H#{149}. Color Doppler Sonography in the Evaluation of Erectile Dysfunction: Patterns of Temporal Response to Papaverine

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1 x/9i/ C American Roentgen Ray Society Steven W. Fitzgeral& Scott J. Erickson2 w. Dennis Foley2 Elliot 0. Lipchik2 Thomas L. Lawson2 Received September 21, 1990; accepted after revision March 20, Presented at the annual meeting of the American Roentgen Ray Society, Washington, DC, May Department of Radiology, Northwestem Memortal Hospital, 7i0 N. Fairbanks Ave., Chicago, IL Address reprint requests to S. W. Fitzgeraid. 2 Department of Radiology, Medical College of Wisconsin, 8700 W. Wisconsin Ave., Milwaukee, WI Color Doppler Sonography in the Evaluation of Erectile Dysfunction: Patterns of Temporal Response to Papaverine H#{149}. Most studies of duplex Doppler sonography for the assessment of erectile dysfunction involve determination of peak systolic velocities 5 mm after intracavemosal injection of papaverine. The purpose of this study was to determine the effect of the timing of Doppler measurements of flow after papaverine injection for establishing the presence of arterial and venous abnormalities. Color Doppler sonography was performed in 75 patients for evaluation of vasculogenic impotence. After intracavemosal injection of 60 mg of papavenne, measurements of peak systolic and end-diastolic velocities were obtained in each cavemosal artery at 5-mm intervals for a total of 30 mm. A peak systolic velocity of less than 25 cm/sec was used as the threshold for arterial insufficiency. An end-diastolic velocity of greater than 5 cm/sec was used to predict venous incompetence. Scanning was performed for direct assessment of dorsal venous flow. Thirty patients were subsequently evaluated by cavemosometry and cavemosography. In most patients (76%), maximum response to papaverine was achieved within the first 5 mm. In eight patients, significant increases in systolic velocity were seen only after 5 mm. In 10 patients, significant changes in end-diastolic velocity between 5 and 30 mm resulted in diagnostic reclassification. Data acquisition for 30 mm significantly improved the sensitivity (95%) and specificity (83%) for the prediction of venous incompetence in patients with correlative cavemosography. Transient, early dorsal vein flow was noted in normal subjects. Persistent dorsal vein flow had an 80% sensitivity and 100% specificity for venous incompetence. Our results suggest that, when using color Doppler sonography, gathering data for 30 mm may improve the prediction of vasculogenic impotence. AJR 157: , August 1991 Duplex Doppler and colon Doppler sonography have been shown to be useful in the evaluation of patients with erectile dysfunction. Specific diagnostic criteria have been reported for the assessment of arterial insufficiency [1-5J and venous incompetence [4, 5]. A study in normal volunteers has demonstrated that papaverineinduced erection is a complex multiphasic event that can be characterized by color Doppler sonography [6]. However, the time course of these events in normal subjects and in impotent men has not been well established. Most Doppler studies of erectile dysfunction are based on data acquisition from the cavernosal arteries within the first 3-5 mm after papavenine injection [1-4]. Some authors emphasize the need for data acquisition in the first 5 mm to avoid inaccuracies [1, 2, 7]. Although we believe that scanning should commence immediately after papaverine injection, we have noted that dynamic changes may occur in cavernosal artery flow and dorsal vein flow for up to mm after papaverine injection. These temporal changes may be useful in the evaluation of patients with erectile dysfunction. The purpose of this study was to evaluate the temporal response to intracorporeal papaverine in men with suspected vasculogenic impotence and to assess the impact of the temporal response pattern on the diagnostic accuracy of color Doppler sonography.

2 332 FITZGERALD ET AL. AJR:157, August 1991 Materials and Methods Seventy-five men years old referred consecutively from the urology clinic for the evaluation of suspected vasculogenic impotence were examined from November i 988 until January i 990. All examinations were performed with a 7.5-MHz transducer with a standoff wedge (QAD-i E, Quantum Medical Systems, Issaquah, WA). The transducer was placed over the dorsum of the penis with initial scanning performed in longitudinal and transverse planes before papaverine injection. A divided dose of 60 mg of papavenine hydrochloride was injected with a 25-gauge needle, with 30 mg injected into each corpus cavernosum near the penile base. Scanning was resumed approximately 2 mm after papaverine injection, and each of the corpora was evaluated within each 5-mm interval for a total of 30 mm. Real-time color flow segments and angle-corrected spectral traces were recorded on digital videotape for review. Peak systolic and end-diastolic velocities were determined for both cavernosal arteries within each 5-mm interval. All velocity measurements were obtained at the proximal penile shaft near the base. Doppler angles ranged from 45#{176} to 65#{176}. These velocities were recorded separately without averaging. Variations in flow velocity between the left and right cavernosal arteries of greater than i 0 cm/sec were noted. The greater peak systolic velocity was used for classification. Velocities were corrected retrospectively from review of the digital videotape. Scanning was routinely performed dorsally. In patients progressing to more complete erection, ventral scanning was occasionally necessary. Scanning of the midline dorsum of the penis was also performed during most of the 5-mm intervals. Dorsal vein flow was sought by visual inspection and confirmed by spectral analysis. Care was taken to avoid compression of the relatively superficial dorsal veins during scanning. Visual inspection of papavenine response and penile tumescence was recorded. After completion of the examination, patients were released after brief observation with instructions regarding possible complications. One patient returned with priapism requiring decompression. No other complications were observed. Diagnostic criteria for determination of arterial and venous insufficiency were based on the published literature. A peak systolic velocity greater than 25 cm/sec was considered the threshold for a normal arterial supply [i, 4]. An end-diastolic velocity of 5 cm/sec or higher was used as an indicator of venous incompetence [4]. The presence of persistent dorsal vein flow was also used as an indicator of venous incompetence [2]. Dorsal vein flow that was detected beyond the initial 5 mm and for at least i 0 mm was defined as persistent. For the purpose of this study, a delayed response was defined as any 5-cm/ sec change in either peak systolic or end-diastolic velocity that occurred after the initial 5-mm interval within the same cavernosal artery. The only exception to this definition was a decline in cavernosal artery velocities associated with loss of papaverine response and return to the flaccid state. Patients were grouped by patterns of temporal response to papaverine injection as follows: no change in either peak systolic velocity or end-diastolic velocity occurring beyond 5 mm or steady decline (group 1); delayed increase in peak systolic velocity to more than 25 cm/sec, stable end-diastolic velocity (group 2); stable or delayed increase in peak systolic velocity to greater than 25 cm/sec and delayed decrease in end-diastolic velocity (group 3); delayed increase in peak systolic velocity to greater than 25 cm/sec and delayed increase in the end-diastolic velocity to 5 cm/sec or higher (group 4); and stable or declining peak systolic velocity and delayed increase in end-diastolic velocity to 5 cm/sec or higher (group 5). Correlative cavernosometry and cavernosography were subsequently performed in 30 patients. These studies were performed and interpreted according to techniques previously described [8, 9]. Cayernosometric criteria for venous incompetence include at least three of the following: a saline infusion rate of greater than i20 mi/mm, maintenance infusion rate of greater than 60 mi/mm, intracavernosal pressures less than 1 00 mm Hg, intracavernosal pressure drop of greater than 2 mm Hg/sec after termination of saline infusion, and contrast leakage into the venous system. Results Temporal Response by Group Overall, 57 (76%) of our 75 patients had no significant change in either peak systolic or end-diastolic velocity beyond the first 5-mm interval (group 1, Fig. 1). Of these patients, four met our criteria for normal arterial and venous integrity. Thirty-three men had peak systolic velocities less than 25 cm/ sec and were thought to have arterial insufficiency. The remaining 20 had systolic velocities greater than 25 cm/sec but also had persistently elevated diastolic velocities consistent with venous incompetence. Eight men (1 1 %) had a significant rise in systolic velocity after the initial 5 mm (group 2) that resulted in a change in their diagnostic classification (Fig. 2). Diastolic flow was stable in these patients. Two of the eight had normal diastolic velocities, whereas the other six had elevated diastolic flow. Seven patients (9%) had significant changes in systolic and/or diastolic velocities (group 3) beyond 5 mm and were reclassified as normal. Five of the seven in group 3 had a delayed rise in systolic velocity above 25 cm/sec that was associated with a dramatic drop in diastolic flow (Fig. 3). The other two patients had stable systolic velocities but also manifested diastolic flow loss and reversal. Three patients (4%) had a delayed rise in systolic and diastolic velocities (group 4) that resulted in their reclassification as having venous incompetency (Fig. 4). None of the patients in our series had a significant rise in diastolic velocity with stable systolic velocities (group 5). Peak Systolic Velocity Although maximum peak systolic velocity was reached within the first 5 mm in most of the 75 patients, 1 8 patients (groups 2-4) achieved maximum systolic velocity in the 6- to 25-mm time range. Thirteen of these 1 8 patients had velocities exceeding 25 cm/sec only after 5 mm. The range of systolic velocities was 6-72 cm/sec, and the mean time to maximum peak systolic velocity was 4.8 mm. The temporal distribution of peak systolic velocities is shown in Figure 5. Forty-two patients had a peak systolic velocity greater than 25 cm/sec. The remaining 33 did not exceed the threshold of 25 cm/sec. No significant variation in either systolic or diastolic velocity was noted in the latter group of patients. Thus, all of the patients meeting our criteria for arterial insufficiency were in group 1. Significant asymmetry of systolic velocities between the left and right cavernosal arteries was found in five of these patients; however, no temporal variation was seen in this group (group 1).

3 AJR:157, August 1991 COLOR DOPPLER IN ERECTILE DYSFUNCTION 333 Fig. 1.-Group 1: maximum response within first 5 mm. A, Longitudinal color Doppler sonogram shows dorsal artery and cavemosal artery with angle-corrected cursor placement. B, Spectral waveform 5 mm after papaverine injection shows peak systolic velocity greater than 25 cm/sec and end-diastolic reversal. C, Spectral waveform 10 mm after papaverine injection, during rigid erection, shows slight decrease in peak systolic velocity. No further changes were seen at 15 mm. Fig. 2.-Group 2: delayed peak systolic velocity achieved after more than 5 mm. A, Spectral trace 4 mm after papaverine injection shows peak systolic velocity less than 20 cm/sec with continuous diastolic flow; end-diastolic velocity is less than 5 cm/sec. B, Spectral trace io mm after papavermne injection shows peak systolic velocity now greater than 30 cm/sec and end-diastolic velocity equal to zero. C, Spectral trace 15 mm after papaverine Injection shows peak systolic velocity stable at 30 cm/sec with end-diastolic flow reversal. Full erection Is now present clinically. Diastolic Flow Diastolic flow in the cavernosal artery manifested a wide range of velocities, with end-diastolic velocities ranging from -7 to 31 cm/sec. In 10 (1 3%) of our 75 patients, significant changes in diastolic flow were seen after the initial 5 mm. All seven of the patients in group 3 had a significant decline in diastolic velocity from greater than 5 cm/sec initially to diastolic flow loss or reversal. The three patients in group 4 had a delayed rise in end-diastolic velocity that exceeded the threshold of 5 cm/sec only after 5 mm. Dorsal Vein Flow Overall, dorsal vein flow was identified in 44 (59%) of our 75 patients during some segment of the examination. Early, transient dorsal vein flow that was no longer seen during later intervals was seen in 12 patients. In none of these patients were diastolic velocities suggestive of venous leak. Interestingly, four of the patients were found to have retrograde dorsal vein flow during subsequent rigid tumescence. Reversal of dorsal vein flow was not identified in any other patients. Persistent dorsal vein flow was identified throughout the

4 334 FITZGERALD ET AL. AJR:157, August 1991 C D Fig. 3.-Group 3: delayed decline in end-diastolic velocity and diastolic flow after 5 mm. This example shows potential for false-positive prediction of venous incompetence if early data only are acquired. A, Spectral trace 4 mm after papaverine injection shows normal peak systolic velocity and elevated end-diastolic velocity (15-20 cm/see). B, Spectral trace 10 mm after papaverine injection shows waveform progression with decreasing diastolic flow, end-diastolic velocity now is loss than threshold of 5 cm/sec. C, Spectral trace 22 mm after papaverine in- _on now shows diastolic flow reversal during full erection. D, Spot film from pharmacocavemosogram shows no evidence of venous leak. Cavemosometry was also normal. Fig. 4.-Group 4: delayed increase in peak systolic velocity accompanied by delayed increase in end-diastolic velocity. Representative example of potential false-negative diagnosis of venous incompetence if data acquisition is terminated before 10 mm. A, Spectral trace 4 mm after papaverine injection shows peak systolic velocity less than 20 cm/sec and end-diastolic velocity 3-4cm/see. B, Spectral trace 13 mm after papavermne injection shows peak systolic velocity greater than 35 cm/sec and elevated end-diastolic velocity (12-14 cm/ see). These velocities were stable at 20 and 25 mm. C, Spot film from pharmacocavemosogram shows contrast leak into periprostatic plexus.

5 AJR:157, August 1991 COLOR DOPPLER IN ERECTILE DYSFUNCTION 335 I- z w 0 cc w 0. ioo Maximum PSV (No. = 75) I Psv 25 crrvsec (No. = 42) ri:.-,_ Ml NLJTES POST-PAPAVERI NE Fig. 5.-Temporal distribution of peak systolic velocity (Psv). White bars indicate percentage of patients who achieved maximum peak systolic velocity during various time intervals. Black bars indicate only those patients who achieved a systolic velocity of greater than 25 cm/sec. study in 32 patients. All of these patients had elevated enddiastolic velocities consistent with venous incompetence. Cavernosometry and Cavernosography Thirty patients had correlative cavernosal studies. Six patients had normal pressure and contrast-enhanced studies. Two of these six were from group 1 and four were from group 3. The remaining 24 patients had abnormal pressure and abnormal contrast-enhanced studies consistent with venous incompetence. Of these patients, 17 were in group 1, five in group 2, and two in group 4. If the diastolic velocity from only the first 5-mm interval after papaverine injection was used to predict venous incompetence, an end-diastolic velocity of 5 cm/sec or higher had an 87% sensitivity and 50% specificity with an overall 80% accuracy. However, if diastolic data from the full 30-mm study were used, sensitivity increased to 95%, specificity to 83%, and accuracy to 93%. This improvement occurred because patients in groups 3 and 4 were reclassified as a result of delayed changes in diastolic flow velocity. The presence of persistent dorsal vein flow had an 80% sensitivity and 1 00% specificity for venous leak when compared with cavernosal studies. Persistent dorsal vein flow did not identify any additional venoincompetent patients who were not already identified by elevated diastolic flow velocity in the cavernosal artery. Discussion Papavenine hydrochloride works at the cavernosal level by producing smooth muscle relaxation at the level of the arterioles and sinusoids. This results in a loss of resistance to arterial inflow. The increased blood flow into the corpora cavernosa produces sinusoidal enlargement. Expansion of the sinusoids compresses the lacunar and emissary veins against the relatively rigid tunica albuginea and results in loss of venous egress from the corpora cavernosa producing erection [ ]. The effectiveness of papavenine can be influenced by facilitating agents such as phentolamine and may be modified by the psychological state of the patient. In particular, anxiety may result in a diminished response to papavenine injection [13]. Intracavernosal injection of papaverine has been used dinically as a diagnostic and therapeutic technique in impotent men. It is interesting to note the timing of the tumescent response. Vmrag et ai. [1 4] reported on the use of intracavernosal papaverine injection in 45 men. In 16 patients, including 1 0 patients with psychogenic impotence and six normally potent volunteers, the time to maximum response was 8-12 mm. This was in contrast to a group of 29 patients with organic causes of impotence, in which the time to maximum response ranged from 1 0 to 20 mm. Other authors have suggested that the normal response to intracavernosal papavenine injection may include a latency of 5-20 mm [15]. This experience suggests that the Doppler evaluation of papavenine response may require extended observation times. The use of intracavernosal papavenine injection and Doppler sonography for the investigation of erectile dysfunction was pioneered by Lue et al. [1 }. In their initial article, measurements of peak systolic velocity were obtained 1, 3, and 5 mm after papaverine injection. This decision was based on their experience with animal models in which there was a loss of systolic velocity during the rigid phase of erection. Subsequent work on the evaluation of arterial insufficiency has routinely used the acquisition of peak systolic velocities within the first 3-5 mm after papavenine injection [2-4]. These studies report a high sensitivity (95-1 0O%)for the use of peak systolic velocity measurements when compared with angiography for the documentation of arterial abnormalities. In addition, it has been suggested that delayed measurements will result in a decrease in diagnostic accuracy [2-4]. Our results in the extended evaluation of papavenine response in patients with suspected vasculogenic impotence confirm the need for early assessment of papaverine response for cavernosal artery flow. The majority of our patients did achieve their maximum peak systolic velocity within the first 2-5 mm after papavenine injection. However, 24% of our patients subsequently reached their maximum peak systolic velocity mm after papavenine injection. In fact, 13(31%) of 42 with maximum peak systolic velocities greater than 25 cm/sec went on to exceed the velocity threshold of 25 cm/ sec only 6-25 mm after papavenine injection. We believe that our data not only confirm the need for early initial assessment of cavernosal artery flow, but also argue for an extended study with repeated sampling of the cavemosal arteries for mm or until there is a plateau or decline in papaverine response. Although the observation of temporal progression did allow for improvement in the theoretical predictive value of peak systolic velocity criteria for arterial incompetence, a much greater effect was observed in the accuracy of color Doppler sonography for the diagnosis of venous incompetence. After the injection of papavenine in many patients, the marked

6 336 FITZGERALD ET AL. AJA:157, August 1991 increase in arterial inflow results in a concomitant initial increase in diastolic flow, end-diastolic flow velocity, and dorsal venous flow. In patients with an intact venocclusive mechanism, diastolic flow reversal may ensue. However, these events may require mm. The use of diastolic velocities and dorsal vein flow from the initial mm of examination may yield an elevated false-positive rate. We believe this is supported by the comparison between the report of Quam et al. [4] and our series. When we evaluated our patients for end-diastolic velocities at 5 mm, we found correlation with cavernosography to yield results similar to their published report. However, including diastolic velocities from the entire 30 mm in our patients produced a significant increase in specificity by accurately characterizing those patients (group 3) with a delayed response and subsequent demonstration of an intact venous mechanism. The Mayo Clinic group has also made this observation, and they have subsequently revised their study protocol to include data acquisition at 5-20 mm (King B, personal communication). Delayed scanning also identified several patients who went on to exceed the diastolic threshold of 5 cm/sec at times beyond 5 mm (group 4). These cases represented potential false-negative diagnoses for venous incompetence. Two of these three patients subsequently underwent cavernosography and were confirmed to have venous leakage. In these three patients, the rise in end-diastolic velocity was accompanied by a delayed rise in peak systolic velocity. In no patients in our study was a rise in end-diastolic velocity demonstrated without a concomitant rise in peak systolic velocity. This observation supports the decision to terminate scanning and data acquisition when peak systolic velocity remains stable at mm or begins to decline. Experience with dorsal vein flow as a diagnostic indicator of venous incompetence is limited. Benson and Vickers [2] detected dorsal vein flow in four of 1 1 patients proved to have venous leak at cavernosography. They did not report the detection of dorsal vein flow in any patients with an intact venous mechanism. In our experience with color flow imaging, dorsal vein flow is readily detected if care is used to avoid compression of the dorsal veins with the transducer. Dorsal vein flow was identified in 59% of our patients. Early dorsal vein flow, which was associated with the continuous diastolic flow pattern, was seen in both normal and abnormal cases. In patients who progressed to diastolic flow reversal, a loss of dorsal vein flow occurred. We further observed an interesting phenomenon of dorsal vein flow reversal occurring in some patients who achieved rigid tumescence. The physiologic and diagnostic significance of this observation is uncertam. We believe early dorsal vein flow normally precedes the occlusion of the emissary veins as sinusoidal engorgement progresses, but should disappear as the venoocdlusive mechanism is engaged. Persistence of dorsal vein flow had an 80% sensitivity and 1 00% specificity in patients with venous leak at cavernosography. Although we believe our experience suggests that data acquisition should be extended to 30 mm after papaverine injection, our study does have several limitations. Because arterial revasculanization procedures are not currently performed at our institution, we do not routinely perform angiography and no angiographic correlation was available in this series of patients. The delayed response in our patients could be related to proximal arterial disease, which is not predicted by our systolic velocity threshold. Some workers [2, 4] have suggested a higher systolic velocity threshold might be more appropriate. Additionally, it may not be appropriate to use these early criteria for delayed scanning. The delayed response that we have observed may have some diagnostic significance with respect to vascular, psychogenic, or possibly neurogenic mechanisms. Further work in the assessment of patients response to papavenine may help determine whether our patients represent a spectrum of the normal response or a subset of patients with dysfunction. We believe that color Doppler sonography in association with intracavernosal papaverine plays an important role in the diagnostic workup of patients with erectile dysfunction. Color Doppler sonography is useful in the identification of both arterial and venous abnormalities in patients with suspected vasculogenic impotence. We suggest that sonographic data acquisition should begin immediately after papavenine injection, but should continue at regular intervals for mm after papaverine mnjectmon. This extended observation may improve diagnostic accuracy. ACKNOWLEDGMENT We thank Marilyn Bell for assistance in manuscript preparation. REFERENCES 1. Lue TF, Hricak HH, Marich KW, Tanagho EA. Vasculogenic impotence evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Radiology 1985;155: Benson CB, Vickers MA. Sexual impotence caused by vascular disease: diagnosis with duplex sonography. AJR 1989;1 53: i Collins JP, Lewandowski BJ. Experience with intracorporeal injection of papaverine and duplex ultrasound scanning for assessment of arteriogenic impotence. Br J Urol 1987;59: Quam JP, King BF, James EM, et al. Duplex and color Doppler sonographic evaluation of vaculogenic impotence. AJR 1989;153:ii4l-i Shabsigh A, Fishman IJ, Quesada ET, Scale-Hawkins CK, Dunn JK. Evaluation of vasculogenic erectile impotence using penile duplex ultrasonography. J Urol 1989;142: Schwartz AN, Wang KY, Mack LA, et al. Evaluation of normal erectile function with color flow Doppler sonography. AJR 1989;153: Paushter DM. 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