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What is the optimal dosing of intracavernous phenylephrine for acute ischemic priapism?

Introduction

Priapism is a prolonged erection of the penis that persists hours beyond or in the absence of sexual stimulation.1-3 Although studies differ on defining duration of erection, any erection lasting at least 4 hours is typically considered priapism. Early treatment and detumescence do not typically result in long-term erectile dysfunction.3 Permanent damage is done if priapism lasts longer than 24 hours. Because priapism has such a rare incidence, literature and clinical trials on management are scarce and are generally of low-quality evidence, such as case reports and case series. There are no randomized controlled trials available on the management strategies used in priapism and most clinical guidelines are based on expert opinion.2 Management may consist of medical or surgical treatment and can differ based on the extent of ischemic damage the patient presents with. The mainstay of medical management for ischemic priapism is the use of intracavernous phenylephrine injections. This article will summarize existing evidence for appropriate doses of intracavernous phenylephrine in the emergent treatment of acute ischemic priapism.

Background

The incidence of priapism is estimated to be 0.73 cases per 100,000 men annually, based on a study describing emergency department visits in the United States between 2006 and 2009.4 It can occur in any age group, but appears to have a bimodal presentation, with peak incidence in ages 7 to 10 years in children and 20 to 50 years in adults.5 Certain medications and disease states have been implicated as possible triggers for priapism. It is estimated that the cause for up to 25% of patients presenting with priapism is the use of erectile dysfunction medications, such as phosphodiesterase type 5 inhibitors and intracavernosal injections.1 Antidepressant medications and illicit drugs may also cause priapism. Sickle cell disease is a common disease state that accounts for many cases as well.1,3 Younger patients tend to have priapism due to sickle cell disease, while older populations more commonly have priapism caused by medication use. In some cases, no underlying explanation can be found for the disorder.

Priapism can be categorized as ischemic or nonischemic.2,6 Ischemic priapism is a persistent erection characterized by little to no cavernous blood flow (low arterial flow), causing rigid and prolonged corpora cavernosa.2,6,7 The increased intracorporal pressure can lead to tissue ischemia, abnormal blood gases due to hypoxia and cavernosal acidosis, and penile pain.2,6 Ischemic priapism is a urological emergency. Nonischemic priapism (high arterial flow) is usually a result of direct trauma or injury and is less common than ischemic priapism. Nonischemic priapism is not painful and typically does not require emergent medical care. Most cases of nonischemic priapism, even if untreated, will resolve spontaneously in these instances.

In order to avoid permanent erectile dysfunction, ischemic priapism needs to be treated immediately to return to flaccidity.2,8 Physiological changes typically start 4 to 6 hours after onset of priapism.8 After 12 hours, permanent structural changes of the corporal smooth muscle tissue begin to develop. At 24 hours, cellular damage and significant structural changes occur, leaving 90% of men who maintain an erection for that long no longer able to have sexual intercourse.3 Management should proceed in a stepwise fashion to achieve resolution of symptoms as quickly as possible.2

Intracavernous Phenylephrine

Phenylephrine is a pure alpha-adrenergic agonist and is considered the sympathomimetic agent of choice for treatment of ischemic priapism by the American Urological Association (AUA) and Sexual Medicine Society of North America (SMSNA) due to its rapid onset and short duration of action.2 Compared with other sympathomimetic medications, cardiovascular side effects with use of phenylephrine are of minimal risk due to its alpha-1 selectivity. Trial data are lacking, but several small observational studies or case studies have demonstrated prompt resolution of priapism with injection of intracavernosal phenylephrine.9-12

As a class, sympathomimetics induce contraction of the cavernous smooth muscle, permitting venous outflow.13 Alpha adrenergic-mediated hypertensive effects and beta adrenergic-mediated inotropic and chronotropic effects are possible with use of sympathomimetics. Acute hypertension, headache, and cardiac arrhythmias are all possible side effects with use of phenylephrine. The following sections will summarize clinical data on efficacious and safe doses of phenylephrine injections in the treatment of ischemic priapism.

Guidelines

The AUA and SMSNA published joint guidelines on the management of acute ischemic priapism in September 2021.2 Recommendations were developed based on studies found through a comprehensive literature search. When insufficient evidence existed, the recommendations were made primarily based on expert opinion and clinical expertise. Table 1 summarizes the recommendations made by the AUA regarding the administration of intracavernosal phenylephrine and the level of certainty, magnitude of benefit or risk/burden, and body of evidence strength.

Table 1. Summary of 2021 AUA/SMSNA guideline statements on the use of intracavernosal phenylephrine.2
AUA and SMSNA Recommendation
Recommendation statement: level of certainty, magnitude of benefit or risk, and body of evidence strength
Initial Management of Acute Ischemic Priapism
Patients presenting with a prolonged erection of < 4 hours following intracavernosal injection for ED should receive intracavernosal phenylephrine as the initial treatment option.
Expert Opinion
A statement, achieved by consensus of the Panel, that is based on members’ clinical training, experience, knowledge, and judgement for which there is no evidence.
Pre-Surgical Management of Acute Ischemic Priapism
First-line therapy for acute ischemic priapism should be intracavernosal phenylephrine and corporal aspiration, with or without irrigation, prior to surgical interventions.
Moderate Recommendation, Evidence Level: Grade C
Benefits outweigh risks/burden
Net benefit appears moderate
Applies to most patients in most circumstances but better evidence is likely to change confidence
Clinicians should monitor blood pressure and heart rate in patients receiving intracavernosal phenylephrine injections.
Clinical Principle
A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature.  
Dosing and Administration of Phenylephrine
Phenylephrine 100 to 500 mcg doses suspended in 1 mL of normal saline (optimally premixed by pharmacy to minimize risks of miscalculation) administered intracavernosallyaExpert Opinion
A statement, achieved by consensus of the Panel, that is based on members’ clinical training, experience, knowledge, and judgement for which there is no evidence.
aAlthough no upper limit to number of injections exists, injections should be stopped if blood pressure changes are detected or if erection persists despite repeated attempts with injections and aspiration/irrigation over a period of 1 hour or more
Abbreviations: AUA=American Urological Association; ED=erectile dysfunction; SMSNA=Sexual Medicine Society of North America

As first-line therapy and prior to any surgical interventions, the AUA/SMSNA recommends that acute ischemic priapism be managed with intracavernosal phenylephrine injection as quickly as possible following diagnosis.2 Intracavernosal treatments should never be delayed due to other systemic therapies. In most cases, therapies can be administered concomitantly, but intracavernosal therapy should take precedence if a decision must be made between systemic and intracavernosal treatments. Phenylephrine is recognized as the preferred agent of choice even though use in the context of acute ischemic priapism is off label. The AUA/SMSNA provided evidence to support the use of phenylephrine over other sympathomimetic agents. Phenylephrine has been compared to other agents, including epinephrine and ethylephrine, and was found to have a 28% higher rate of detumescence, while the other agents were comparable to aspiration alone.

The recommendations provided in the AUA/SMSNA guidelines for the dosing range of phenylephrine injections are based solely on expert opinion due to the paucity of evidence.2 The question surrounding appropriate dosing of phenylephrine (lower doses closer to 100 mcg or higher doses closer to 500 mcg) stems from possible concerns for adverse cardiovascular effects. Systemic absorption following intracavernosal administration can theoretically potentiate coronary vasospasm via the alpha-adrenergic effect of phenylephrine. This mechanism of action spurred the AUA/SMSNA recommendation to monitor blood pressure and heart rate throughout administration. Although rare, case reports have described adverse events such as myocardial infarction and intracranial bleeding after intracavernosal phenylephrine injection. However, these case reports are not enough to determine causation, as confounding factors such as low dose of administered medication (100 mcg), underlying cardiovascular disorders, or excessive use of oral pseudoephedrine prior to presentation cloud the clinical picture.

The Panel of AUA and SMSNA experts acknowledge that larger doses than what is recommended in the guidelines may be tolerated.2 The recommended range of 100 to 500 mcg seems to be based on evidence that may be outdated. It appears that higher doses of intracavernosal phenylephrine may have a potential benefit for faster resolution of priapism while also requiring fewer injections. Lower doses, conversely, reduce risk for potential hemodynamic effects. There does not seem to be enough literature available to fully weigh the risks and benefits, which is why clinical judgement is imperative during treatment.

Additional literature

More recent clinical trials have demonstrated potential safety with higher doses of phenylephrine in some patients. Larger trials demonstrating this are summarized in Table 2.

Table 2. Literature from the past 10 years demonstrating use of higher dose intracavernosal phenylephrine.14,15
Study design and durationSubjectsInterventionsResultsConclusions
Sidhu 201814
 
Retrospective chart review from May 1, 2014 to August 15, 2016
52 unique patients presenting to the emergency department on 74 different encounters with acute ischemic priapismMedian dose of 1000 mcg intracavernous injection of phenylephrine (range 500 to 2000 mcg)58 (74%) patients received phenylephrine
 
No association was made between phenylephrine dose and change in HR or BP with univariate linear regression
 
No ADEs were noted in any patient encounter
High concentration and dosing of intracavernous phenylephrine demonstrated high success rate in treatment
 
No patients included had baseline coronary artery disease or peripheral artery disease, and no patient had a history of using MAOI
Ridyard 201615
 
Retrospective chart review from January 1, 2010 to February 1, 2015
58 unique patients presenting to the emergency department on 136 occasions and receiving diagnosis of ischemic priapismMedian dose of 1500 mcg intracavernous injection of phenylephrine (range 300 mcg to 12000 mcg)38 (65%) patients were treated with phenylephrine alone, 12 (21%) patients were treated with phenylephrine and irrigation, and 8 (14%) patients required surgery.
 
Success rate of high-dose phenylephrine was higher in patients presenting within less than 24 hrs of priapism (n=45; p<0.001)

When controlled for patients presenting before and after 24 hrs of priapism, there was no variability in success rate of phenylephrine based on etiology (p>0.05)
 
Total amount of phenylephrine used to achieve detumescence in patients presenting within less than 12 hrs of priapism was significantly smaller than in patients presenting after 12 hrs (1400 mcg vs 3500 mcg, p<0.05)
 
Changes in HR and DBP were statistically significant from admission to discharge, (mean decrease in HR of 6.8 beats/min; 95% CI, 3.3 to 10.7; mean decrease in DBP of 10.8 mm Hg; 95% CI, 6.2 to 15.0)
High concentration and dosing of intracavernous phenylephrine demonstrated high success rate in treatment
 
Changes in DBP and HR were considered clinically insignificant via chart review and possibly confounded by change in pain level and overall clinical condition
Abbreviations: ADE=adverse event; BP=blood pressure; CI=confidence interval; DBP=diastolic blood pressure; HR=heart rate; MAOI=monoamine oxidase inhibitor.

Conclusion

Very limited evidence exists to direct the optimal dose or concentration for intracavernous phenylephrine in the management of acute ischemic priapism. The 2021 AUA and SMSNA guidelines are primarily based on expert opinion. The historical recommendation of 100 to 500 mcg phenylephrine is seemingly based on low levels of evidence due to fears of potential hemodynamic adverse effects. More recent studies, although still of low-quality evidence, demonstrate that these fears may be unfounded. The use of a higher dose of phenylephrine (500 mcg in 1 mL saline) may demonstrate advantages in achieving detumescence faster. Modern day monitoring of vital signs and the short duration of action of phenylephrine could provide for a safe approach in most patients, with cautions taken in individuals with cardiovascular comorbidities or those with a higher likelihood of hemodynamic changes. As with many rare disease states or disorders, new, high-quality evidence is unlikely to emerge, as randomized controlled trials may not be ethical or possible. However, with continued clinical experience, these recommendations may be updated in the future, giving clinicians a better sense of an appropriate dose of phenylephrine to use in the medical management of ischemic priapism.

References

  1. Burnett AL, Bivalacqua TJ. Priapism: current principles and practice. Urol Clin North Am. 2007;34(4):631-642, viii. doi: 10.1016/j.ucl.2007.08.006.
  2. Bivalacqua TJ, Allen BK, Brock G, et al. Acute Ischemic Priapism: An AUA/SMSNA Guideline. J Urol. 2021;206(5):1114-1121. doi: 10.1097/JU.0000000000002236.
  3. Pryor J, Akkus E, Alter G, et al. Priapism. J Sex Med. 2004;1(1):116-120. doi: 10.1111/j.1743-6109.2004.10117.x.
  4. Roghmann F, Becker A, Sammon JD, et al. Incidence of priapism in emergency departments in the United States. J Urol. 2013;190(4):1275-1280. doi: 10.1016/j.juro.2013.03.118.
  5. Cherian J, Rao AR, Thwaini A, Kapasi F, Shergill IS, Samman R. Medical and surgical management of priapism. Postgrad Med J. 2006;82(964):89-94. doi: 10.1136/pgmj.2005.037291.
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  7. Kim NN, Kim JJ, Hypolite J, et al. Altered contractility of rabbit penile corpus cavernosum smooth muscle by hypoxia. J Urol. 1996;155(2):772-778.
  8. Spycher MA, Hauri D. The ultrastructure of the erectile tissue in priapism. J Urol. 1986;135(1):142-147. doi: 10.1016/s0022-5347(17)45549-2.
  9. Dittrich A, Albrecht K, Bar-Moshe O, Vandendris M. Treatment of pharmacological priapism with phenylephrine. J Urol. 1991;146(2):323-324. doi: 10.1016/s0022-5347(17)37781-9.
  10. Muruve N, Hosking DH. Intracorporeal phenylephrine in the treatment of priapism. J Urol. 1996;155(1):141-143.
  11. Siegel JF, Reda E. Intracorporeal phenylephrine reduces thioridazine (Mellaril) induced priapism in a child. J Urol. 1997;157(2):648.
  12. Wen CC, Munarriz R, McAuley I, Goldstein I, Traish A, Kim N. Management of ischemic priapism with high-dose intracavernosal phenylephrine: from bench to bedside. J Sex Med. 2006;3(5):918-922. doi: 10.1111/j.1743-6109.2005.00140.x.
  13. Westfall TC, Macarthur H, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill; 2018; chap 12. Accessed January 14, 2022. https://accessmedicine.mhmedical.com/book.aspx?bookid=2189.
  14. Sidhu AS, Wayne GF, Kim BJ, et al. The hemodynamic effects of intracavernosal phenylephrine for the treatment of ischemic priapism. J Sex Med. 2018;15(7):990-996. doi: 10.1016/j.jsxm.2018.05.012.
  15. Ridyard DG, Phillips EA, Vincent W, Munarriz R. Use of high-dose phenylephrine in the treatment of ischemic priapism: Five-year experience at a single institution. J Sex Med. 2016;13(11):1704-1707. doi: 10.1016/j.jsxm.2016.09.010.

Prepared by:
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2022

The information presented is current as of January 14, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.