Annals of Tropical Pathology

REVIEW ARTICLE
Year
: 2017  |  Volume : 8  |  Issue : 1  |  Page : 5--10

Priapism in sickle-cell disease: Emergency room intervention


Akinsegun Akinbami, Ebele Uche, Adedoyin Dosunmu 
 Department of Hematology and Blood Transfusion, College of Medicine, Lagos State University, Lagos, Nigeria

Correspondence Address:
Dr. Akinsegun Akinbami
Department of Hematology and Blood Transfusion, College of Medicine, Lagos State University, PMB 21266, Ikeja, Lagos
Nigeria

Abstract

Priapism is one of the diverse complications of sickle cell disease (SCD). SCD is one of the many causes of priapism. Ischaemic and stuttering priapisms are the types seen in SCD. Apart from pain and psychological trauma associated with ischaemic and stuttering priapism, erectile dysfunction and impotence are the most severe complications of priapism in SCD that may require the use of penile prosthesis in SCD patients. The outcome of priapism complications is time-dependent and dependent on the type of management administered. This review highlights, the anatomy of the penis, physiology of normal erection, focusing on pathophysiology and management of priapism in SCD so as to create better awareness of this condition amongst physicians involved in the management of SCD.



How to cite this article:
Akinbami A, Uche E, Dosunmu A. Priapism in sickle-cell disease: Emergency room intervention.Ann Trop Pathol 2017;8:5-10


How to cite this URL:
Akinbami A, Uche E, Dosunmu A. Priapism in sickle-cell disease: Emergency room intervention. Ann Trop Pathol [serial online] 2017 [cited 2019 Sep 21 ];8:5-10
Available from: http://www.atpjournal.org/text.asp?2017/8/1/5/224149


Full Text

 Introduction



Sickle-cell disease (SCD) is a genetic abnormality in which glutamine on the 6th position of the β-hemoglobin chain is replaced with valine as a result of a single point mutation affecting the replacement adenine with thymine on its deoxyribonucleic acid structure. One of the consequences of the mutation is sickling of the red blood cells (RBCs). The sickled RBCs impede free flow of blood of affected vessels causing obstruction, congestion, hypoxia, and lactic acidosis, all contributing to the pathophysiology of priapism in SCD.

Priapism is the development of prolonged penile erections leading to tissue ischemia and development of functional erections in the absence of sexual arousal or desire.[1],[2]

Three types of priapism exist, namely ischemic priapism also known as veno-occlusive or low flow, stuttering priapism or recurrent ischemic priapism (RIP), and nonischemic priapism (arterial high flow).

Ischemic and stuttering priapisms are associated with SCD with prevalence rates of 40%.[3] It is characterized by pain and is a medical emergency. Unlike ischemic priapism, nonischemic priapism is nonpainful and is usually secondary to unregulated cavernous arterial inflow, caused by arteriovenous fistula, iatrogenic needle injury, and pelvic trauma causing arteriosinusoidal fistula formation; it is not a medical emergency.[4] Knowledge of priapism among SCD patients in Nigeria is poor; 74.6% of the patients had no knowledge of priapism [5] despite a high prevalence of priapism of between 30%–40% among them. Nearly, 89% are estimated to experience priapism by the age of 20 years.[3],[6]

Erectile dysfunction (ED) is one of the many complications of priapism. ED is secondary to tissue ischemia and subsequent cavernosal fibrosis which is a time-dependent complication.[7]

 Overview of the Anatomy of the Penis



The penis is made up of three erectile columns, i.e. two corporal cavernosa and a corpus spongiosum which is situated in the central groove of the paired corporal cavernosa. The penis also has columns enclosing fascial layers, nerves, lymphatics, and blood vessels.

The paired corpora cavernosa and the corpus spongiosum are covered by a dense fibrous sheath of connective tissue called tunica albuginea. The space of the corpora cavernosa contains arteries, nerves, muscle fibers, and venous sinuses lined with flat endothelial cells; an areola tissue separates the corpora cavernosa from the tunica albuginea.

The penile skin encloses the three corpora and folds on itself to form the foreskin overlying the glans and corona. There is an abundant smooth muscle of the penis and scrotum, called the dartos fascia fusing with the superficial perineal (Colle) fascia. The Dartos fascia is attached to the deep penile (Buck) fascia and loosely attached to the skin in the penis containing superficial arteries, veins, and nerves of the penis.

The skin of the penis is supplied by external pudendal arteries which arise from the femoral artery, and deep structures are supplied by internal pudendal artery. The superficial, intermediate, and deep veins drain the penis. The penis is supplied by pudendal and cavernous nerves.

 Physiology of Normal Erection



Normal erection is largely driven by nitric oxide (NO/cyclic guanosine monophosphate [cGMP]) pathway. RIP has been described to be induced by dysregulation of NO/cGMP signaling pathway.[8]

Also involved mechanisms in normal erection are the cyclic adenosine monophosphate (cAMP) pathway and vascular/neurogenic pathway regulated by NO synthase (NOS) enzyme, the mediator of NO synthesis. NOS are of three types, nerve NOS (nNOS), endothelium NOS (eNOS), and iNOS (nonspecific – all cells). The three types of NOS and L-arginine in the presence of oxygen catalyze formation of NO.[9],[10]

NO generated majorly from nNOS and partly from eNOS stimulates guanylate cyclase which catalyzes guanosine triphosphate to cGMP, the latter stimulates the production of protein kinase G, opening potassium channels, and closing calcium channels. The effects of cGMP relax smooth muscles of the penis causing tumescence (erection).

Phosphodiesterase-5 (PDE5) degrades the 3'5' bonds of cGMP to its inactive 5'GMP; this induces detumescence.[11] PDE5 is targeted by sildenafil, vardenafil, and tadalafil which have estrogenic properties. PDE 2, 3, and 4 (PDE2, PDE3, and PDE4) mediate the cAMP pathway which is targeted by papaverine.

 Priapism in Sickle-Cell Disease



Stasis and low blood flow rates within the sinusoids of the corpora cavernosa predispose the penis to veno-occlusive crises, thus obstructing its venous drainage, resulting in viscous and hypoxic blood. Normal neuronal production and surges in cGMP causes nocturnal erections, insufficient basal level of PDE5 which degrades the 3'5' bonds of cGMP to its inactive 5'GMP is responsible for uninhibited cGMP, and this causes recurrent ischaemic priapism in sickle cell disease.

Pathophysiology of priapism in SCD is associated with a reduction in bioavailability of endothelium-derived NO.[12] A reduction in NO is consequent on hemoglobinemia associated with chronic hemolysis in SCD; hemoglobin is an avid scavenger of intravascular NO. Second, arginase, a byproduct of hemolysis, degrades L-arginine in the vasculature, thus causing a reduction in L-Citrulline. Third, the function and formation of endothelium-derived NO is impaired by excess reactive oxygen species (ROS) and their mediators produced from chronic hemolysis.[13],[14]

Ischemic priapism induced-vascular endothelium damage causes loss of eNOS which also contributes to a significant reduction in NO bioavailability.[15]

Posttranslational modification of eNOS at Ser-1177 site has been reported to cause functional impairment and subsequent reduction in the level of NO.[16]

In SCD, chronic reduction in activation of eNOS causes decreased production and function of NO, thus downregulation of PDE5.[17]

Following stimulation either neurologically or erectogenically in sexual activity or sleep, cavernosal relaxation is induced by accumulation of cGMP; however, normal detumescence mechanism is impaired because of reduced basal levels of PDE5 due to reduced level of eNOS in SCD.

Pentapeptides such as opiorphins have also been implicated in the pathogenesis of priapism in SCD; they mediate cavernosal smooth muscle function causing excessive relaxation and engorgement of corpora cavernosa associated with priapism.[18] Opiorphin homolog genes are expressed significantly in the prostrate and penile smooth muscle.[19]

In animal models, there is an improved erectile function in aged rats at lower doses and priapic-like condition at higher doses following experimental gene transfer of opiorphin homologs.[20],[21],[22]

In SCD, there is a loss of maintenance of ROS such as superoxide, hydrogen peroxide, hydroxyl radicals, and reactive nitrosative species (RNS) such as peroxynitrite and s-nitrosothiols by antioxidant enzymes and scavengers of oxygen radicals such as superoxide dismutase and glutathione peroxidase that under normal physiologic conditions maintain them.[23]

The loss is due to increased sources of oxidative stress and activation of protein degradation pathways in the corporal tissues of animal models of priapism as confirmed by increased levels of NADPH oxidase subunits.[24],[25] The implication of the loss of maintenance of both ROS and RNS in association with penile reperfusion injury occurring during the period of ischemia relief following priapism episodes contributes to cavernosal tissue damage associated with priapism.[26]

Superoxide decreases NO bioavailability by degrading NO to peroxynitrite, thus distorting NO/cGMP pathway and promoting priapism. Heme and globin are products of hemoglobin degradation. Heme oxygenase (HO) degrades heme to biliverdin, iron, and carbon monoxide.[27],[28] HO exists as three isoforms HO1, HO2, and HO3; HO1 reacts to a variety of stress mediators such as heat and NO donors, it is upregulated in cavernosal tissues of artificially-induced, animal priapic models.[27] It is thought to have antioxidant properties as it is upregulated in vascular smooth muscle, endothelial cells, and cardiac tissue in hypoxia.[29] The antioxidant protective mechanism during hypoxia is facilitated by interactions between HO and NO/cGMP pathways.[30] It is not clear whether the up-regulation of HO-1 in response to tissue hypoxia is an alternative induction mechanism of priapism.[30]

 RHO/RHO Kinase



Rho A/Rho-kinase (ROCK) signal transduction pathway is responsible for maintaining the penis in a flaccid state.[31],[32] There is a dysregulation of Rho signaling with reduced Rho A expression in human SCD penis.[33] Reduced Rho A/Rock signaling causes reduced vasoconstriction in the penis in SCD, thus enhancing altered vasodilatory effects of the penis contributing to priapism.[19]

 Diagnosing Ischemic Priapism



Diagnosis is self-evident, history of time of onset is important to determine whether the duration of priapism is below 4 h or more, priapism shorter than 4 h may not be considered for medical therapy and priapism longer than 4 h should be attended to emergently. Previous history of priapism highlights recurrent priapism which is a recurrent form of ischemic priapism associated with painful erections occurring repeatedly with intervening period of detumescence. Drug history is important because some drugs induce priapism; they are antihypertensives, anticoagulants, alcohol, marijuana, cocaine, papaverine, phentolamine, and prostaglandin E.

Physical examination includes examination of the genitalia, perineum and abdomen for any evidence of trauma, although non-ischaemic priapism is usually secondary to trauma, it is important to examine these areas even when ischaemic priapism is being considered. The physical inspection should include the phallus to determine the extent of tumescence. In priapism generally, corpora cavernosa are affected, and the spongiosum and glans penis are spared. The penis is completely rigid in ischemic priapism unlike in nonischemic priapism.

Laboratory investigations include a full blood count and peripheral smear; these give an insight into the diagnosis of SCD; priapism secondary to myeloproliferative or lymphoproliferative disorders are elucidated if the total white blood cell count is markedly elevated. Reticulocyte count is elevated in SCD. Hemoglobin electrophoresis and quantification determine the type of hemoglobinopathy; penile blood gas measurement is required to confirm ischemic priapism in which blood sample aspirated from corpora cavernosa is usually hypoxic, hyperbaric, and acidotic; PO2 2 in ischemic priapism should be >60 mmHg, normal arterial should be <40 mmHg, and the normal mixed venous blood should be 50 mmHg; the pH will be <7.25, normal arterial should be 7.40, and the normal mixed venous blood should be 7.35 [Table 1].{Table 1}

Penile color duplex ultrasound is noninvasive and confirms little or no blood flow in the cavernosal arteries in ischemic priapism. Lithotomy or frog-leg positions are the recommended positions for performing color duplex ultrasound. Penile arteriography is a substitute for duplex ultrasound; it is, however, invasive, not recommended but may be performed as part of embolization procedure.

Urine toxicology is useful for screening psychoactive drugs intake which could induce priapism in SCD.

 Treatment of Priapism in Sickle-Cell Disease



Treatment could be medical or surgical. The goal of treatment is to intervene as early as possible to prevent subsequent episode and reduce the significant risk of ED.

 Medical Management



A stepwise treatment plan should start with intracavernosal injections of phenylephrine dosed 100–200 μg every 5 min until detumescence but not exceeding 1000 μg/h which vasoconstrict corporal cavernosal smooth muscle causing detumescence.[34]

Phenylephrine has minimal beta-adrenergic stimulatory effects unlike other sympathomimetics which have cardiac inotropic and chronotropic side effects.

An intracavernosal injection of phenylephrine is followed by aspiration and irrigation with saline, followed by irrigation with phenylephrine. A local penile shaft block which may be a circumferential penile block, a subcutaneous local penile shaft block, a dorsal nerve block, or oral conscious sedation for pediatric patients is recommended before intracavernosal injections of phenylephrine, aspiration, and irrigation which provides local pain control.[35] Other oral adrenergic agents used are terbutaline,[36] pseudoephedrine, and epheredin.[4] The priapism in sickle cell study could not establish advantage of oral adrenergic agents such as ephedrine and etilefrine over placebo in the prevention of priapism.[37]

PDE5 inhibitors use was found to reduce priapism and restore PDE5 gene activity.[38] The use of PDE5 inhibitors in acute cases of priapism has been reported;[39] however, improvement in symptoms may not be due to short-term changes in PDE5 levels and may potentially worsen priapic events.[40]

The use of PDE5 inhibitors is paradoxical to it eretogenic properties, the mechanism of action is to re-establish basal levels of cGMP in the penis, thus reseting PDE 5 levels expression and activity.[40] Burnett et al. conducted a controlled clinical trial to determine safety and efficacy of sildenafil for priapism prevention;[41] they concluded that the use of sildenafil by systemic dosing may offer strategy to prevent RIP in patients with SCD. They could not establish any significant adverse effects on the use.

Hydroxyurea use seems to be beneficial in RIP prevention.[42],[43] Anele et al. reported on the advantage of hydroxyurea use in the prevention of RIP.[44] The mechanism of action may be due to the fact that hydroxyurea is an NO donor because it reacts with hemoglobin to form NO, thus correcting the reduced bioavailability of NO associated with RIP.[45],[46]

Induction of fetal hemoglobin and reduction of hemolysis also correct NO bioavailability of severe hemolysis.[47] Hydroxyurea is also useful in reversing ED because it downregulates endothelin-1, a pro-fibrotic molecule, with a likely role in the corporal fibrosis associated with priapism.[48],[49]

Nocturnal oxygen desaturation has been reported to contribute to the pathogenesis of priapism;[50] therefore, prophylactic nocturnal oxygen or use of continuous positive airway has been advocated.

Treatment with hormonal therapy such as stilbestrol and GnRH analogs were proposed by Chow and Payne [51] and Serjeant et al.[52] because they downregulate pituitary gland function. Similarly, antiandrogenic agent like ketoconazole was suggested [53] because it reduces serum testosterone. However, side effects of hormonal therapy such as infertility, gynecomatsia, delayed growth/development due to premature epiphyseal plate closure, and reduced libido pose significant disadvantages; they are therefore contraindicated in boys in reproductive age groups and men wishing to conceive.

The advantages of the use of red cell exchange or simple transfusions in preventing or treating acute priapism have not been well substantiated, rather neurologic complications such as convulsions, hemiparesis, and cerebral hemorrhages associated with the procedure have been reported.[54]

Newer agent like pentoxyfylline reduces fibrosis and TGF-β mediated deposition of collagen in the tunica albuginea [55] it facilitates recovery of erections in a rat model of erectile dysfunction post prostatectomy [56] it also reduces collagen density in an ischaemic induced priapism rat model.

 Surgical Management



Surgical management is indicated if priapism duration is >72 h and in failed medical treatment. It should be considered a second-line management because of higher risk of ED. The objective of surgical management is to establish anastomosis between corpora cavernosa and glans, corpos spongiosum or vein for drainage in order to reduce congestion in the corpora carvernosa. This is done by opening up the tunica albuginea.

There are four types of surgical shunts, i.e. the distal (corporaglanular shunt), proximal (corpora spongiosal shunt), Burnett's technique, and vein anastomosis/shunts (Grayhack's Procedure). The distal shunt consists of creating an open bilateral excision of circular cone segments of distal tunica albuginea through the glans penis, along with a subsequent glans closure by means of a running suture with absorbable material. This is the Al-Ghorab's prodecure [57] while the proximal shunt is done by creating a communication between corpora cavernosum and the corpus spongiosum through a trans-scrotal or perineal approach; this is the Quackle's technique.[58] Burnett's technique is a modification of Al-Ghorab shunt involving a retrograde insertion of a 7/8 Hegar dilator into the distal end of each corpus cavernosum through the original Al-Ghorab glanular excision.[59] The vein anastomosis/shunts also known as Grayhack's procedure, in which there is mobilization of the saphenous vein below the junction of the femoral vein and anastomosing the vein end-to side onto the corpos cavernosum.[60]

 Conclusion



If priapism is presented after >36 h of onset or if there is failure of both medical and surgical interventions, ED becomes inevitable and penile prosthesis implantation should be considered as early as possible because severe corporal fibrosis makes penile implantation difficult at a later date.[61]

Acknowledgment

The authors thank Miss Oluwatosin Soetan for editorial assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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