Continuing Education Activity

Stuttering priapism is one of the three types of priapism. It is common amongst males with Sickle Cell Disease and can develop into more serious ischemic priapism. To avoid its complications, prevention should be the aim of treatment. This activity outlines the evaluation and management of stuttering priapism and highlights the role of the interprofessional team in improving the care for patients with this condition.

Objectives:

• Identify the etiology of stuttering priapism.
• Describe the pathophysiology of stuttering priapism.
• Outline the typical presentation of a patient with stuttering priapism.
• Explain management options for patients with stuttering priapism.

Introduction

Priapism is defined as prolonged and sustained penile erection usually lasting more than three to four hours without the presence of a stimulus.[1] It has been classified into three types: Low-flow or ischemic priapism which is the most common type, high-flow or oxygenated priapism which is often the result of a penile injury, and recurrent or stuttering priapism which is the least common variety.[2] Stuttering priapism is generally self-limiting and usually lasts less than three to four hours per episode. However, it has the potential to develop into complete ischemic priapism in one-third of the cases, requiring urgent intervention.[3] Ischemic priapism can cause many morbidities including erectile dysfunction, this is why it should be treated within four hours to minimize the chance of developing long-term complications and permanent damage to the erection bodies or corpora.[4] 

The body of the penis is formed of three parts: the corpora cavernosa, the corpus spongiosum, and the urethra. The penile corpora are vascular beds and sinusoidal spaces supported by smooth muscles, nerves, and capillaries. Blood is supplied from the common penile artery and cavernosal arteries which are branches of the internal pudendal artery. Venous drainage is through the superficial, intermediate, and deep venous systems which drain into the cavernous and the deep dorsal veins. The parasympathetic nerve supply to the penis is through the cavernosal nerves which arise from the pelvic ganglionic plexus. When sexual excitement occurs, the parasympathetic nerves stimulate the release of vasodilating neurotransmitters which relax the intracorporal trabecular smooth muscles which increase sinusoidal compliance resulting in substantial dilation of the arterioles and arteries. This dramatic and substantial increase in blood flow expands the corpora cavernosa until pressure and compression of the subtonic venular plexus decreases venous outflow trapping the blood at maximum capacity inside.  The venous outflow stops as the compression builds. The increased hydrostatic pressure inside the inelastic corporal space results in rigidity and a full erection.[5][6][7]  The process is similar to filling a car tire with 200 lbs per square inch of air pressure. The steel belts in the tire are inelastic so as the tire pressure increases, it becomes harder and more rigid without stretching or enlarging.

Etiology

The causes of stuttering priapism are similar to the causes of ischemic priapism. They can be classified as hematological, pharmacological, neurological, and malignancy. Sickle cell disease is the commonest cause of stuttering priapism. Although stuttering priapism is not common in the general population, it is relatively frequent amongst males with Sickle cell disease (SCD). It affects between 30% and 45% of all adult males with SCD.[8] Most of the SCD patients with priapism have stuttering priapism, and most will be homozygous for hemoglobin S, although it can also occur in the Sickle cell trait. Other hematologic causes include leukemia, thalassemia, and platelet abnormalities. Medications most closely linked to priapism are psychoactive agents and the use of erectile dysfunction (ED) drugs in non-prescribed combinations or at higher than recommended dosages.[9][10] Testosterone supplementation does not appear to play a major role in causing priapism, and neither does urination or having a full bladder.

Epidemiology

Different studies have reported significantly different rates of priapism in the general population and in specific populations. This means that there is a lack of real information on the prevalence of different types of priapism.[11] The incidence of stuttering priapism in men with SCD was reported to be 42%. However, another study reported the incidence in adolescents and children with SCD to be 65%.[12] The vast majority (82%) of all patients with SCD who have had any type of priapism reported a history of stuttering variety. Moreover, 49% of patients who have experienced stuttering priapism had an acute episode. The frequency of episodes generally ranges from 4 per week to 3 a year, with a median of 3 episodes per month.[13] The occurrence of priapism typically follows a bimodal distribution, with the first peak being between 5 to 10 years in children and 20 to 50 years in adults.[14] The probability of experiencing priapism in males with SCD disease is 12% in the first 10 years of life, up to 50% when they reach 15 years old, and almost 90% by the time they are 20 years of age. The mean age to have the first episode is 15 years.[15] Another study found that virtually all SCD patients who reported priapism had their first episode before the age of 30.[13]

In children, about 2/3 of all those who demonstrate priapism will also have SCD. Thus, among children with SCD, the rate of pediatric priapism is about 25% to 30%.

Pathophysiology

The mechanism for normal erectile function initially involves activation of cyclic GMP by nitric oxide. This causes relaxation of the cavernosal smooth muscle tissue resulting in increased blood flow into the corpora with a resulting erection. This process is limited by the action of the phosphodiesterase type 5 enzyme which converts cyclic GMP back to its inactive state.[16] Adrenergic mediators stimulate the RhoA/Rho kinase pathway which leads to cavernosal vasoconstriction and penile flaccidity.[17] There is a natural balance between these two functions that allow for normal penile flaccidity with intermittent, limited erectile rigidity. When this balance is disrupted, one result is priapism.[18]

Although the pathophysiology of stuttering priapism is not fully understood, it appears to result from dysregulated dynamics of the normal erection process leading to venous stasis, compartment syndrome, and diminished blood flow. This eventually leads to tissue damage and ultimately corporal fibrosis with permanent loss of erectile ability. The mechanism underlying stuttering priapism is thought to be similar to that of ischemic priapism.[12] The most common reported precipitants of priapism are sexual arousal, fever, and sleep.[13]

The molecular mechanism thought to cause stuttering priapism involves reduced cavernosal nitric oxide in the endothelial cells, which downregulates phosphodiesterase type 5 (PDE-5) and reduces RhoA/Rho-Kinase activity while increasing adenosine and opiorphin levels. Within the corporal, cavernosal tissue, nitric oxide - cyclic GMP - phosphodiesterase type 5 signaling is downregulated along with increased oxidative stress and disruptions in the usual vasoconstrictive mechanisms. All of these effects taken together cause a reduced cavernosal smooth muscle tone, leading to enhanced tissue relaxation and an exaggerated response to normal stimuli, resulting in prolonged erections.[19]

The conventional method of explaining priapism related to SCD is based on the principles of increased blood viscosity and venous congestion. Normal erections reduce the oxygen saturation in the corpora cavernosa. In patients with SCD, this predisposes the red blood cells to sickle inside the corpora cavernosa creating a higher viscosity which induces venous stasis, leading to increased congestion and ultimately priapism. The priapism further reduces blood flow, causing acidosis, damage to the smooth muscle tissue, and an inflammatory reaction, eventually resulting in penile corporal fibrosis and permanent erectile dysfunction (ED).[20]  

History and Physical

History

In the emergency department, it is very important to know what type of priapism the patient is presenting with to initiate treatment promptly. Ischemic priapism presents with progressive penile pain with the duration of the erection. Past medical history of SCD, other hematological disorders, or is known to have a neurological condition provides the history of a risk factor. In high-flow priapism, the patient usually presents with a history of a prolonged erection but no pain. It usually follows a perineal or penile trauma, penile injections or procedures, or pelvic surgery. 

When a patient presents with stuttering priapism, it is important to know the number and frequency of episodes, their average duration, and what were the precipitating factors. They usually occur as a non-resolving morning erection or after sexual stimulation. A history of high-risk or underlying causative factors such as SCD and other hematological diseases, as well as a complete medication history is very important. Psychoactive medications or a history of mental health issues can be critically important. Many patients will have learned ways to resolve this at their homes such as hot or cold packs, cold baths, or exercise. It should also be established if this ever progressed to an acute ischemic attack and, if so, how often. As this has the potential to cause permanent erectile dysfunction and difficulties in the patients' sex life, it is pertinent and reasonable to establish its effect on their life.[21] 

Physical Examination

The aim of the physical examination in the acute attack is also to determine the type of priapism the patient is presenting with. In ischemic attacks, the corpora cavernosa is fully rigid and somewhat tender. In high-flow priapism, it is the opposite; full but relatively soft and painless. Inspection and palpation of the perineum should be done to identify for signs of trauma like discoloration and tenderness, as this is one of the main causes of high-flow priapism. In recurrent priapism, examination of the testicles, abdomen, perineum, rectum, and prostate should be undertaken to look for masses. Although they are a rare cause of priapism, there is a possibility they can be identified so the examination is recommended.[22] Since priapism does not cause an increase in temperature, any fever would likely be from some other cause.

Evaluation

Laboratory Testing

Evaluation in the emergency department aims to find the cause of priapism. A complete blood count (CBC) and a clotting profile are to assess for anemia, infection and detect any hematological abnormality. Urine and plasma toxicology is requested if suspicion of recreational narcotics use rises. If the patient has a psychological history, tests for psychoactive medication levels in the blood should also be sought. Additionally, in the acute phase, a corporal blood aspirate should be analyzed to rule out ischemic priapism. In ischemic priapism, the first aspirate will show acidity (pH <7.25), high PCO2 (>60 mmHg), and low PO2 (<30 mmHg). Also, a sickle cell screen should be done selectively to rule out SCD as a cause of stuttering priapism. Other hematologic causes should be looked for like leukemia, thalassemia, and platelet abnormalities.[22][23] 

Imaging

In the acute phase, color duplex Doppler ultrasonography can be used to measure the blood flow in the penis and perineum. Ischemic priapism will not show any blood flow in the cavernous arteries.[23] CT scans in the elective setting, to rule out suspected malignancy as a cause of priapism, can be done if clinically indicated. Penile arteriography is rarely needed except when high-flow priapism is suspected, and an embolization attempt is being considered. High flow priapism does not typically cause frequent recurrences.

Treatment / Management

The main aim of treating stuttering priapism is to prevent future episodes from happening. An acute episode of prolonged ischemic priapism of more than four hours needs to be managed as an emergency. Aspiration of penile blood and intracorporal infusion of diluted α-adrenergic agents needs to be done within 24 hours. However, presenting with such episodes carries a high risk of developing complications, which is why the treatment aim in stuttering priapism is preventative. The advances in understanding the mechanism of stuttering priapism have led to the trial of new medications with the aim of prevention. The specific medical management of stuttering priapism options can generally be grouped into hormonal agents, drugs that change the corporal muscle tone, and others.[24] Treatments for acute episodes of priapism are described elsewhere.[1][25] In general, acute priapism in patients with frequent recurrences should generally be treated the same as for those without such recurrences. This report will focus on treatment and prophylactic therapies of stuttering priapism.

Hormonal Manipulation

There are multiple options for treatment with hormones for patients with stuttering priapism, but they all aim towards reducing the levels of circulating testosterone. Studies suggest that reducing testosterone level to 10% of its normal level will reduce libido and nocturnal erections, which will reduce the number of priapism episodes. The treatment lasts from 2 weeks to 2 months and was then stopped with sustained treatment results. Options for hormonal manipulation include gonadotropin-releasing hormones (GnRH) agonists/antagonists (downregulate the pituitary gland), antiandrogens (block androgen receptors), ketoconazole (reduces testosterone production as a side effect), and finasteride (5α-reductase inhibitor). However, these agents will affect sperm production, growth, and sexual maturation. This is why they are contraindicated in males who are still in their growth phase and relatively contraindicated in those wanting to conceive. Other treatment options, like self-administering α-adrenergic agonists in acute attacks, can be used cautiously in this patient group where possible.[26][27]

A treatment regimen for ketoconazole has been suggested which involves an initial dose of 200 mg TID with prednisone 5 mg daily for 2 weeks followed by a reduced dose of 200 mg of ketoconazole nightly for an additional 6 months.[28] In a small study, this regimen resolved the stuttering priapism in 94% of patients while on treatment and in 79% after the ketoconazole therapy was completed.[28]

Increasing the Cavernosal Smooth Muscle Tone

The first option of these medications is the intracavernosal injection of diluted pseudoephedrine. This is usually used as an injection directly into the cavernosal tissue making it more of a treatment option for acute attacks rather than prevention. The standard recommended dilution is from 100 to 500 mcg/mL and treatment involves the injection of 1 ml roughly every 5 minutes until either resolution or 1 hour of treatment.[25] It exerts its effect as an α-agonist acting on the α-adrenergic receptors in the cavernosal smooth muscles, causing contraction and detumescence. There have been suggestions to use this as an oral agent for prevention but there are no studies on this yet.

Digoxin inhibits the sodium-potassium pump and leads to increased intracellular calcium which causes smooth muscle contraction and detumescence. However, only a small study has been conducted on this agent.

Terbutaline, a β2-adrenergic agonist, has long been recommended for preventing recurrent episodes of stuttering priapism. The dosage of oral terbutaline is 5 mg immediately, with another 5 mg taken 15 minutes later. The prophylactic dose of terbutaline has been proposed as 5 to 10 mg daily. Recently, the role of terbutaline has been questioned due to lack of proven efficacy in acute priapism so ti si not currently recommended. 

Other Agents

Gabapentin is used for the treatment of convulsions and as an anxiolytic. It has also been found to reduce the influx of calcium into smooth muscle cells and inhibits muscle contraction. This may explain why it has been sometimes been effective in treating refractory priapism.[18] 

In SCD patients, hydroxyurea has been used with some success.[29] Originally designed as an anti-cancer drug, hydroxyurea affects the bone marrow and reduces the overall concentration of hemoglobin S (Hb S). It also reduces hemolysis and causes vasodilation through increased nitric oxide production. It is only used for priapism in SCD patients.[29][30][31] Patients with SCD generally have decreased nitric oxide levels in the blood due to chronic hemolysis. Free hemoglobin in the blood acts as a nitric oxide sink.[32][33][34] There are also other mechanisms involved. Clearly, however, SCD patients with stuttering priapism tend to have more severe disease, a higher incidence of stroke, an increased rate of acute chest syndrome, and lower average Hgb levels.[35] The initial dose of hydroxyurea is 20 mg/kg daily. This can then be increased until clinical success, or the maximum tolerable dose has been achieved based on periodic laboratory CBC examinations.

Other agents found to be effective against stuttering priapism are hydralazine, baclofen, and procyclidine. Also, conventional treatment of SCD has been found effective in the prevention of priapism in the patient group. This includes analgesia, fluids, oxygen, alkalinization, and transfusions. However, these treatments are useful only after the initial management of the acute priapism episode.[24]

Sildenafil at a low daily dose (25 to 50 mg) has been investigated to help moderate nitric oxide signaling and normalize/reprogram phosphodiesterase type 5 activity. There have been some limited studies suggesting a benefit in stuttering priapism in men both with and without sickle cell disease.[36][37][38][39] This can be combined with 5-alpha reductase inhibitors such as finasteride.[40][41][42]

Some patients can be taught how to prepare, mix and perform intracavernosal self-administration of diluted α-agonist medication.[27][43] While this is often effective, it is not a cure and requires substantial patient skills, motivation, and abilities.[27] It has also rarely been associated with thromboembolic events such as intracerebral hemorrhages and myocardial infarctions.[44][45][46]

Special Considerations for SCD Patients Including Automated Red Cell Exchange Transfusions

Initial therapy for SCD patients presenting with priapism generally includes alkalinization, adequate analgesia, IV hydration, and supplemental oxygen to prevent more sickling. The American Urological Association Guidelines on the Management of Priapism recommends intracavernosal therapy together with systemic treatment of SCD. Surgical shunts can be considered after intracavernosal therapy has failed. Initial shunting should be between the glans (corpora spongiosa) and the corpora cavernosa. Tunneling, where a dilator is passed through the corpora from the tip to the tail to provide additional drainage, may also help in some cases but is more invasive than just the shunt.[25]

In SCD patients, hydroxyurea has been used prophylactically with some success.[31][47] Originally designed as an anti-cancer drug, hydroxyurea affects the bone marrow and reduces the overall concentration of hemoglobin S (Hb S). It also reduces hemolysis and causes vasodilation through increased nitric oxide production and reduced scavenging.[29][30][48] It is only used for priapism in SCD patients.[29][30][31] Patients with SCD generally have decreased nitric oxide levels in the blood due to chronic hemolysis. Free hemoglobin in the blood acts as a nitric oxide sink.[32][33][34] There are also other mechanisms involved. Clearly, however, SCD patients with stuttering priapism tend to have more severe disease, a higher rate of stroke, an increased rate of acute chest syndrome, and lower average Hgb levels.[35] The initial dose of hydroxyurea is 20 mg/kg daily. This can then be increased until clinical success, or the maximum tolerable dose has been achieved based on periodic laboratory CBC examinations.

Sildenafil can be used as an additional therapeutic option for those who continue to have episodes of priapism despite hydroxyurea therapy. It has shown some efficacy in resolving priapism in SCD patients.[37][49]

Finasteride blocks the enzymatic conversion of testosterone to the more active dihydrotestosterone. There is some limited evidence of reducing the frequency of priapism episodes in SCD patients with stuttering priapism, but it can also cause gynecomastia, decreased libido, and ED in some individuals.[40]

There are also very limited studies on using GnRH agonists for stuttering priapism in SCD patients, although we have used it anecdotally with success.[50] Theoretically, a GnRH antagonist should also be effective, but there is no data on this. Clearly more studies on this type of therapy are needed.

Standard transfusions can improve tissue oxygenation and reduce the percentage of sickled erythrocytes in the circulation for SCD patients suffering from stuttering priapism. They also have the advantage of not requiring any special staffing or equipment. Unfortunately, standard transfusions are also associated with iron overloads, are relatively slow, and are substantially less effective than exchange transfusions in reducing the Hb S level. Exchange transfusions can be performed manually using donor red blood cells and normal saline, but this is a lengthy and laborious process. In addition, it is not as rapid or effective as automated red cell exchanges and can still cause an iron overload.

Automated red cell exchanges are performed by using an apheresis system. The patient's blood is removed, and the red cells are replaced with donor erythrocytes, after which the blood is returned to the original patient. While this process requires special staffing and equipment, it can rapidly reduce the Hb S level and avoid excessive iron loading. Therefore, it is the recommended method of exchange transfusion in SCD patients.[51][52][53] Automated red cell exchange transfusions have been successfully used to manage stuttering priapism in patients with SCD.[51][54][55] Target post-transfusion Hb S is usually 10% or less, but a clinical response may begin starting at just 30%. This technique has been successful in SCD patients who otherwise suffered intractable, recurrent episodes of stuttering priapism. It has been recommended to treat SCD patients with severe, intractable stuttering priapism who do not otherwise respond to or tolerate pharmacotherapy or hormonal manipulation.[8][51] Negatives include the need for specialized equipment and staffing, traveling to treatment locations, the requirement for ongoing therapy, limited studies proving efficacy, and the cost. Prophylactically, most SCD patients do not develop additional episodes of priapism as long as their Hb S levels are at 30% or less. Despite some favorable evidence of efficacy, the use of automated red cell exchange transfusions for acute priapism is not officially recommended by Guidelines from the American Society of Apheresis or by the 2014 NIH Guidelines on SCD. Nevertheless, several experts, including ourselves, will consider this therapy when all other treatments have been unsuccessful and as an alternative to proceeding to a penile prosthesis with its irreversible sequelae. 

Insertion of a Penile Prosthesis

When all other reasonable means fail, complete corporal dilation can resolve the priapism but will also destroy the patient's natural erectile function. A prosthesis is usually considered when the patient presents with an acute, low flow, ischemic priapism >36 hours duration or in those who have failed surgical shunting procedures. The insertion of a penile prosthesis at the time of the corporal dilation can resolve the ED problem if a suitable implant is available and the tunica has not been overly weakened, especially at the tip, by attempts at creating a shunt. To the extent that any prior shunt procedures may have weakened part of the tunica albuginea, the likelihood of an extrusion increases. However, waiting too long after a complete corporal dilation can lead to scarring and fibrosis making the eventual insertion of a prosthesis much more difficult. It is therefore recommended to implant the penile prosthesis either at the time of the corporal dilation surgery or shortly thereafter; preferably within a few weeks. Overall, there are higher failure rates with penile prosthesis implantation for priapism than for routine, elective placement.[56] The general consensus is that earlier penile prosthesis placement is recommended to avoid fibrosis, reduce the infection rate, and minimize penile shortening. Malleable prostheses are usually recommended in these cases.[57] There may also be a reduced rate of device erosion associated with earlier prosthesis placement as long as the tunica is intact after shunting.[25][57] 

Unfortunately, there are no clear guidelines on the management and prevention of stuttering priapism, and it is a topic that requires more research. In the absence of clear guidelines, the following is suggested:[41]

• Any testosterone abnormalities should be corrected. 
• There is good evidence that stuttering priapism patients with SCD will benefit from hydroxyurea.
• The prophylactic value of various oral agents, such as gabapentin, sildenafil, and finasteride, is somewhat uncertain.
• Terbutaline is no longer recommended.
• Of these, there is reasonable evidence of a prophylactic benefit to sildenafil and finasteride; either alone or taken together.
• If previous measures fail, third-line agents can be used such as digoxin and baclofen. However, digoxin can cause weakness or undesirable cardiac effects while baclofen may lead to drowsiness.
• Hormonal manipulation with GnRH therapy and/or ketoconazole appears reasonably effective prophylactically but may have side effects particularly with regards to fertility. 
• Patients can give themselves diluted α-agonist medication intracavernosal injections at home, although there is a small risk of thromboembolic complications.
• SCD patients can benefit from prophylactic automated red cell exchanges. 
• Consideration should be given to the early insertion of a penile prosthesis in difficult or intractable cases that do not respond to standard therapies. This will eliminate the recurrent priapism problem, but at the cost of a surgical implant.

Differential Diagnosis

The most important thing is to differentiate stuttering priapism from acute ischemic priapism and to initiate management immediately to avoid complications.

Prognosis

Stuttering priapism in itself causes erectile dysfunction in only one-quarter of patients. However, as about half of all patients who have stuttering priapism develop acute ischemic priapism, it can cause erectile dysfunction if not treated properly.[13]

Complications

The complications arise not from stuttering priapism itself but from acute ischemic episodes if they arise. If not treated within 24 hours, ischemic priapism can lead to fibrosis of the corpus cavernosum and eventually to significant erectile dysfunction.

Half or more patients with even one episode of prolonged priapism will develop erectile dysfunction (ED). This rate increases with the repeated episodes found in stuttering priapism. Liability exposure to the treating physicians is relatively high as patients may become upset with a poor outcome (ED) or repeated episodes of priapism despite correct treatment and counseling on presentation. Meticulous documentation is therefore recommended.

There are also several psychological issues that arise from stuttering priapism like sadness (70%), embarrassment (62%), fear (44%), and exhaustion (39%) which should be recognized and addressed appropriately.[58]

Deterrence and Patient Education

One survey showed that only 7% of patients with SCD disease who have never experienced priapism were familiar with priapism as a possible complication of the disease.[13] In addition, only 50% of patients who have experienced priapism related to SCD have sought medical advice for it, meaning that priapism may be more common than previously thought.[58]

Educating patients recognized to have a disease putting them at higher risk of developing priapism (like SCD, other hematological diseases, and various cancers) is of paramount importance. This should include some of the techniques that can be done at home to relieve the episode and when to seek medical advice to avoid or minimize complications. In addition, counseling about its effect on the patient's future sexual life might help mitigate its effect on his mental health and on the family.   

Pearls and Other Issues

Readers interested in the diagnosis and management of acute priapism are directed to our companion article by Silberman, Stormont, and HU on Priapism [PMID: 29083574] and Acute Ischemic Priapism: An AUA/SMSNA Guideline [PMID: 34495686] from the American Urological Association.[1][25]

Enhancing Healthcare Team Outcomes

A multidisciplinary approach to this issue is very important. Once a patient has been diagnosed with any disease that is associated with priapism, the treating physician should counsel them about the relative risk of developing it, how to initially treat it at home, and when to seek medical advice. This will help reduce the anxiety associated with the disease and the number of patients who present to the emergency department late with acute ischemic attacks and complications. This also applies to counseling when starting medications with priapism as a potential side effect. Having the hospital pharmacy ready to prepare a diluted phenylephrine treatment pack for intracavernosal injections in patients with priapism can greatly speed up the process and minimize delays in therapy. Quick recognition and prompt treatment of acute attacks in the emergency department will help reduce the incidence of complications like erectile dysfunction and improve treatment outcomes.