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Phentolamine re-dosing during penile dynamic colour Doppler ultrasound: a practical method to abolish a false diagnosis of venous leakage in patients with erectile dysfunction

Departments of ¹ Urology and ² Radiology, King's College Hospital, Denmark Hill, London SE5 9RS and ³ Institute of Psychiatry and Biostatistics, Guy's, King's and St. Thomas' School of Medicine, King's Denmark Hill Campus, King's College Hospital, London SE5 9RS, UK

Correspondence: Dr Paul S Sidhu, Department of Radiology, King's College Hospital, Denmark Hill, London SE5 9RS, UK

	Abstract

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Increased sympathetic tone may cause an equivocal response to a prostaglandin E1 (PGE1) penile Doppler ultrasound (US) examination interpreted as a venous leak. We evaluated the US parameters and erectile response to the addition of phentolamine to a PGE1 penile Doppler US examination to ascertain whether addition of phentolamine would abolish a suboptimal response. 32 patients (median age 29 years, range 17–70 years) with either a previous Doppler US pattern of venous leakage or a clinical suspicion of venogenic impotence, underwent Doppler US after a total dose of 20 µg of PGE1. Peak systolic velocity (PSV), end diastolic velocity (EDV) and grade of erection were documented. If erectile response was suboptimal irrespective of the EDV measurement, 2 mg-intracavernosal phentolamine was administered and measurements repeated. Six patients had a normal erectile response, the remaining 26 received phentolamine. A significant increase in PSV between baseline and 20 µg PGE1 (p<0.001) was observed in all cases. Following phentolamine there was a significant increase in grade of erection (p=0.0001) and a significant reduction in the EDV (p=0.0001). A reduction of the EDV to below 0.0 cm s^–1 was observed in 16 patients. Four patients with EDV <5.0 cm s^–1 but >0.0 cm s^–1 had improved erectile response following phentolamine while six showed persistent EDV elevation >5 cm s^–1. No priapism was documented. It is essential to ensure cavernosal relaxation using phentolamine before a Doppler US diagnosis of venous leak is made. This two-stage assessment will allow this to be done efficiently and with a low risk of priapism.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
The prerequisite for normal erectile function is good arterial inflow for adequate volume expansion of the cavernosal sinusoids, sufficient to cause restriction of venous outflow and retention of the penile blood flow [1]. This veno-occlusive mechanism requires sufficient cavernosal smooth muscle relaxation and adequate function of the tunica albuginea. In the flaccid penis, cavernosal smooth muscle is contracted by tonic alpha-adrenergic tone. During tumescence relaxation of smooth muscle produces dilatation of the artery and filling of the sinusoidal spaces, with compression of subalbugineal vessels against the tunica albuginea reducing venous outflow and increasing intracavernous pressure [2]. Impairment of these mechanisms leads to leakage of blood through open venous channels causing loss of rigidity [3, 4]. Inadequate relaxation of smooth muscle is thought to be the most common cause of primary venous leakage, particularly in young men [5].

The reference standard for diagnosis of venous impotence remains dynamic cavernosography with cavernosometry, a procedure that is invasive, involves ionizing radiation and use of iodinated contrast media [6]. Doppler ultrasound (US), performed following intracavernosal administration of prostaglandin E1 (PGE1) to induce an erection, is less invasive and reliably documents venous leakage in the presence of maximal corporeal smooth muscle relaxation [7, 8]. However, Doppler US assessment may lead to an erroneous interpretation of venous leakage when there is a suboptimal response to PGE1 injection due to anxiety related elevated adrenergic tone [9, 10]. Although anecdotal evidence suggests many clinics use "Trimix" for Doppler US assessment, there is no reference standard and PGE1 alone is widely used.

Phentolamine, a selective alpha-adrenoreceptor antagonist, when injected into the penis, is believed to block the tonic sympathetic neuronal activity producing smooth muscle relaxation. Phentolamine mesylate, although not yet available for clinical use, has some activity when given orally [11]. Phentolamine in combination with other agents such as PGE1 and vasoactive intestinal peptide is used with success in the treatment of impotence [12, 13]. In a randomized study on 24 young patients a mixture of 20 µg PGE1 and phentolamine 0.5 mg was found to significantly improve the "valid for intromission" erection rate over a control group injected with 20 µg PGE1 alone [14]. In the same study a strong inverse correlation between the anxiety score (assessed by a questionnaire) and the achievement of a "valid for intromission" pharmacological erection was observed for the PGE1 arm but not for the mixture arm.

The present study was undertaken to assess the objective erectile response and the colour Doppler US parameter changes after sequential intracavernous administration of PGE1 and phentolamine in a group of impotent patients with a clinical history or a previous colour Doppler US suggestive of venous leakage.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients
32 consecutive patients of varying ages with a prolonged history (>2 years) of inability to attain or maintain a satisfactory erection were recruited. Strict inclusion criteria were one or both of the following: 1) a previous colour Doppler US pattern of venogenic impotence; 2) a clinical suspicion of venous leakage based on the absence of any vasculogenic risk factor in patients who had failed to achieve good rigidity following intracavernous 10 µg PGE1 or oral Sildenafil. 15 patients had been identified as venous leak impotence on a previous PGE1 (20 µg) Doppler US, performed within 6 months, defined on spectral Doppler by an end diastolic velocity (EDV) >5 cm s^–1 in the presence of a maximum peak systolic velocity (PSV) >35 cm s^–1. 17 patients had a high clinical suspicion of venous leakage according to the above criteria. All patients underwent physical examination of the external genitalia; evaluation of bulbocavernous reflex, perineal and abdominal sensation were normal.

Artificial erection was categorized into four grades by two observers (PG, SIS), using the following criteria [15]; Grade I: partial tumescence; Grade II: full tumescence with inability to penetrate; Grade III: incomplete rigidity adequate for penetration, but not maximal; Grade IV: full rigidity.

All patients gave informed consent to undergo a Doppler US examination with intracavernosal administration of a single dose of 20 µg PGE1 followed by 2 mg of phentolamine. The presence of full rigidity (defined as erection grade IV) and flow reversal in diastole (EDV <0.0 cm s^–1) was accepted as an unequivocal response to PGE1. Phentolamine was administered in any patient where there was an incomplete erectile response to PGE1 (defined as an erection grade III), including patients where the EDV was <5.0 cm s^–1 but >0.0 cm s^–1. An EDV measurement of <5.0 cm s^–1 is generally accepted as excluding venogenic impotence, but in the current study full rigidity, the clinical requirement of the patients, was the end-point [7, 9]. Only patients with full rigidity and flow reversal in diastole (EDV <0.0 cm s^–1) did not proceed to receive phentolamine.

Doppler ultrasound
Doppler US examinations were performed with either an Acuson 128XP/10 (Acuson; Mountain View, CA) using a 7–10 MHz extended frequency linear probe or an Acuson Seqouia 512 using a 8–13 MHz extended frequency linear probe, both machines giving comparable spectral Doppler US assessment.

All patients underwent the same US examination protocol. A grey-scale US examination of the penis was performed to identify any fibrosis or calcification. The right cavernosal artery was imaged on colour Doppler US, in a longitudinal direction, and a "gate" (width 2 mm) placed over the proximal artery to record a spectral Doppler waveform. The baseline PSV was recorded by measuring the highest angle-corrected velocity (<60°) using the internal callipers of the machine and the software measurement package provided by the manufacturers.

The following measurements were obtained at 5 min, 10 min and 15 min following the intracavernosal injection of 20 µg PGE1; 1) PSV in cm s^–1, defined as the highest velocity measured on the spectral Doppler waveform. 2) EDV in cm s^–1 defined as the lowest velocity on the spectral Doppler waveform. The EDV could be below the baseline demonstrating flow reversal. 3) Grade of erection estimated 15 min after the PGE1 injection. Care was taken to obtain measurements at the same point along the right cavernosal artery at the base of the penis. The same two experienced radiologists (PSS, CJW) performed all the Doppler US investigations including those that preceded the enrolment.

Patients with an erection grade III, even in the presence of an EDV <5 cm s^–1 proceeded to intracavernosal administration of 2 mg phentolamine. Blood pressure was measured prior to and 15 min after phentolamine administration. Repeat measurements were recorded at 5 min intervals and grade every 10 min for 30 min.

Statistical methods
Analysis of variance with repeated measures for PSV was used to assess the longitudinal change over time from baseline to 10 min, 15 min and 20 min, and over the increasing doses of PGE1 and phentolamine. For the other measures (EDV and grade) the longitudinal change over time was only evaluated between baseline and 15 min for which we had complete data.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
The median age of the patients was 29 years (range 17–70 years). Following 20 µg PGE1, six out of 32 patients with grade IV erection and EDV either dropping to 0.0 cm s^–1 (n=4) or demonstrating flow reversal (n=2), did not receive phentolamine and were excluded from the final analysis. 13 patients had an EDV of <5 cm s^–1 but >0.0 cm s^–1 (the lowest of all recorded EDV measurements), and the remaining 13 patients had an EDV >5 cm s^–1, all with an erection grade III. All these 26 patients received intracavernosal phentolamine.

Significant increases were observed in PSV between baseline and 20 µg PGE1 (p=0.02). In the 26 patients who received phentolamine there was a slight but non-significant further elevation in the mean PSV compared with the value obtained after 20 µg PGE1 (p=0.09). Table 1 presents the pair-wise comparisons between PGE1 20 µg and phentolamine 2 mg for each of the three outcome variables of PSV, EDV and erection grade. Grade was significantly increased with the addition of 2 mg phentolamine (p=0.0001). The median increase in grade was of 1 category when comparing phentolamine (p=0.0001) with PGE1 alone. A significant reduction in EDV was obtained with the addition of 2 mg phentolamine (p=0.001), indicating that phentolamine reverses the apparent venous leak. In four of the 26 patients the EDV dropped to <5 cm s^–1 and in 16 there was flow reversal (Figure 1). All these 20 patients achieved a grade IV erection. In six out of 26 patients the EDV did not fall below 5 cm s^–1 and the rigidity was suboptimal (grade III) despite the use of phentolamine (Figure 2).

View larger version (35K): [in this window] [in a new window]   Figure 1. (a) Following an intracavernosal injection of prostaglandin E1, at 15 min the peak systolic velocity of the right cavernosal artery measures 55.4 cm s–1 and the end diastolic velocity remains above the baseline, measuring 2.4 cm s–1. The degree of tumescence is suboptimal. (b) Following intracavernosal phentolamine (2 mg), the peak systolic velocity increases to 75.7 cm s–1, but the end diastolic velocity demonstrates flow reversal (measured at –5.4 cm s–1). This corresponds to a good degree of tumescence suggesting that the apparent leak in this patient was not structurally based but could be functional.

View larger version (45K): [in this window] [in a new window]   Figure 2. (a) Spectral Doppler ultrasound, at 15 min following 20 µg prostaglandin E1, demonstrates an excellent arterial response (peak systolic velocity=77.1 cm s–1) but a high forward diastolic flow of 16.7 cm s–1, suggesting the presence of a venous leak. (b) Following the administration of 2 mg intracavernosal phentolamine, there is no change of the spectral Doppler ultrasound waveform, with a slight rise in the peak systolic velocity to 89.4 cm s–1. There is little change in the end diastolic velocity (17.5 cm s–1), suggesting the presence of a "true" venous leak.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
In patients with corporovenous occlusive dysfunction, ultrastructural studies have demonstrated a reduced percentage of smooth muscle fibre as a result of exposure to toxic risk factors (hypercholesterolaemia, smoking) or chronic ischaemic processes [2]. However, it has been hypothesised that anxiety-mediated raised sympathetic tone may maintain the corporeal smooth muscle in a state of contraction, resulting in cavernovenous incompetence from a psychogenic rather than an organic mechanism [5]. Failure to respond to intracavernous PGE1 or oral Sildenafil does not necessarily indicate the presence of an organic problem as anxiety, or the embarrassment of an erection, either during sexual intercourse or during the course of a Doppler US examination may block the effect of pharmacological stimulation.

Doppler US is recognised as a reliable investigation to assess penile arterial integrity, although some authors report a lower sensitivity of Doppler US over cavernosometry in the assessment of venogenic impotence [9, 16]. In the current study, following 20 µg PGE1, a small number of patients responded with a normal Doppler US pattern and developed full rigidity. In the majority (n=26) an equivocal pattern of venous leakage emerged; a suboptimal erection, PSV >35 cm s^–1 limit (which defines cavernous arterial integrity) and an EDV >0.0 cm s^–1. An EDV >5 cm s^–1 is thought to indicate significant venous leakage, although in the presence of an incomplete erectile response, uncertainty exists when the EDV remains elevated above 0.0 cm s^–1 [17, 18]. Interpretation may lead to a possible diagnosis of venogenic impotence, leading to further and more invasive investigations. A completely normal unequivocal response would be full rigidity (grade IV) and an EDV <0.0 cm s^–1 (reversal of flow in diastole). With the addition of intracavernous phentolamine 20 out of 26 patients (76%) achieved a fully rigid erection. In four of these patients the EDV dropped below 5 cm s^–1 while a complete flow reversal was observed in the remaining 16. These findings are highly suggestive that the majority of our patients had a "non-anatomical" corporovenous occlusive dysfunction.

Following the addition of phentolamine a slight (although not significant) increase in the PSV was evidenced compared with 20 µg PGE1. This effect may be explained by the blockade of sympathetic neuronal tone that phentolamine exerts on the arteriolar smooth muscle [12, 14, 19].

In order to promote maximal smooth muscle relaxation during vascular testing, other additional regimens of vasoactive medications have been proposed. In a study employing two additional, repeated doses of a mixture of papaverine and phentolamine during dynamic infusion cavernosometry, of the 70% of patients requiring additional doses, a 32% false diagnosis of venogenic erectile dysfunction was corrected following the additional vasoactive drug dose [20]. However, all patients were initially given phentolamine, whereas in the present Doppler US study a false diagnosis of cavernovenous occlusive dysfunction was detected in 20 out of 26 patients who were then re-injected with phentolamine with good results. A further similar study examined a group of unselected impotent patients, who were re-dosed with a mixture of PGE1 and phentolamine [21]. There was a 35% (statistically significant) improvement in colour Doppler US parameters in the group receiving both PGE1 and phentolamine compared with a 15% observed in the control group of patients re-dosed with PGE1 alone. The percentage of "false positive" diagnosis of venous leakage unmasked by phentolamine re-dosing was particularly high in our study (76%). The selection of a relatively young subgroup of impotent patients (median age 29 years) as a result of our inclusion criteria, is likely to have been a major contributing factor. Young patients are deemed to be more prone to intracavernosal PGE1 response failure due to a high adrenergic tone [14].

Other authors advocate audio-visual sexual stimulation combined with genital self-stimulation to augment the vasoactive erectile response during Doppler ultrasound. A significant decrease of the EDV after serial administration of intracavernous drugs combined with genital plus audio-visual sexual stimulation has been reported [22]. A false diagnosis of venous leakage was found in four out of 17 patients. Despite the fact that an improvement of erectile response using the audio-visual sexual stimulation has been demonstrated, we consider this method unlikely to be as successful in eliminating the anxiety-related low response rate to PGE1, although we have no data to support this hypothesis.

One concern with administering multiple vasoactive agents is that it may increase the risk of post-investigation priapism: in our experience with 230 studies using both the PGE1 and a combination of PGE1 with phentolamine, a single patient developed priapism (0.4%) with PGE1 alone. It is possible that the sequential administration of the drugs instead of injecting a mixture of PGE1 and phentolamine as a "one shot" may account for this low risk of priapism [14, 21]. Additionally, widespread routine use of phentolamine re-dosing raises concerns about the potential cardiovascular risk in the presence of pre-existing risk factors. We did not observe significant changes in blood pressure or documented side effects in our sample, although widely used phentolamine remains unlicensed for intracavernous administration.

In conclusion our results seem to indicate that the addition of intracavernous phentolamine during PGE1 stimulation Doppler US examination is safe and can provide useful further information in a significant number of impotent patients when appropriately selected. We advocate the use of a re-dosing protocol with phentolamine any time a dynamic Doppler US study with a full PGE1 dose shows a pattern consistent with venous leakage. The application of this protocol in our practice has enabled a consistent reduction in the number of Doppler US diagnoses of venous leakage erectile dysfunction.

	Footnotes

 
Current address for Dr Paolo Gontero, Reader in Urology, Dipartimento di Scienze Mediche Universita’ del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy.

Received for publication October 13, 2003. Revision received April 30, 2004. Accepted for publication June 29, 2004.

	References

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