Practical Management of Patients with Priapism

Transcription

1 eau-ebu update series 4 (2006) available at journal homepage: Practical Management of Patients with Priapism Ates Kadioglu *, Oner Sanli, Murat Celtik, Murat Cakan, Hakan Taskapu, Tolga Akman Section of Andrology, Istanbul Faculty of Medicine, Istanbul University, Turkey Article info Keywords: Priapism Alpha adrenergic agonists Surgery Abstract Objectives: Priapism is a persistent unwanted erection that is not associated with sexual desire or sexual stimulation. The aim of this present review is to discuss the practical management of priapism with the current data obtained from the contemporary literature. Methods: Based on MEDLINE database searches, all aspects of the management of priapism were examined. Results: Priapism can be classified as ischemic or non-ischemic depending on the status of penile arterial flow. Ischemic priapism is a true urological emergency requiring a prompt and accurate diagnosis and treatment. Delayed treatments have little documented benefit in terms of potency preservation. After the diagnosis of ischemic priapism with corporal blood gas analysis, aspiration of the corporeal hypoxic blood and injection of a selective alpha-adrenergic sympathomimetic agent should precede surgical shunting or early insertion of penile prosthesis. For non-ischemic priapism, blood gas analysis should be followed by color Doppler ultrasonography to confirm the diagnosis. Intervention is not urgent and expectant management or embolisation of the fistula may be performed. In patients with recurrent priapism, treatment for ischemic episodes as well as specific treatment for underlying etiological factor should be initiated concurrently. Conclusion: Modern management of priapism depends on the difference between ischemic and non-ischemic episodes. To protect the erectile function of the patients with priapism, urologists should know how to manage this urgent condition. # 2006 European Association of Urology and European Board of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Androloji Bilim Dali, Cerrahi monoblok zemin kat, Capa-Istanbul, Turkey. Tel ; Fax: address: itfabd@istanbul.edu.tr (A. Kadioglu). Priapism was known since the ancient Greeks, derived from the god Priapos, who was the symbol of masculinity and fertility. According to the legend in ancient Asia Minor (today s Turkey), Hera, with her jealousy, caused a child born with an erect gigantic phallus nearly as tall as him and curved /$ see front matter # 2006 European Association of Urology and European Board of Urology. Published by Elsevier B.V. All rights reserved. upward from Aphrodite, because of her husband s (Zeus) illegitimate love affair with her [1]. The status of the god Priapos in mythology has transferred to medical dictionaries as the word priapism. Priapism is a persistent unwanted erection that is not associated with sexual desire or sexual doi: /j.eeus

2 eau-ebu update series 4 (2006) stimulation [2]. To date, three studies have addressed the overall incidence rate of priapism. Kumala et al. reported the incidence of priapism varied between 0.3 and 1.1 per person years during 1975 to 1990 in the Finnish population [3]. A rise was encountered in the last 3 years of the study, which was attributed to the introduction of intracavernosal injection therapy. In the Netherlands, Eland et al. calculated the overall incidence rate as 1.5 per person years in the general practice population. The age specific incidence rate was 2.9 per person years for all men 40 years old or older [4]. And lastly, Earle et al. reported an overall incidence of 0.84 per males per year in Western Australia [5]. Three types of priapism are usually noted; 1-Ischemic priapism, 2-Non-ischemic priapism, 3-Recurrent (stuttering) priapism. Among these, ischemic priapism is a urological emergency. Since it has the potential to cause erectile dysfunction through ischemic injury to cavernous tissue, necessitates early evaluation and treatment. For this reason, it is vital to determine the type of priapism. Ischemic (veno-occlusive, low flow) priapism is the most common form. The duration of erection time for the definition of ischemic priapism is still controversial. However, evidence from experimental and clinical studies revealed that hypoxemia and acidosis after 4 hours leads to cavernosal fibrosis and interventions before this time may prevent cavernosal fibrosis [6 8]. Priapism is characterized by a rigid and painful erection. An analysis of cavernous blood gases usually reveals hypoxic, hypercarbic and acidotic values. Ultrastructural changes of cavernous smooth muscle in ischemic priapism can be observed after 12 hours, focal necrosis of cavernous smooth muscle become apparent after 24 hours and finally wide necrosis and transformation into fibroblast-like cells take place after 48 hours [9]. If left untreated or treated late (over 24 hours), it may lead to cavernous smooth muscle necrosis, irreversible corporal fibrosis and impotence [2]. Non-ischemic (arterial, high flow) priapism is the less common form of priapism and is caused by unregulated flow of cavernous artery. This is often (82.5% in adults and 96.1% in children) due to a rupture of the cavernosal artery or one of its branches within the corpus cavernosum [10]. Also, cases with high-flow priapism due to needle laceration of the cavernosal artery during intracavernosal treatment were also reported [11]. After trauma, unregulated arterial flow by-passes the protective, high resistant helicine arteries and enters the lacunar spaces directly. The cavernosal sinusoids distend but the compression of the subtunical venules is not complete which prevents complete tumescence [12]. For this reason, the erection is usually painless and not completely rigid. Cavernous blood gas analysis reveals normal arterial oxygen pressure; there is no hypoxia or acidosis. Aspirated blood is bright red in color and urgent medical treatment is not required. The last form, recurrent (stuttering) priapism is rather an uncommon type, where detumescence periods are observed between unwanted painful erections. Although it is often idiopathic and more prone to be ischemic, especially in children it may be associated with sickle cell disease [13]. The objective of management in these patients is to develop preventive treatment protocols to avoid future priapism episodes [14]. The proposed guidelines for the diagnosis and management of the patients with priapism is given in the Table Initial management of patients with priapism In the evaluation of patients that do not have a diagnosis or no intervention performed, the first and most important purpose is to determine the type of priapism [14]. Components of the evaluation of patients with priapism are as follows: 1.1. History In history, duration of priapism, presence of pain (ischemic priapism is typically painful and pain usually starts at 1 hour of the episode), recent perineal (especially straddle type) or penile trauma should be investigated. Also, patients with posttraumatic priapism typically have delayed onset of a few days, which is probably due to the segmental necrosis of the traumatized cavernosal artery over time or NPT (nocturnal penile tumescence) causing ejection of the cloth plug on the rupture site, leading to unregulated blood flow [15]. In addition, nonpenetrating injury to the flaccid penis usually follows blunt perineal traumas producing extratunical or cavernosal haematomas [16]. Cavernosal hematomas should be differentiated from high-flow priapism. Currently, excessive dosage of intracavernous agents (papaverin, prostaglandin E 1 (PGE1), phentolamine and related vasoactive drugs) is the most common cause of priapism. The incidence of prolonged erection ranges from 1% to 21% depending on the type of the agent and the dose used [17 19]. The rate of prolonged erections for papaverine, bimix, (papaverine/phentolamine), PgE 1

3 152 eau-ebu update series 4 (2006) Table 1 Guidelines for the management of patients with priapism (adopted from refs. [2,6]) alone and trimix (papaverine/phentolamine/pge 1 ) are 7.1%, 7.8%, 0.36% and 4.75%, respectively [20 22]. Predictive factors for prolonged erection include as younger men with better baseline erectile function, patients with overt neurological disease and patients without cardiovascular disease [23]. On the other hand, many drugs used orally such as antihypertensives (hydralazine, prazosin, guanethidine), anticoagulants (heparin), antidepressants (trazodone), antipsychotics (chlorpromazine, clozapine) may be associated with priapism [2]. For this reason, drug history should be carefully investigated. Hematological and thrombotic causes such as sickle cell anemia and other forms of hemoglobinopathies such as b thalasemia, different forms of leukemia and total parenteral nutrition may lead to priapism. Identification of these diseases has a special importance since they may be treated with medically. In addition, many types of malignancies may result in priapism via obstruction of the venous outflow by the tumor. Common cancers that can result in priapism are bladder (30%), prostate (30%), rectosigmoid (16%) and renal (11%) cancers [24]. Neurological diseases such as spinal cord lesions (especially at high levels) or spinal stenosis may also cause priapism [25,26]. Among the large scale epidemiological studies, Earle et al. reported the specific causes of priapism in Western Australia over a 16 year period ( ) [5]. During this period, 82 episodes of priapism in 63 patients were recorded. In 48 (76.1%) patients the reason for priapism was ICI (intracavernosal injection) therapy (mostly papaverine) and the remaining patients had various causes including, drugs (10, 15.8%), hyperviscosity syndromes (1), venous thrombosis (1), cord compression, scuba diving (1) and idiopathic (2). In addition, the authors reported a diminished occurrence of priapism after oral pharmacotherapy became available in Physical examination Evaluation of genital organs and perineum may reveal signs of a recent trauma which may suggest non-ischemic priapism. In patients with priapism, the corpora cavernosa are rigid, while the corpus spongiosum and glans penis are not. Assessment of the corpus cavernosum, which is fully rigid in ischemic priapism and semi-rigid in non-ischemic priapism, may help to determine the type of priapism. This may be explained by the roles of nnos (neuronal nitric oxide synthase) and enos (endothelial nitric oxide synthase) respectively, which are responsible for mediating the initiation (rapid tumescence) and sustained phases of penile erection respectively [27]. Since there is no neurally derived NO in the corpus cavernosum in nonischemic priapism, penile erection mainly depends on NO derived from enos caused by shear force on the endothelium of penile vasculature leading to

4 eau-ebu update series 4 (2006) inadequate tumescence. For this reason, corpus cavernosum is semi-rigid in non-ischemic priapism. Tricorporal priapism has been described due to sickle cell disease and primary and metastatic tumors of the penis [28,29]. In children, perineal compression resulting in detumescence may be indicative of non-ischemic priapism [10]. This sign is often unsuccessful in adults due to the structure of the perineum. In addition, abdominal and rectal examination should be done to rule out the presence of a malignancy that may cause ischemic priapism Laboratory/radiological assessment Blood analyses Complete blood count with special attention to thrombocyte and white blood cell counts, and white blood cell differential should be performed. Any abnormal values in the hematologic examinations should be referred to a hematologist to plan additional examinations (e.g. reticulocyte count or hemoglobin electrophoresis for sickle cell disease) Blood gas testing Corporal aspiration and blood gas analysis should be done in all patients, because it is the mainstay of the diagnosis. Blood gas values in ischemic priapism are hypoxic and acidotic (PO 2 <30 mmhg, PCO 2 >60 mmhg, ph < 7.25) and the color of aspirated blood is dark red because of hypoxia. Recently, assessment of glucose level in the aspirated corporal blood was proposed since hypoxia combined with glucopenia is found to be associated with irreversible corpus cavernosum smooth muscle cell dysfunction [30]. It should be mentioned that one should not wait for the results of the diagnostic tests for the treatment of priapism. Diagnosis may be performed by sending the aspirated blood derived for corporal drainage for blood gas analyses. Also, obtaining blood gas values may be important because of the medicolegal issues. Blood gas values in non-ischemic priapism are similar to arterial blood levels and the color of aspirated blood is bright red. At this level of the management, if the patient is diagnosed with ischemic priapism, there may not be a need for further diagnostic methods Color duplex ultrasonography (CDU) CDU can be used as an adjunct to blood gas analysis in the evaluation of priapism. However, it is crucial for non-ischemic priapism to demonstrate the abnormalities such as cavernous artery fistula or preudoaneurism, especially in patients with perineal injury. Cavernous blood flow is usually normal or somewhat increased in non-ischemic priapism. CDU should be performed in the lithotomy or frogleg position, scanning the perineum first and then along the entire penile shaft. Color duplex ultrasonography will reveal absent or low levels of flow through cavernous artery in ischemic priapism. Recently, disappearance of blood flow with Duplex ultrasonography in the cavernous artery an hour after intracavernosal injection was proposed by Shamloul et al. as an accurate predictor of persistent erection requiring intervention [21] Penile arteriography In patients with non-ischemic priapism, the site of cavernous artery fistula may be demonstrated and meanwhile embolized selectively with penile arteriography. Also, superselective embolisation of the minor arterial branches may be performed through a bilateral approach when the erection did not cease after unilateral embolisation [31]. 2. Treatment for non-ischemic priapism A stepwise approach to priapism has been recommended starting from the least invasive (corporal aspiration of blood) to more invasive modalities (shunting procedures or prosthesis implantation) [2] Non-surgical treatment The goal of the management of all patients with priapism is to achieve detumescence for relieving pain and preserve erectile function. Etiologic factors that are likely to cause ischemic priapism should be reviewed according to data obtained before the intervention and treatment should be directed to the underlying etiologic factors. In sickle cell anemia, hydration, alkalization, transfusion and oxygen are the available treatment alternatives, and in hematologic malignancies chemotherapy and radiotherapy may help to reverse the priapism [2,6,14]. However, systemic treatment specific to the etiologic cause should not be perceived as the treatment of priapism. Intracavernosal interventions and systemic treatments should be started concurrently [14]. Before any specific treatment, in the early stages of priapism, ice packs or cold showers may be helpful for relieving priapism, probably via inducing reflex vasoconstriction [2]. Thus, the act of micturation or mounting stairs may be helpful. In addition, adequate analgesia should be provided and opiates may be needed for this purpose.

5 154 eau-ebu update series 4 (2006) Cavernosal treatment Aspiration of the hypoxic, acidotic and glucopenic blood is often the first intervention for resolution of the ischemic priapism. In ischemic priapism, 20 ml of blood is aspirated with a 19 G butterfly needle and further aspirations should be continued until bright red blood is observed in the syringe. Supplying fresh blood the into corpus cavernosum has a significant importance because recent evidence suggests that corpus cavernosum smooth muscle tone fails to recover in conditions of hypoxia and glucopenia [30]. Kim et al. demonstrated that cavernosal smooth muscle contractions were significantly attenuated when oxygen tension decreased to 10 mm Hg which can be seen at the late stage of a priapism episode [32]. In addition, under anoxic conditions, a- adrenergic agonists produced poorly sustained phasic contractile responses, explaining the lack of responsiveness of corpus cavernosum to a- adrenergic drugs in patients with a long duration of priapism [33,34]. It is recommended to wait 5 min for resolution, if detumescence does not occur, intracavernosal injection of a- adrenergic agent may be used. On the other hand, corpora may be irrigated with saline for the wash-out of the hypoxic blood. For this purpose, fluids at body temperature should be used since irrigation of solutions of either room or fridge temperature suppresses nerve-mediated contractions, independent of associated corporal acidosis [35]. The efficacy of aspiration with or without irrigation is approximately 30% [14]. Epinephrine, norepinephrine, phenylephrine, ephedrine, and metaraminol are the alpha adrenergic agents that are used for intracavernosal injections. It was reported that, for all patients with ischemic priapism resolution occurred in 81% treated with epinephrine, 70% with metaraminol, 43% with norepinephrine and 65% with phenylephrine [14]. Despite its lower efficacy compared with epinephrine, phenylephrine should be the preferred agent for intracavernosal injections because of its minimal cardiovascular risk. The human corpus cavernosum predominantly expresses a 1a (44%), a 1b (22%) and a 2a (34%) adreneceptors and phenylyeprine is a selective a-1 adrenergic agonist with minimal b-adrenergic effects [36]. Before injection, phenylephrine should be diluted with saline to a concentration of 100 to 500 mg/ml [37]. The phenylephrine solution is prepared by adding 10 mg/ml of phenylephrine to 19 ml of normal saline. It is suggested to perform 1 ml injection of the above-mentioned solution in every 3 to 5 minutes for approximately 1 hour, before the decision that the treatment has been unsuccessful. A rapid and bolus injection of intracavernous alpha adrenergic agents may produce headache, acute hypertension, reflex bradycardia, tachycardia, sweating and arrhythmia. Patients with cardiovascular risk should be observed using blood pressure and ECG monitoring. Methylene blue, an antagonist of the guanylate cyclase of the corporal smooth muscle, may be another option for the treatment of ischemic priapism [38]. In a recent study, Hübler et al. injected methylene blue after aspiration of blood to five patients with priapism for 6 to 10 hours due to intracavernosal therapy [39]. The authors reported sufficient detumescence in all cases. In another study, Martinez et al. treated 22 drug-induced, 2 idiopathic high flow and 1 leukemia induced priapism with methylene blue [40]. The patients received intracavernosal methylene blue after evacuation of the hypoxic blood for 5 minutes and intracavernosal metyhlene blue was also aspirated. All patients except 3 who needed intracavernosal phenyelphrine administration or pudendal embolisation, were cured with the treatment. In another study, deholl et al. successfully treated 6 (67%) out of 9 patients using methylene blue alone [41]. There was a 100% response in patients following intracavernosal PgE1 therapy. Moreover, in this study, a-agonists offered no benefit in cases where methylene blue was unsuccessful. Because of the limited data, routine use of methylene blue for priapism is controversial. However, its minimal side effects make it desirable for the routine use. Transient penile burning and a blue discoloration that can persist for 3 days are the reported side effects of this treatment [42]. If detumescence is not achieved by repeated intracavernosal injections of alpha adrenergic agents within 1 hour, surgical treatment options should be considered Penile anesthesia Penile anesthetic block induced by lidocaine is considered to work by blunting sensory input conveyed in the dorsal nerve of the penis of reflexive erectile pathways. The dorsal penile nerve block was offered as a treatment for intraoperative erection [43]. However, penile block should be considered as a tool for pain management rather than a definitive therapy for ischemic priapism Oral systemic treatment Terbutaline, a b 2 -adrenergic agonist has been used to treat priapism. In one of the three randomized studies, Lowe and Jarow randomized a total of 75 patients to receive terbutaline, pseudoephedrine and placebo. The authors concluded that, terbutaline

6 eau-ebu update series 4 (2006) was significantly better than placebo (36%, 28% vs 12%) [44]. However, Govier et al. randomized 24 patients and did not find any benefit of terbutaline over placebo [45]. Recently, Priyadarshi randomized 68 patients who had prolonged erections due to ICI therapy and observed that detumescence was achieved in 42% and 15% of the cases with oral terbutaline and placebo, respectively [46]. In this study, the patients received a maximum of 15 mg terbutaline at 15 minutes intervals. Oral terbutaline probably has little effect on corpus cavernosum because it reaches very low levels in the cavernosal blood and the density of alpha adrenergic receptors in corporal tissue was found to be almost ten times greater than the density of beta adrenergic receptors [47]. However, its effect may be due to stimulation of the sympathetic nervous system via its minor a and b 1 agonistic activities. Consequently, there is a limited number of placebo controlled trials providing insufficient data for the use of oral terbutaline and all were performed in patients with prolonged erections due to ICI therapy. For this reason, according to the in 2nd Consultation on Sexual Dysfunction, oral terbutaline is longer recognized as a first aid measure, because intracavernosal therapy has now largely been replaced by oral PDE5 inhibitors [2]. Pseudoephedrine and etilephrine are two other oral drugs that are thought to be sometimes successful. However, similar to terbutaline, data regarding these drugs is not sufficient for further suggestions. In addition, intravenous injection of procyclidine and clonidine that block para-symphathetic pathway were used before the precavernosal therapy era and were found to be sometimes successful. According to the authors of this review, it is useless to insist on oral or intravenous drugs and consume a critical time for preventing the necrosis of the cavernosal smooth muscle cells because the above-mentioned drugs will probably not pass through the cavernosal blood during priapic episode. On the other hand, it is well established that, after aspiration and intracavernosal injection of alpha-adrenergic agonists, the vast majority of the patients will achieve detumescence Surgical treatment Surgical treatment of ischemic priapism provides detumescence by creating a new path for drainage of the old blood pooled in the corpus cavernosum. Distal shunts (Winter, Ebbehoj, Al-Ghorab) should be preferred initially as the surgical procedure. If flaccidity cannot be obtained by these methods, proximal shunt procedures (Quackels, Grayhack) may be applied Distal shunts Among the distal shunts, corporaglanular shunt (Winter) is the easiest procedure with the lowest complication rates and may be performed under local anesthesia. In this procedure, for creating a fistula between glans penis and corpus cavernosum, a tru-cut biopsy needle or a scalpel (Ebbehoj) is inserted into corpus cavernosum through the glans penis [48]. After detumescence is obtained through drainage of the hypoxic blood in corpora, the glans penis is sutured. Another variant of corporaglanular shunt is described by Lue et al. In this method multiple incisions are made between the glans and the distal part of the corpus cavernosum by a number 11 blade. Intracavernous pressure is monitorized by a 21 G needle to maintain detumescence. ICP (intracavernousal pressure) monitoring is continued until the end of the procedure and it should be <40 cm H 2 O (29.44 mm Hg) [37]. In the Al-Ghorab procedure, the tunica albuginea at the top of the both corpora is excised through a 2 cm glanular incision distal to the coronal sulcus to create a larger shunt, which makes this procedure more effective than the other two procedures. However, the other two procedures should be preferred initially because of the invasiveness of the latter. It is reported that success rates for Winter, Ebbehoj and Al-Ghorab procedures were 66%, 73% and 74%, respectively [14]. In addition, another shunt type between the corpus cavernosum and the dorsal vein (Barry) was described. However, it has not been successful probably due to the small size of dorsal vein Proximal shunts In patients with failed distal shunts, more proximal shunting procedures should be considered. The two major effective proximal shunting procedures are cavernosa-spongiosal shunt (Quackels) and cavernosa-sapheneous shunt (Grayhack). In Quackels shunt, an opening (or excision of an ellipse) is created in the spongiosal and cavernosal bodies and sutured together. If unilateral shunting is not enough for decreasing the intracavernosal pressure, a shunt on the opposite side is recommended. A more proximal shunt is Grayhack, which involves mobilization of 8 10 cm of the sapheneous vein distal to the fossa ovalis and anatomosed with the corpus cavernosum (after excision of an ellipse) at the base of the penis. The reported success rate for Quackels shunt was 77%, while it was 76% for Grayhack shunt [14].

7 156 eau-ebu update series 4 (2006) Despite the shunting procedure, priapism is followed by ED in approximately half of the patients and in more than half of the cases a second procedure is needed [2]. It should be mentioned that, the failure of the shunt to achieve detumescence is not due to the shunt closure but due to the inability of the smooth muscle to contract due to the smooth muscle necrosis. Also shunting procedures may result in serious complications such as urethral fistula and purulent cavernositis [49]. For this reason, currently, biopsy of the cavernous muscle and implantation of a penile prosthesis is suggested as a part of the initial management [2] Penile prosthesis Ninety percent of patients with priapism over 24 hours develop complete erectile dysfunction [2]. It has been suggested that treatments initiated beyond 72 hours may have benefits in relieving the unwanted erection and associated pain, but have little documented benefit in terms of potency preservation [6]. On the other hand, failure to treat priapism causes significant cavernosal fibrosis that makes the subsequent insertion of penile prosthesis difficult with subsequent high complication rates. For this reason, management of ischemic priapism with immediate insertion of penile prosthesis has recently been proposed [50]. In the study by Kumar et al., penile prostheses were inserted to 27 patients with ischemic priapism with a mean duration of 8 days [51]. A Mentor malleable prosthesis was inserted initially in 25 patients, 9 of which were later revised to 3 piece inflatable prosthesis. After a mean follow-up of 17 months, all patients were satisfied and reported normal erectile function with only 2 complications (infection and curvature). Actually, this concept was previously used in patients with recurrent priapism due to sickle cell disease. Monga et al. inserted a malleable penile prosthesis to 6 patients suffering from recurrent priapism (mean 5.4 times) [52]. The authors reported a satisfactory outcome with this treatment. Only one patient in this report needed prosthesis revision surgery. 3. Treatment for non-ischemic priapism Spontaneous resolution has been reported to be the outcome of untreated non-ischemic priapism in up to 62% of the published cases [2]. Since it is not a medical emergency, these patients may be followed up conservatively and wait for the closure of the rupture site spontaneously [53,54]. To achieve detumescence, at early stages, ice or pressure packing that may be expected to cause vasospasm and thrombosis of the ruptured artery may be helpful [55]. However, this may happen in days to weeks and may cause inconvenience and embarrassment [56]. If this option is chosen in consensus with the patient, regular follow-up examinations are suggested to assess erectile function, as well as serial color Doppler ultrasound studies to measure the stability of the fistula. On the other hand, despite a case complicated with ED in the long term, the impact of high-flow priapism in the long term is obscure [57]. However, it has been suggested that high oxygen levels associated with chronic erection for many years may be deleterious to the cavernosal smooth muscle because in normal physiology cyclic episodes of corporal blood oxygen levels are required for normal regulation of connective tissue matrix [58]. In the management of non-ischemic priapism, corporal aspiration with or without injection of sympathomimetic agents has no role because it is not the failure of the detumescence mechanism, it is the unregulated arterial inflow to the corpus cavernosum. Despite a few encouraging case reports, according the authors of this review, any drug that acts locally on the smooth musculature of corpus cavernosum (such as methylene blue) may not stay long enough in the sinusoidal spaces due to rapid washout of the corpus cavernosum. For nearly half of the cases, definitive treatment of the disease is selective angiographic embolisation of the arterio-sinusoidal fistula. For this purpose, autologous blood cloth and absorbable materials (gelfoam) or non-absorbable materials (coils, ethanol, polyvinyl alcohol particles and acrylic glue) have been used. Despite the risk of recurrence, embolisation with non-absorbable material provides the opportunity for transient occlusion of the cavernous artery for 1 or 2 days which protects the erectile capacity of the patients. Resolution and ED rates of non-ischemic priapism with absorbable and non-absorbable materials are 78%, 39% and 74% and 5% respectively [14]. Ifthe angiographic attempt fails, a repeat embolisation may be performed or lastly open surgical ligation with the aid of intraoperative color Doppler ultrasonography of the ruptured artery may be needed. Penile exploration and direct ligation of the sinusoidal fistulas are efficacious in up to 63% of caseswithanassociatededrateof50%[14]. After achieving detumescence, elastic bandage for 7 10 days may be needed for preventing nocturnal erections.

8 eau-ebu update series 4 (2006) Recurrent (stuttering) priapism Recurrent priapism is a rare condition which is often idiopathic and its pathophysiology is not yet understood. Recurrent priapism in children is usually associated with hematological disorders, but it is often idiopathic in adults [59]. The term of stuttering attacks was first used by Emond et al., who reported multiple, self-limiting, recurrent priapism episodes in men with sickle cell disease [60]. Priapism frequently starts in sleep and detumescence does not take place immediately after awakening. Also, it may be associated with prolonged durations of sexual activity. Management of recurrent priapism is rather difficult, because both ischemic and non-ischemic priapism can develop in the same patient [2,14]. Furthermore, these priapic episodes of patients with sickle cell disease do not any have relationship with the other veno-occlusive crisis encountered in these patient and may not always predispose to ED [61] Oral systemic treatment for recurrent priapism The treatment goals of the patients with recurrent priapism are to perform specific treatments for the ischemic priapism episodes and to establish some measures to prevent new priapism episodes. For the preventive treatment of priapism, antipsychotic drugs, oral ethylephrine, diethylstilbestrol, antiandrogen therapy, baclofen, and digoxin [62 69] were used. However, limited data is available for the above-mentioned systemic drugs and the authors of this review find terbutaline, digoxin, antiandrogens and gabapentine therapy more desirable. Recently, Matlaga et al. used oral digoxin therapy in 13 patients with recurrent priapism. The authors reported that 69% (9) of patients experienced no further priapic episodes [70]. On the other hand, Filho et al. used finasteride therapy in 23 patients and controlled the new episodes of priapism with a maximum dose of 3mg/d[71]. However, it should be mentioned that hormonal therapy is associated with adverse effects, including reduced libido and ED. Furthermore, hormonal agents are contraindicated for the individuals who have not achieved sexual maturation and growth and those trying to conceive. Finally, gabapentine was used successfully in 3 patients with recurrent priapism [72]. The exact mechanism of action is unknown, but it is hypothesized that its action is mainly due the inhibiton of calcium efflux from smooth muscle cells Intracavernosal treatment for recurrent priapism Intracavernosal injection of etilefrine or phenylephrine can be used as alternative in the treatment of stuttering priapism when the use of systemic treatment is rejected by the patient or impossible or unsuccessful. It has been demonstrated that intracavernosal injection with a-agonists are effective for relieving priapic episodes for up to 10 years [73 75]. However, this method of management should not be preferred over systemic therapies because priapism in such cases is being treated rather than prevented [14]. Recently, Ralph et al. introduced a drug delivery implant for the treatment of recurrent priapism [76]. The implant is implanted through a penoscrotal incision and the cannula of the implant is inserted to the lateral aspect of corpus cavernosum for delivering 0.8 mg phenylephrine in each squeeze of the pump. After a 4 month follow-up, the patient experienced no further priapic episeodes The role of PDE5 enzyme for recurrent priapism A role for dysregulated PDE5 in the pathogenesis of recurrent priapism has recently been demonstrated by Champion et al. [77]. The rationale of the hypothesis depends on the observation that genetically modified mice lacking enos or combined nnos and enos isoforms display priapic activity and prolonged erectile responses to electrical cavernous nerve stimulation, compared with genetically nnos lacking mice and wild-type controls. Moreover, double mutant mice were highly responsive to stimulation even at low voltages and a more substantial response was obtained with direct injection of an NO donor or sildenafil citrate to the corpus cavernosum. These results suggest that enos exerts a constant stimulus for the production of cgmp and depleted endothelial NO in the penis yielding a state of PDE5 downregulation due to longstanding NO understimulation. The priapic behaviour in enos mutant mice was explained by the physiologically supersensitization to cgmp after intense erectile stimulation. The same group carried the outcome of this novel finding into a clinical practice with a clinical study comprising 4 patients with recurrent (3 sickle cell, 1 idiopathic) priapism [78]. The authors reported significant reduction in priapism recurrences with 25 or 50 mg sildenafil daily or 5 mg tadalafil for three days a week with a follow-up of 3 to 11 months. They explained the favorable results by reseting the erection regulatory function of erection of PDE5 to normative levels protecting for further episodes. On the other hand, Rajfer et al. tested the same phenomenon in 2

9 158 eau-ebu update series 4 (2006) patients with refractory priapism. After failed treatment for priapism including shunting, the patients were prescribed a daily regimen comprising the phosphodiesterase inhibitors pentoxifylline and sildenafil, and the NO donor L-arginine. [79] After 1 year the authors reported supple corpora without evidence of fibrosis. Consequently, recent evidence suggests that PDE5A dysregulation in the corpora may be a mechanism of ischemic priapism. However, before carrying this novel information into clinical practice, the results of further experimental models and clinical studies with a sufficient number of patients should be warranted. 5. Conclusions Modern management of priapism depends on the difference between ischemic and non-ischemic episodes because 90% percent of patients with ischemic priapism over 24 hours develop complete erectile dysfunction due to the penile fibrosis. If ischemic priapism is suspected clinically, aspiration of corporeal blood, injection of a selective alpha adrenergic sympathicomimetic and, if necessary, surgical shunting or early insertion of penile prosthesis should be performed in sequential manner. For non-ischemic priapism, color Doppler ultrasonography is the confirming diagnostic tool and expectant management or embolisation of the fistula should be viewed as the standard care. In patients with underlying etiological causes of priapism, specific treatment for ischemic episodes with preventive measures of systemic disease should be initiated concurrently. Data from animal models and early clinical studies suggest that PDE5 inhibitors may play an important role in the treatment and prevention of priapism. References [1] Acar O. Anatolia: The land of the father god. In: Kendirci M, KadıoğluA,Miroğlu C, editors. The history of male female sexuality and fertility in Asia minor (today s Turkey). Istanbul: Turkish Society of Andrology; p [2] Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L, et al. Priapism, Peyronie s disease, penile reconstructive surgery. In: Lue TF, Basson R, Rosen R, Gıiliano F, Khoury S, Montorsi F, editors. Sexual Medicine, Sexual dysfunctions in men and women. Paris: Health publications; p [3] Kulmala RV, Lehtonen TA, Tammela TL. Priapism, its incidence and seasonal distrubution in Finland. Scand J Urol Nephrol 1995;29:93 6. [4] Eland IA, van der Lei J, Stricker BH, Sturkenboom MJ. Incidence of priapism in the general population. Urology 2001;57: [5] Earle CM, Stuckey BG, Ching HL, Wisniewski ZS. The incidence and management of priapism in Western Australia: a 16 year audit. Int J Impot Res 2003;15: [6] Berger R, Billups K, Brock G, Broderick GA, Dhabuwala CB, Goldstein I, et al. AFUD Thought Leader Panel on Evaluation and Treatment of Priapism. Report of the American Foundation for Urologic Disease (AFUD) Thought Leader Panel for evaluation and treatment of priapism. Int J Impot Res 2001;13(Suppl 5):S [7] Ul-Hassan M, et al. Expression of TGF-beta 1 m-rna and ultrastructural alterations in pharmacologically induced prolonged penile erection in a canine model. J Urol 1998; 160: [8] Sanli O, Armagan A, Kandirali E, Ozerman B, Ahmedov I, Solakoglu S, et al. TGF-b1 neutralizing antibodies decrease the fibrotic effects of ischemic priapism. Int J Impot Res 2004;16: [9] Spycher MA, Hauri D. The ultrastructure of the erectile tissue in priapism. J Urol 1986;135: [10] Hatzichristou D, Salpiggidis G, Hatzimouratidis K, Apostolidis A, Tzortzis V, Bekos A, et al. Management strategy for arterial priapism: therapeutic dilemmas. J Urol 2002;168: [11] McMahon CG. High flow priapism due to an arterial-lacunar fistula complicating initial veno-occlusive priapism. Int J Impot Res 2002;14: [12] Witt MA, Goldstein I, Saenz de Tejada I, Greenfield A, Krane R. Traumatic laceration of intracavernosal arteries: the pathophysiology of nonischemic, high flow, arterial priapism. J Urol 1990;143: [13] Rogers ZR. Priapism in sickle cell disease. Hematol Oncol Clin North Am 2005;19: [14] Montague DK, Jarow J, Broderick GA, et al. American Urological Association Guideline on the management of priapism. J Urol 2003;170: [15] Ricciardi R, Bhatt GM, Cynamon J, Bakal CW, Melman A. Delayed high flow priapism: pathophysiology and management. J Urol 1993;149: [16] Bertolotto M, Calderen L, Cova MA. Imaging of penile traumas therapeutic implications. Eur Radiol 2005;15: [17] Lomas GM, Jarow JP. Risk factors for papaverine induced priapism. J Urol 1992;147: [18] de Meyer JM, Oosterlinck W. Influence of the method of intracavernous injection on penile rigidity: a possi-ble pharmacocinetic explanation. Urology 1997;49: [19] Kulmala R, Lehtonen T, Nieminen P, Tammala T. Aetiology of priapism in 207 patients. Eur Urol 1995;28: [20] Porst H. Current perpectives on intracavernosal pharmacotherapy for erectile dysfunction. Int J Impot Res 2000; 12: [21] Shamloul R, Ghanem HM, Salem A, Kamel II, Mousa AA. The value of penile duplex in the prediction of intracavernous drug-induced priapism. Int J Impot Res 2004; 16:78 9. [22] Mulhall JP, Jahoda AE, Cairney M, et al. The causes of patient dropout from penile self-injection therapy for impotence. J Urol 1999;162: [23] Lomas GM, Jarow JP. Risk fators for papaverine-induced priapism. J Urol 1992;147:

10 eau-ebu update series 4 (2006) [24] Powell BL, Craig JB, Muss HB. Secondary malignancies of the penis and epididiymis: a case report and the review of the literature. J Clin Oncol 1985;3: [25] Gordon SA, Stage KH, Tansey KE, Lotan Y. Conservative management of priapism in acute spinal cord injury. Urology 2005;65: [26] Baba H, Maezawa Y, Furusawa N, et al. Lumbar spinal stenosis causing intermittant priapism. Paraplegia 1995;33: [27] Hurt KJ, Musicki B, Palese MA, et al. Akt-dependent phosphorialtion of endothelial nitirc-oxide synthase mediates penile erection. PNAS 2002;99: [28] Sharpsteen Jr JR, Powars D, Johnson C, et al. Multisystem damage associated with tricorporal priapism in sickle cell disease. Am J Med 1993;94: [29] Wen CC, Munarriz R, Goldstein I. Three-chamber priapism in a patient with primary epithelioid hemangioedothelioma of penis. Urology 2004;64: [30] Muneer A, Cellek S, Dogan A, Kell PD, Ralph DJ, Minhas S. Investigation of cavernosal smooth muscle dysfunction in low flow priapism using an in vitro model. Int J Impot Res 2005;17:10 8. [31] Callewaert P, Stockx L, Bogaert G, Baert L. Post-traumatic high-flow priapism in a 6-year old boy: management by percutaneous placement of bilateral vascular coils. Urology 1998;52: [32] Kim NN, Kim JJ, Hypolite J, et al. Altered contractility of rabbit penile corpus cavernosum smooth muscle hypoxia. J Urol 1996;155: [33] Saenz de Tejada I, Kim NN, Daley JT, Royai R, Hypolite J, et al. Acidosis impairs rabbit trabecular smooth muscle contractility. J Urol 1997;157: [34] Broderick GA, Gordon D, Hypolite J, Levin RM. Anoxia and corporal smooth muscle dysfunction: a model for ischemic priapism. J Urol 1994;151: [35] Li CY, Kell DP, Ralph DJ, Minhas S, Fry CH. The effect of temparature on cavernosal smooth muscle contractile function. P , ESSM [36] Goepel M, Krege S, Price DT, et al. Characterisation of a- adreneceptor subtypes in the corpus cavernosum of patients undergoing sex change surgery. J Urol 1999; 162: [37] Bochinski DJ, Deng DY, Lue TF. The treatment of priapism when and how? Int J Impot Res 2003;S [38] Steers WD, Selby Jr JB. Use of methylene blue and selective embolization of the pudendal artery for high flow priapism refractory to medical and surgical treatments. J Urol 1991;146: [39] Hubler J, Szanto A, Konyves K. Methylene blue as a means of treatment for priapism caused by intracavernous injection to combat erectile dysfunction. Int Urol Nephrol 2003; 35: [40] Martinez Portillo TJ, Fernandez Arancibia MI, Bach S, et al. Methylene blue: an effective therapeutic alternative for priapism induced by intracavernous injection of vasoactive agents. Arch Esp Urol 2002;55: [41] deholl JD, Shin PA, Angle JF, Steers WD. Alternative approaches to the management of priapism. Int J Impot Res 1998;10:11 4. [42] Keoghane SR, Sullivan ME, Miller MA. The aetilogy, pathogenesis and management of priapism. BJU Int 2002;90: [43] Seftel AD, Resnick MI, Boswell MV. Dorsal nerve block for management of intraoperative penile erection. J Urol 1994;151: [44] Lowe FC, Jarow JP. Placebo-controlled study of oral terbutaline and pseudoephedrine in management of prostoglandin E1 induced prolonged erections. Urology 1993;42:51 3. [45] Govier FE, Jonsson E, Kramer-Levien D. Oral terbutaline for the treatment of priapism. J Urol 1994;151: [46] Priyadarshi S. Oral terbutaline in the management of pharmacologically induced prolonged erection. Int J Impot Res 2004;16: [47] Levin RM, Wein AJ. Adrenergic alpha receptors out-number beta receptors in human corpus cavernosum. Invest Urol 1980;18: [48] Winter CC, McDowell G. Experience with 105 patients with priapism: update review of all aspects. J Urol 1988; 140: [49] Ochoa Undangarain O, Hermida Perez JA. Priapism. Our experience. Arch Esp Urol 1998;51: [50] Rees RW, Kalsi J, Minhas S, Peters J, Kell P, Ralph DJ. The management of low-flow priapism with the immediate insertion of a penile prosthesis. BJU Int 2002;90: [51] Kumar P, Minhas S, Brown C, Muneer A, et al. Ischemic priapism: acute implant insertion and long-term followup. AUA annual meeting 2005 (abst. no: 1271). [52] Monga M, Broderick GA, Hellstrom WA. Priapism in sickle cell disease: the case for early implantation of the penile prosthesis. Eur Urol 1996;30:54 9. [53] Ilkay AK, Levine LA. Conservative management of highflow priapism. Urology 1995;46: [54] Moscovici J, Barret E, Galinier P, et al. Post-traumatic arterial priapism in the child. A study of five cases. Eur J Pediatr Surg 2000;10:72 6. [55] Ficarra V, Beltrami P, Sarti A, Rubilotta E, Righetti R, Malossini G. High flow priapism due to a bilateral arteriosinusoidal fistula. Scand J Urol Nephrol 2001;35: [56] Marotte JB, Brooks JD, Sze D, Kennedy 2nd WA. Juvenile posttraumatic high-flow priapism: current management dilemmas. J Pediatr Surg 2005;40:E25 8. [57] Hakim LS, Kulaksızoglu H, Mulligan S, et al. Evolving concepts in the diagnosis and treatment of arterial high-flow priapism. J Urol 1996;155: [58] Moreland RB, Traish A, McMillin MA, Smith B, Goldstein I, Saenz de Tejada I. PGE1 suppresses the induction of collagen synthesis by transforming growth factor b1 in human corpus cavernosum smooth muscle. J Urol 1995; 153: [59] Pautler SE, Brock GB. Priapism. From Priapus to the present time. Urol Clin North Am 2001;28: [60] Emond AM, Holman R, et al. Priapism and impotence in homozygous sickle cell disease. Arch Intern Med 1980; 140: [61] Fowler JE, Koshy M, Strub M, et al. Priapism associated with sickle cell hemoglobinopathies: prevelance, natural history and sequelae. J Urol 1991;145:65 8.

11 160 eau-ebu update series 4 (2006) [62] Pryor JP, Henir M. The management of priapism. Br J Urol 1982;54: [63] Virag R, Bachir D, Lee K, Galateros F. Preventive treatment of priapism in sickle cell disease with oral and self administered intracavernous injection of etilefrine. Urology 1996;47: [64] Gbadoe AD, Atakouma Y, Kusiaku K, Assimadi JK. Management of sickle cell priapism with etilefrine. Arch Dis Child 2001;85:52 3. [65] Serjeant GR, De Ceulaer K, Maude GH. Stilboestrol and stuttering priapism in homozygous sickle-cell disease. Lancet 1985;2: [66] Levine LA, Guss SP. Gonadotropin-releasing hormone analogues in the treatment of sickle cell anemia-associated priapism. J Urol 1993;150: [67] Dahm P, Rao DS, Donatucci C. Antiandrogens in the treatment of priapism. Urology 2002;59:138. [68] Rourke KF, Fischler AH, Jordan GH. Treatment of recurrent idiopathic priapism with oral baclofen. J Urol 2002; 168: [69] Gupta S, Salimpour P, Saenz de Tejada I, Daley J, Gholami S, Daller M, et al. A possible mechanism for alteration of human erectile function by digoxin: inhibition of corpus cavernosum sodium/potasium adenosine triphosphatase activity. J Urol 1998;159: [70] Matlaga BR, Hodges SJ, Carbone DJ et al. Management of idiopathic recurrent veno-occlusive priapism. AUA annual meeting 2003 (abst. no: 1415). [71] Filho DR, Braganca C, Cavalcante a et al. Treatment of recurrent priapism in sickle cell anemia with finasteride.? CME questions Please visit to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. What is the proposed erection time for the definition of priapism? A. 4 h B. 12 h C. 24 h D. 72 h 2. Which of the folowing diagnostic techniques is the mainstay of the diagnosis for differentiating ischemic from non-ischemic priapism? A. Color Doppler ultrasonography B. Corporal blood gas analyses C. Penile angiography D. Complete blood count 3. What should be the preferred drug for the intracavernosal treatment of ischemic priapism? A. Metaraminol A new approach. AUA annual meeting 2004 (abst. no: 1170). [72] Perimenis P, Athanasopoulos A, Papathanasopoulos P, Barbalias G. Gabapentin in the management of the recurrent, refractory, idiopathic priapism. Int J Impot Res 2004; 16:84 5. [73] Teloken C, Ribeiro EP, Chammas M, Teloken P, Souto CAV. Intracavernosal etilefrine self-injection therapy for recurrent priapism: one decade of follow-up. Urology 2005; 65:1002. [74] Gbadoe AD, Atakouma Y, Kusiaku K, Assimadi JK. Management of sickle cell priapism with etilefrine. Arc Dis Child 2001;85:52 3. [75] Van Driel MF, Joosten EA, Mensink HJ. Intracorporeal selfinjection with epinephrine as treatment for idiopathic recurrent priapism. Eur Urol 1990;17:95 6. [76] Ralph D, Pescatori E, Brindley G, Pryor J. Intracavernosal phenylephrine for recurrent priapism: Selfadministration by drug delivery implant. J Urol 2001;165: [77] Champion HC, Bivalacqua TJ, Takimoto E. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. PNAS 2005;102: [78] Burnett AL, Bivalacqua TJ, Champion HC, et al. Long-term oral phosphodiesterase-5 inhibitor therapy alleviates recurrent priapism. J Sex Med 2006;3: [79] Rajfer J, Gore JL, Kaufman J, et al. Case report: Avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide. J Sex Med 2006;3: B. Epinephrine C. Izoproterenol D. Phenyephrine 4. Which of the following drugs may be an alternative for the oral treatment of recurrent priapism? A. Tamsulosin B. Alfuzosin C. PDE5 inhibitors D. Izoproterenol 5. Which of the following distal shunting procedure is the most efficient? A. Ebbehoj B. Winter C. Barry D. Al-Ghorab 6. What is the rationale for early implantation of the penile prosthesis for priapism? A. To protect the corpora from fibrosis B. To make the patient sexually active as soon as possible C. To escape from a challenging prosthesis procedure due to significant fibrosis in the corpora due to priapism