaluation of erectile dysfunction. Med Arh 2003;57: Melman A. An intermediate approach to impotence evaluation. Contemp Urol 1995;7: Lee U, Lee MH, Kim SY, Ji YH, Hong JH, Ahn TY. Clinical efficacy and safety of sildenafil in the men with erectile dysfunction in Korea. Korean J Urol 2001;42: Lue TF. Erectile dysfunction. N Engl J Med 2000;342: Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93: Saenz de Tejada I, Angulo J, Cuevas P, Fernández A, Moncada I, Allona A, et al. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 2001;13: Broderick GA, Arger P. Duplex Doppler ultrasonography: noninvasive assessment of penile anatomy and function. Semin Roentgenol 1993;28: Oates CP, Pickard RS, Powell PH, Murthy LN, Whittingham TA. The use of duplex ultrasound in the assessment of arterial supply to the penis in vasculogenic impotence. J Urol 1995; 153: Mellinger BC, Fried JJ, Vaughan ED Jr. Papaverine-induced penile blood flow acceleration in impotent men measured by duplex scanning. J Urol 1990;144: Meuleman EJ, Bemelmans BL, Doesburg WH, van Asten WN, Skotnicki SH, Debruyne FM. Penile pharmacological duplex ultrasonography: a dose-effect study comparing papaverine, papaverine/phentolamine and prostaglandin E1. J Urol 1992;

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untitled 발기부전환자에서심혈관계위험인자와음경혈역동학적지표와의연관성 The Correlation between Cardiovascular Risk Factors and Penile Hemodynamic Parameters in Men with Erectile Dysfunction Woong Jin Bae, Dong Wan Sohn, Sung Dae Kim 1, Su Jin