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Dual Radioisotopic Study: A Technique for the Evaluation of Vasculogenic Impotence
0022-5347/92/1471-0042$03.00/0
Vol. 147, 42-46, January 1992 Printed in U.S.A.
THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
DUAL RADIOISOTOPIC STUDY: A TECHNIQUE FOR THE EVALUATION OF VASCULOGENIC IMPOTENCE ADIL ESEN, MEHMET KITAPCI, ALI ERGEN, BELKIS ERBAS, DOGAN REMZI COSKUN BEKDIK
AND
From the Departments of Urology and Nuclear Medicine, Hacettepe University School of Medicine, Ankara, Turkey
ABSTRACT
Arterial and venous systems are the main points for the evaluation of vasculogenic impotence. To evaluate both of these systems in the same study we propose a dual radioisotopic study in which 99m technetium (99mTc) and 133xenon ( 133Xe) were used. The changes in 99mTc and 133Xe radioactivities administered intravenously and intracavernously, respectively, were monitored before and after intracavernous papaverine injection. These changes were determined as time activity curves, which were generated from the region of interest over the penis. A 99mTc penogram index derived from the 99m Tc time activity curve was significantly different in the control and arteriogenic impotence groups (131.67 ± 74.6 versus 62.94 ± 51.6, p <0.01). A meaningful correlation between 99mTc penogram index results and duplex ultrasonographic findings were observed (r = 0.905). 133Xe penogram index, derived from the 133Xe washout curve was significantly different in the control and venogenic impotence groups (-25.65 ± 24.9 versus -56.09 ± 13.4, p <0.01). Also, a meaningful correlation was obtained between pharmacocavernosometry and 133Xe penogram index results of venogenic impotent patients (r = 0.86). These findings suggest that the dual radioisotopic study will be a useful technique in the evaluation of the entire vascular system of the penis, since it is a noninvasive method. KEY WORDS:
impotence, radionuclide angiography, technetium, xenon, penile erection
Erection is a complex and integrated response that depends upon vascular and neurological mechanisms. The vascular proc esses that occur during erection can be described as an increase in arterial inflow, sinusoidal relaxation and restriction of ve nous outflow.1• Any pathological condition of these mecha nisms results in erectile dysfunction. Several invasive and noninvasive diagnostic modalities, such as penile brachial in dex, duplex ultrasonography, angiography, pharmacocaverno sography and pharmacocavernosometry, have been used to evaluate vasculogenic impotence.3 Unfortunately, most of these modalities are capable of evaluating only 1 of the vascular components and, consequently, they often have certain limita tions.4· 5 To find a noninvasive method to evaluate the arterial and venous systems of the penis during the same study with papaverine-induced erection,6 we propose a dual radioisotopic method in which 99mtechnetium (99mTc) and 133xenon ( 133Xe) were used. We describe the methodology and discuss the results of this technique in comparison to the other techniques of measuring penile hemodynamics.
systolic velocity greater than 25 cm. per second and mean diameter increase of more than 75% after papaverine injection indicated normal arterial inflow.3 Patients who had less than these values constituted the arterial insufficiency group.
2
Technique of pharmacocavernosography and pharmacocaver nosometry. These techniques were performed according to the
methods of Tanagho3 and Aboseif 7 et al. Both cavernous bodies were punctured with a 19 gauge cannula and then 60 mg. papaverine hydrochloride were injected. If the intracavernous pressure remained less than 80 mm. Hg until 12 minutes after injection, perfusion was begun and increased until a rigid erection developed. We determined the rate required to main tain the intracavernous pressure at 80 mm. Hg (maintenance flow rate). Cavernosography films were obtained to visualize the site of venous leakage. Subnormal clinical response to papaverine and a maintenance flow rate of greater than 5 ml. per minute indicated venous incompetence.3• 7 Patients who had greater than this value were included in the venogenic incom petence group. The patients who had both of these criteria were included in the arterial and venous insufficiency group. Technique of dual radioisotopic study. The patient was placed in the supine position under the detector of a gamma camera with a parallel hole collimator (Toshiba GCA 501 SA). A lead shield that was designed by us for this study was placed over the patient. The shield had a curved lower edge with a hole through which the penis was placed and fixed over the shield with tape. The purpose of this shield design was to measure only the penile radioactivity. Then a 25 gauge butterfly needle was inserted into the corpus cavernosum. Potassium perchlo rate (400 mg. in 20 ml. water) was given orally and 40 mg. stannous pyrophosphate were injected intravenously for the labeling of red blood cells via an in vivo technique.8• 9 Then, 20 minutes after injection 10 mCi. 99mTc were given intravenously. After 30 minutes 5 mCi. (0.1 ml.) of 133Xe dissolved in saline were administered via the intracavernous needle (fig. 1) and the activity of the 2 radioisotopes was monitored. The computer was programed to monitor acquisition at 1 minute per frame
PATIENTS AND METHOD
We studied 17volunteers (mean age 44.57 ± 14.8 years) with normal sexual function and 19 vasculogenic impotence patients (mean age 52.75 ± 11.05 years). Informed consent was obtained. Before dual radioisotopic study the patients underwent a com plete evaluation, including history taking, physical examina tion, biochemical and endocrine assays, bulbocavernosus reflex latency time determination, papaverine test, penile brachial pressure index, duplex ultrasonography, pharmacocavernosog raphy and pharmacocavernosometry. Each volunteer under went all of these studies except for the latter 2 tests. Technique of duplex ultrasonography. The diameter of the cavernous arteries and the blood flow velocity were measured before and 5 minutes after papaverine injection with a real time sector scanner (imaging frequency 10 MHz.) and a 4.5 MHz. pulsed Doppler system. The echogenity of the arterial wall and cavernous smooth muscle was recorded. Mean peak Accepted for publication May 10, 1991. 42
4 00
DUAL RADIOISOTOPIC STUDY IN VASCULOGENIC IMPOTENCE tntracavernous papaverine
PROCEDURE:
40 mg stannous pyrophosphate i.v. ���chl�r�te -----+ p.o
1
IOmCi 99 Tc i.v. �
SmCi 133Xe lntr acavernosa I
1
0 min. ��---.____... 20 min.
20 min.
40 min.
20 min . ...,___________ Acquisition :
60 min. ____.,,
1 min / 60 frame
FIG. 1. Technique of dual radioisotopic study. p.o, oral administra tion. i. v., intravenous
FIG. 3. 99mTc and 133Xe time activity curves of normal man. A, marked increase in 99mTc time activity curve in early minutes after papaverine injection. B, after papaverine injection there is �harp and gentle decrease in 133Xe washout curve. H. U., Hounsfield umts.
FIG. 2. Images of99mTc and 133Xe ofv?lun_te_er. ".1-, increase i� volume and radioactivity (99mTc) after papaverme mJectwn ai:e �ar_ufe�t. Fj, decrease of radioactivity ('33Xe washout) after papaverme mJectwn 1s observed. H. U., Hounsfield units.
for 60 minutes with a dual energy setting mode and 20% window adjusted to 80 kev. ( 133Xe) and 140 kev. (99mTc, fig. 2). Twenty minutes after the 133 Xe plus 99mTc injection 60 mg. papaverine hydrochloride were injected via the intracavernous needle without ending the study. Erection was graded by the same consultant urologist according to the Penrig scale. 6 The erection was normal in the control group and insufficient in all of the patient groups. At the end of the study time activity curves of each isotope were generated from the region of interest over the penis for the determination of penile hemodynamics (fig. 3). A 10 mCi. dose of 99mTc administered intravenously was diluted in patient blood. Approximately less than 1% was present in the penis. On the othe� hand 5 mCi. of 133Xe �ere directly administered into the pems totally under observat10n. The contribution from the Compton peak of 99mTc to the 13 3Xe
window is negligible. Experimentally determined Compton scatter contribution was approximately 3% so scatter correction was unnecessary. When we examined the 99mTc time activity curve and 133Xe washout curve we observed that both were affected by papav erine. We described the 99mTc penogram index and the 133Xe penogram index for the evaluation of the arterial inflow and venous outflow, respectively: 99mTc penogram index = [(counts per minute at 3 minutes after papaverine - counts per minute at papaverine injection time)/counts per minute at papaverine injection time] X 100 and 133Xe penogram index = [(counts per minute at end of study - counts per minute at peak penile volume)/counts per minute at peak penile volume] X 100. 99rnTc penogram index and 133Xe penogram index results of the con trol, arteriogenic insufficiency and venogenic incompetence groups were compared (see table). The results of 99mTc peno gram index were compared to measurements of duplex ultra sonography as described by Tanagho3 and Lue 10 et al, and results of 133Xe penogram index were compared to pharmaco cavernosography and pharmacocavernosometry. 3 • The results were analyzed by analysis of variance, the Mann-Whitney U test, regression analysis and confidence interval. 7
RESULTS
According to the clinical evaluation of impotence 19 patients were classified into 3 groups: 1) arteriogenic insufficiency, 2)
44
ESEN AND ASSOCIATES 99
mTc and
Group
No. Pts.
Control Arteriogenic impotence Venogenic impotence Arteriogenic plus venogenic impotencet
17 7 8 4
Xe penogram index values for each group
133
99
mTc Penogram Index*
131.67 ± 62.94 ± 132.13 ± 83.06 ±
1
Groups/P Value
74.6 51.6 77.5 39.3
1:2/<0.0l 2:3/<0.05 l:3/>0.05
33
Xe Penogram Index*
Groups/P Value
-25.65 ± 24.9 -36.84 ± 18.5 -56.09 ± 13.4 -57.23 ± 16.9
l:2/>0.05 2:3/>0.05 1:3/<0.0l
Statistical analysis was done by variance analysis, Mann-Whitney U test. * Mean ± standard deviation. t This group was excluded from statistical analysis.
venous incompetence and 3) arteriogenic plus venous insuffi ciency. The control group included 17 volunteers. Distribution of patients into the groups is shown in the table. The arteri ogenic plus venous impotence group was excluded from the statistical study because of insufficient number of patients. The 99mTc time activity curve of a volunteer is shown in figure 3, A. After papaverine injection a marked increase in the initial few minutes followed by a gradual increase that reached a plateau was noted. The average time activity curves of the arteriogenic and control groups are shown in figure 4. The average 99mTc penogram index results of the control and venogenic impotence groups were significantly higher than those of the arteriogenic impotence groups (p <0.01, see table). A significant correlation was observed between duplex meas urement of mean cavernous arterial peak systolic velocity after papaverine injection and 99mTc penogram index results (fig. 5, r = 0.904). Results of greater than 93 were accepted as a normal finding. This is the lower limit of the 95% confidence level derived from the data of the 17 normal men. In the control group 82% of the volunteers had values higher than the lower limit. However, 71.4% of the arteriogenic impotent patients had values below the limits and 75% of the venogenic impotence group had normal 99mTc penogram index values according to our limit (fig. 6). The 33Xe washout curve of a volunteer is shown in figure 3, B. The curve was biexponential, that is it showed a sharp initial decline and then a gentle decline. 133Xe washout curves of a 1
20000
volunteer and of the venogenic impotence group are shown in figure 7. 33Xe penogram index results of the control group were significantly different from those of the venogenic impotence groups (p <0.01, see table). However, the 33Xe penogram index results of the arteriogenic impotence group were not statisti cally different from those of either the control or venogenic impotence group. A significant correlation was obtained be tween the results of 133Xe penogram index and erection main tenance rates that were obtained from pharmacocavernosome try (fig. 8, r = 0.86). Results of greater than -38.45 were accepted as normal. This is the lower limit of the 95% confi dence level derived from the data of the 17 normal men. Of the volunteers 76% had values greater than the normal limit, whereas 100% of those in the venogenic impotence group had lower values (fig. 9). 1
1
DISCUSSION
Organic erectile dysfunction can be attributed to hemody namic factors, arterial insufficiency and/or venous incompe tence in more than 70% of the impotent patients.4 Many techniques have been proposed to determine penile hemody namics but most of them are invasive, time-consuming and associated with some morbidity.4 A number of radioisotopic studies, such as radioisotope bolus, blood-pool and 33Xe wash out scans, have been developed to prevent these problems. 1-13 They have limitations because a reliable method to induce erection was not used. After the use of intracavernous papav erine injection to induce erection6 radioisotopic techniques have improved dramatically. The techniques with 1 radioisotope have been proved to be useful in the evaluation of either arterial or venous system only. 4• 5 Duplex ultrasonography is consid ered to be one of the most accurate methods for evaluation of the arterial system. 3• 10 However, its accuracy in the evaluation of the venous system is debatable.4• 5 In our study dual radio isotopes (99mTc and 133Xe) were used to determine the changes in the penile arterial inflow and venous outflow after papaver ine injection. The study is one of the first examples of penile dual radioisotopic studies.16 It is known that adequate arterial inflow is necessary to provide erection.2' 3 Intracavernous injection of papaverine in creases the arterial inflow and venous resistance that produces artificial erection.3• 6 The maximum increase in arterial inflow after papaverine was reported to occur within the first 2 to 4 minutes.3 It was demonstrated that this interval is essential to evaluate arterial sufficiency.3• Because the arterial inflow greatly exceeds venous-sinusoidal outflow, an increase in arte rial inflow is primarily responsible for the changes in penile volume and rigidity.3• 5• With this assumption Schwartz et al obtained meaningful results by using the 99mTc time activity curve in the evaluation of arterial inflow disorders. 15 When we examined the changes in the average 99mTc time activity curve of our control group, it was observed that the maximum increase occurs within the first few minutes after papaverine injection (fig. 4). The marked increase in the time activity curve might be the result of the increase in arterial inflow at the initial phase of penile erection. This finding was in agreement with the literature. 15• 1 Also, the gradual increase in the time activity curve of the patients with arterial insuffi ciency supported this suggestion (fig. 4). 1
1
1
ARTEROGENIC
FIG. 4.
99
10
15
20
25
30
35
40
45
so
55
60
mTc time activity curve of control and arteriogenic groups y =
70
.18x + 9.407,
A-squared:
.819
u
I Cl. ::, 0
30
1
17
60 50
1
0
40
20
Io 0 50
I 00
150
TPI
200
250
1
300
350
FIG. 5. Regression analysis of 99mTc penogram index (TPI) and mean peak flow velocity of cavernous artery.
17
7
45
DUAL Rl.DI0l801I'1 0PIC ST-UDY IN VASCULOGENIC IIv1POTEI\JCE
TP! 350
- --------------�-------
-
-----------------------
---
--
300 250 200 150 100 50 0
A
C
111111
V
I
PATIENTS A Patient
·--· climit of normal (93)
FIG. 6. 99mTc penogram index (TPI) values of patients in control (C), venogenic impotence (V) and arteriogenic impotence (A) groups 90000 80000
B
I
:::?� A 50000
� PAPAVERINE
40000 30000 20000
Conlrol
10000
Venous 1O
15
20
25
30
35
40
45
50
55
60
FIG. 7. Xe washout curves of control and venogenic impotence groups. A, sharp decline indicates increased venous outflow due to increased arterial inflow during early phase of erection. B, gentle decline and plateau during maintenance period of erection. 133
"��1 '
11 40
35
/;:/<�
/71
/
11 0� � 20
30
40
50 60 Cavernosometry
70
80
90
I
FIG. 8. Regression analysis of 133Xe penogram index (XPI) and maintenance rate of erection in cavernosometry.
According to these findings we described 99mTc penogram index from the 99mTc time activity curve, which was assumed to be an indicator of increase in arterial inflow during the initial 3 minutes after papaverine injection. Also, the meaningful difference of 99mTc penogram index results between the control and arterial impotence groups supports this suggestion (see table). The significant correlation between duplex ultrasonog raphy measurements, considered to be among the most relia ble, 18 and 99mTc penogram index results suggests that the 99mTc
phase of the dual radioisotopic study may be as useful and noninvasive a method to evaluate arterial sufficiency as the former method (fig. 5, r = 0.905). Three volunteers in our control group had 99mTc penogram index values of less than the lower limits of normal subjects (fig. 6). The duplex ultrasonographic measurements of these patients were on the lower border. Also, the erectile responses to papaverine were subnormal. We believe that these 3 false positive results might be due to relative insensitivity to papav erine, which has been reported by other investigators as well. 17 On the other hand, the 133Xe washout method originally de scribed by Conn in 195519 has been used to measure blood flow in a number of organs. Several investigators, especially Shirai et al, have used this method providing an absolute value for penile blood flow.1 1 Haden20 and Nseyo 13 et al performed ra dioisotopic evaluations during the flaccid phase and determined the penile blood flow rate in their groups. Recently, hemodynamic studies have shown that a normal venous closure mechanism, which occurs during erection, is essential not only to initiate but also to maintain erection.7 It has been demonstrated that venous outflow increases because of increased arterial inflow, especially in the early period of erection.3 In our study this was shown as a sharp decline in the 133 Xe washout curve (fig. 7, A). We did not find a significant difference between the normal and venogenic im potent patients in the early period of erection (fig. 7, A). The maintenance period of erection, which occurred only in the control group, was determined with palpation and inspection. During this period there was a gentle decline and a plateau (fig. 7, B), indicating low venous outflow as proposed by Tanagho et al.3 This phase corresponds to the plateau phase of a 99 mTc study. A steady state is obtained by the 99mTc study, which means that the inflow is equal to the outflow. We described the 133 Xe penogram index as a parameter to obtain information about the venous outflow in the maintenance period of erection. Statistically different 133Xe penogram index results of the con trol and venogenic incompetence groups, and the meaningful correlation between 133Xe penogram index results and caver nosometric findings suggest that the 133Xe penogram index will be a useful parameter in the diagnosis of vasculogenic impo tence. Insufficient arterial inflow causes inadequate compression of venous channels and venous leakage continues after papaverine
46
ESEN AND ASSOCIATES
XPI -----1 0 0 _ 80 -- 5 0
V
C lllllm A Pat i e n t
A PAT I E N TS
· --":l i m i t o f n o r m al ( - 3 8 . 4 5 )
FIG. 9.
133
Xe penogram index (XPI) values o fpatients i n control ( C), venogenic impotence ( V ) and arteriogenic impotence (A ) groups
injection in the arteriogenic group. The severity of venous leakage may differ greatly according to arterial inflow. This may explain why the 133Xe penogram index results of the arteriogenic impotence group were not significantly different from those of the other groups (see table). We suggest that if a patient has an arterial pathological condition determination of the venogenic component is inconclusive in this technique. The findings that the 3 volunteers in the control group had lower 133 Xe and 99mTc penogram index levels (figs. 6 and 9) also suggested papaverine insensitivity. To minimize the papaverine insensitivity we decided to combine phentolamine and papav erine in further studies. The dual radioisotopic study proposed is unable to detect a venous pathological condition in patients with arterial plus venous disorders. Although the dual radiois otopic study could differentiate between venous and arterial pathological conditions, it also might be useful to evaluate the long-term results of vascular procedures, such as revasculari zation or venous ligation. However, it could not determine the site of the vascular pathological conditions. In conclusion, although the results are preliminary the ability to evaluate the arterial and venous systems in a noninvasive manner makes the dual radioisotopic study a valuable screening test in the evaluation of vasculogenic impotence. Prof. Meral T. Ercan reviewed and evaluated the manuscript.
7. 8.
9. 10.
11.
12. 13. 14.
REFERENCES
1. Lue, T. F., Takamura, T., Schmidt, R. A., Palubinskas, A. J. and Tanagho, E. A.: Hemodynamics of erection in the monkey. J. Urol., 1 3 0 : 1237, 1983. 2. Lue, T. F., Takamura, T., Umraiya, M., Schmidt, R. A. and Tanagho, E. A.: Hemodynamics of canine corpora cavernosa during erection. Urology, 24: 347, 1984. 3. Tanagho, E. A., Lue, T. F. and McClure, R. D.: Contemporary Management of Impotence and Infertility. Baltimore: Williams & Wilkins, 1988. 4. Vickers, M. A., Jr., Benson, C. B. and Richie, J. P.: High resolution ultrasonography and pulsed wave Doppler for detection of cor porovenous incompetence in erectile dysfunction. J. Urol., 1 4 3 : 1125, 1990. 5. Moore, R. D., Steinberg, E. P., Powe, N. R., White, R. I., Jr., Brinker, J. A., Fishman, E. K., Zinreich, S. J. and Smith, C. R.: Frequency and determinants of adverse reactions induced by high-osmolality contrast media. Radiology, 170: 727, 1989. 6. Virag, R., Frydman, D., Legman, M. and Virag, H.: Intracavernous
15.
16. 17.
18. 19. 20.
injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology, 35: 79, 1984. Aboseif, S. R., Breza, J., Lue, T. F. and Tanagho, E. A.: Penile venous drainage in erectile dysfunction. Anatomical, radiological and functional considerations. Brit. J. Urol. , 64: 183, 1989. Bekdik, C. F., Ercan, M. T., Bernay, I., Caner, B. E. and Turguter, S.: An improved method for the in vivo labelling of red blood cells with 99mTc in gated cardiac imaging. Eur. J. Nucl. Med., 14: 408, 1988. Srivastava, S. C. and Chervu, L. R.: Radionuclide-labeled red blood cells: current status and future prospects. Sem. Nucl. Med., 14: 68, 1984. Lue, T. F., Hricak, H., Marich, K. W. and Tanagho, E. A.: Vascu logenic impotence evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Radiology, 1 5 5 : 777, 1985. Shirai, M., Nakamura, M., Ishii, N., Mitsukawa, S. and Yoshikazu, S.: Determination of intrapenile blood volume using 99mTc labeled autologous red blood cells. Tohoku J. Exp. Med., 120: 377, 1976. Fanous, H. N., Jevtich, M. J., Chen, D . C. P. and Edson, M.: Radioisotope penogram in diagnosis of vasculogenic impotence. Urology, 20: 499, 1982. Nseyo, U. 0., Wilbur, H. J., Kang, S. A., Flesh, L. and Bennett, A. H.: Penile xenon ( 133Xe) washout: a rapid method of screening for vasculogenic impotence. Urology, 2 3 : 31, 1984. Lin, S. N., Liu, R. S., Yu, P. C., Chang, L. S., Yeh, S. H. and Kuo, J. S.: Diagnosis ofvasculogenic impotence: combination ofpenile xenon-133 washout and papaverine tests. Urology, 34: 28, 1989. Schwartz, A. N., Graham, M. M., Ferency, G. F. and Miura, R. S.: Radioisotope penile plethysmography: a technique for evaluating corpora cavernosal blood flow during early tumesence. J. Nucl. Med., 30: 466, 1989. Miraldi, F., Nelson, A. D., Jones, W. T. and Kursh, E. D.: A non invasive technique for the evaluation of male impotence. J. Nucl. Med., 30: 29, abstract 231, 1989. Schwartz, A. N., Wang, K. Y., Mack, L. A., Lowe, M., Berger, R. E., Cyr, D. R. and Feldman, M.: Evaluation of normal erectile function with color flow Doppler sonography. AJR, 1 5 3 : 1155, 1989. Lue, T. F., Mueller, S. C., Jow, Y. R. and Hwang, T. 1-S.: Functional evaluation of penile arteries with duplex ultrasound in vasodi lator-induced erection. Urol. Clin. N. Amer., 16: 799, 1989. Conn, H. L., Jr.: Measurement of organ blood flow without blood sampling. J. Clin. Invest., 3 4 : 916, 1955. Haden, H. T., Katz, P. G., Mulligan, T. and Zasler, N. D.: Penile blood flow by xenon-133 washout. J. Nucl. Med., 30: 1032, 1989.
Vol. 147, 42-46, January 1992 Printed in U.S.A.
THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
DUAL RADIOISOTOPIC STUDY: A TECHNIQUE FOR THE EVALUATION OF VASCULOGENIC IMPOTENCE ADIL ESEN, MEHMET KITAPCI, ALI ERGEN, BELKIS ERBAS, DOGAN REMZI COSKUN BEKDIK
AND
From the Departments of Urology and Nuclear Medicine, Hacettepe University School of Medicine, Ankara, Turkey
ABSTRACT
Arterial and venous systems are the main points for the evaluation of vasculogenic impotence. To evaluate both of these systems in the same study we propose a dual radioisotopic study in which 99m technetium (99mTc) and 133xenon ( 133Xe) were used. The changes in 99mTc and 133Xe radioactivities administered intravenously and intracavernously, respectively, were monitored before and after intracavernous papaverine injection. These changes were determined as time activity curves, which were generated from the region of interest over the penis. A 99mTc penogram index derived from the 99m Tc time activity curve was significantly different in the control and arteriogenic impotence groups (131.67 ± 74.6 versus 62.94 ± 51.6, p <0.01). A meaningful correlation between 99mTc penogram index results and duplex ultrasonographic findings were observed (r = 0.905). 133Xe penogram index, derived from the 133Xe washout curve was significantly different in the control and venogenic impotence groups (-25.65 ± 24.9 versus -56.09 ± 13.4, p <0.01). Also, a meaningful correlation was obtained between pharmacocavernosometry and 133Xe penogram index results of venogenic impotent patients (r = 0.86). These findings suggest that the dual radioisotopic study will be a useful technique in the evaluation of the entire vascular system of the penis, since it is a noninvasive method. KEY WORDS:
impotence, radionuclide angiography, technetium, xenon, penile erection
Erection is a complex and integrated response that depends upon vascular and neurological mechanisms. The vascular proc esses that occur during erection can be described as an increase in arterial inflow, sinusoidal relaxation and restriction of ve nous outflow.1• Any pathological condition of these mecha nisms results in erectile dysfunction. Several invasive and noninvasive diagnostic modalities, such as penile brachial in dex, duplex ultrasonography, angiography, pharmacocaverno sography and pharmacocavernosometry, have been used to evaluate vasculogenic impotence.3 Unfortunately, most of these modalities are capable of evaluating only 1 of the vascular components and, consequently, they often have certain limita tions.4· 5 To find a noninvasive method to evaluate the arterial and venous systems of the penis during the same study with papaverine-induced erection,6 we propose a dual radioisotopic method in which 99mtechnetium (99mTc) and 133xenon ( 133Xe) were used. We describe the methodology and discuss the results of this technique in comparison to the other techniques of measuring penile hemodynamics.
systolic velocity greater than 25 cm. per second and mean diameter increase of more than 75% after papaverine injection indicated normal arterial inflow.3 Patients who had less than these values constituted the arterial insufficiency group.
2
Technique of pharmacocavernosography and pharmacocaver nosometry. These techniques were performed according to the
methods of Tanagho3 and Aboseif 7 et al. Both cavernous bodies were punctured with a 19 gauge cannula and then 60 mg. papaverine hydrochloride were injected. If the intracavernous pressure remained less than 80 mm. Hg until 12 minutes after injection, perfusion was begun and increased until a rigid erection developed. We determined the rate required to main tain the intracavernous pressure at 80 mm. Hg (maintenance flow rate). Cavernosography films were obtained to visualize the site of venous leakage. Subnormal clinical response to papaverine and a maintenance flow rate of greater than 5 ml. per minute indicated venous incompetence.3• 7 Patients who had greater than this value were included in the venogenic incom petence group. The patients who had both of these criteria were included in the arterial and venous insufficiency group. Technique of dual radioisotopic study. The patient was placed in the supine position under the detector of a gamma camera with a parallel hole collimator (Toshiba GCA 501 SA). A lead shield that was designed by us for this study was placed over the patient. The shield had a curved lower edge with a hole through which the penis was placed and fixed over the shield with tape. The purpose of this shield design was to measure only the penile radioactivity. Then a 25 gauge butterfly needle was inserted into the corpus cavernosum. Potassium perchlo rate (400 mg. in 20 ml. water) was given orally and 40 mg. stannous pyrophosphate were injected intravenously for the labeling of red blood cells via an in vivo technique.8• 9 Then, 20 minutes after injection 10 mCi. 99mTc were given intravenously. After 30 minutes 5 mCi. (0.1 ml.) of 133Xe dissolved in saline were administered via the intracavernous needle (fig. 1) and the activity of the 2 radioisotopes was monitored. The computer was programed to monitor acquisition at 1 minute per frame
PATIENTS AND METHOD
We studied 17volunteers (mean age 44.57 ± 14.8 years) with normal sexual function and 19 vasculogenic impotence patients (mean age 52.75 ± 11.05 years). Informed consent was obtained. Before dual radioisotopic study the patients underwent a com plete evaluation, including history taking, physical examina tion, biochemical and endocrine assays, bulbocavernosus reflex latency time determination, papaverine test, penile brachial pressure index, duplex ultrasonography, pharmacocavernosog raphy and pharmacocavernosometry. Each volunteer under went all of these studies except for the latter 2 tests. Technique of duplex ultrasonography. The diameter of the cavernous arteries and the blood flow velocity were measured before and 5 minutes after papaverine injection with a real time sector scanner (imaging frequency 10 MHz.) and a 4.5 MHz. pulsed Doppler system. The echogenity of the arterial wall and cavernous smooth muscle was recorded. Mean peak Accepted for publication May 10, 1991. 42
4 00
DUAL RADIOISOTOPIC STUDY IN VASCULOGENIC IMPOTENCE tntracavernous papaverine
PROCEDURE:
40 mg stannous pyrophosphate i.v. ���chl�r�te -----+ p.o
1
IOmCi 99 Tc i.v. �
SmCi 133Xe lntr acavernosa I
1
0 min. ��---.____... 20 min.
20 min.
40 min.
20 min . ...,___________ Acquisition :
60 min. ____.,,
1 min / 60 frame
FIG. 1. Technique of dual radioisotopic study. p.o, oral administra tion. i. v., intravenous
FIG. 3. 99mTc and 133Xe time activity curves of normal man. A, marked increase in 99mTc time activity curve in early minutes after papaverine injection. B, after papaverine injection there is �harp and gentle decrease in 133Xe washout curve. H. U., Hounsfield umts.
FIG. 2. Images of99mTc and 133Xe ofv?lun_te_er. ".1-, increase i� volume and radioactivity (99mTc) after papaverme mJectwn ai:e �ar_ufe�t. Fj, decrease of radioactivity ('33Xe washout) after papaverme mJectwn 1s observed. H. U., Hounsfield units.
for 60 minutes with a dual energy setting mode and 20% window adjusted to 80 kev. ( 133Xe) and 140 kev. (99mTc, fig. 2). Twenty minutes after the 133 Xe plus 99mTc injection 60 mg. papaverine hydrochloride were injected via the intracavernous needle without ending the study. Erection was graded by the same consultant urologist according to the Penrig scale. 6 The erection was normal in the control group and insufficient in all of the patient groups. At the end of the study time activity curves of each isotope were generated from the region of interest over the penis for the determination of penile hemodynamics (fig. 3). A 10 mCi. dose of 99mTc administered intravenously was diluted in patient blood. Approximately less than 1% was present in the penis. On the othe� hand 5 mCi. of 133Xe �ere directly administered into the pems totally under observat10n. The contribution from the Compton peak of 99mTc to the 13 3Xe
window is negligible. Experimentally determined Compton scatter contribution was approximately 3% so scatter correction was unnecessary. When we examined the 99mTc time activity curve and 133Xe washout curve we observed that both were affected by papav erine. We described the 99mTc penogram index and the 133Xe penogram index for the evaluation of the arterial inflow and venous outflow, respectively: 99mTc penogram index = [(counts per minute at 3 minutes after papaverine - counts per minute at papaverine injection time)/counts per minute at papaverine injection time] X 100 and 133Xe penogram index = [(counts per minute at end of study - counts per minute at peak penile volume)/counts per minute at peak penile volume] X 100. 99rnTc penogram index and 133Xe penogram index results of the con trol, arteriogenic insufficiency and venogenic incompetence groups were compared (see table). The results of 99mTc peno gram index were compared to measurements of duplex ultra sonography as described by Tanagho3 and Lue 10 et al, and results of 133Xe penogram index were compared to pharmaco cavernosography and pharmacocavernosometry. 3 • The results were analyzed by analysis of variance, the Mann-Whitney U test, regression analysis and confidence interval. 7
RESULTS
According to the clinical evaluation of impotence 19 patients were classified into 3 groups: 1) arteriogenic insufficiency, 2)
44
ESEN AND ASSOCIATES 99
mTc and
Group
No. Pts.
Control Arteriogenic impotence Venogenic impotence Arteriogenic plus venogenic impotencet
17 7 8 4
Xe penogram index values for each group
133
99
mTc Penogram Index*
131.67 ± 62.94 ± 132.13 ± 83.06 ±
1
Groups/P Value
74.6 51.6 77.5 39.3
1:2/<0.0l 2:3/<0.05 l:3/>0.05
33
Xe Penogram Index*
Groups/P Value
-25.65 ± 24.9 -36.84 ± 18.5 -56.09 ± 13.4 -57.23 ± 16.9
l:2/>0.05 2:3/>0.05 1:3/<0.0l
Statistical analysis was done by variance analysis, Mann-Whitney U test. * Mean ± standard deviation. t This group was excluded from statistical analysis.
venous incompetence and 3) arteriogenic plus venous insuffi ciency. The control group included 17 volunteers. Distribution of patients into the groups is shown in the table. The arteri ogenic plus venous impotence group was excluded from the statistical study because of insufficient number of patients. The 99mTc time activity curve of a volunteer is shown in figure 3, A. After papaverine injection a marked increase in the initial few minutes followed by a gradual increase that reached a plateau was noted. The average time activity curves of the arteriogenic and control groups are shown in figure 4. The average 99mTc penogram index results of the control and venogenic impotence groups were significantly higher than those of the arteriogenic impotence groups (p <0.01, see table). A significant correlation was observed between duplex meas urement of mean cavernous arterial peak systolic velocity after papaverine injection and 99mTc penogram index results (fig. 5, r = 0.904). Results of greater than 93 were accepted as a normal finding. This is the lower limit of the 95% confidence level derived from the data of the 17 normal men. In the control group 82% of the volunteers had values higher than the lower limit. However, 71.4% of the arteriogenic impotent patients had values below the limits and 75% of the venogenic impotence group had normal 99mTc penogram index values according to our limit (fig. 6). The 33Xe washout curve of a volunteer is shown in figure 3, B. The curve was biexponential, that is it showed a sharp initial decline and then a gentle decline. 133Xe washout curves of a 1
20000
volunteer and of the venogenic impotence group are shown in figure 7. 33Xe penogram index results of the control group were significantly different from those of the venogenic impotence groups (p <0.01, see table). However, the 33Xe penogram index results of the arteriogenic impotence group were not statisti cally different from those of either the control or venogenic impotence group. A significant correlation was obtained be tween the results of 133Xe penogram index and erection main tenance rates that were obtained from pharmacocavernosome try (fig. 8, r = 0.86). Results of greater than -38.45 were accepted as normal. This is the lower limit of the 95% confi dence level derived from the data of the 17 normal men. Of the volunteers 76% had values greater than the normal limit, whereas 100% of those in the venogenic impotence group had lower values (fig. 9). 1
1
DISCUSSION
Organic erectile dysfunction can be attributed to hemody namic factors, arterial insufficiency and/or venous incompe tence in more than 70% of the impotent patients.4 Many techniques have been proposed to determine penile hemody namics but most of them are invasive, time-consuming and associated with some morbidity.4 A number of radioisotopic studies, such as radioisotope bolus, blood-pool and 33Xe wash out scans, have been developed to prevent these problems. 1-13 They have limitations because a reliable method to induce erection was not used. After the use of intracavernous papav erine injection to induce erection6 radioisotopic techniques have improved dramatically. The techniques with 1 radioisotope have been proved to be useful in the evaluation of either arterial or venous system only. 4• 5 Duplex ultrasonography is consid ered to be one of the most accurate methods for evaluation of the arterial system. 3• 10 However, its accuracy in the evaluation of the venous system is debatable.4• 5 In our study dual radio isotopes (99mTc and 133Xe) were used to determine the changes in the penile arterial inflow and venous outflow after papaver ine injection. The study is one of the first examples of penile dual radioisotopic studies.16 It is known that adequate arterial inflow is necessary to provide erection.2' 3 Intracavernous injection of papaverine in creases the arterial inflow and venous resistance that produces artificial erection.3• 6 The maximum increase in arterial inflow after papaverine was reported to occur within the first 2 to 4 minutes.3 It was demonstrated that this interval is essential to evaluate arterial sufficiency.3• Because the arterial inflow greatly exceeds venous-sinusoidal outflow, an increase in arte rial inflow is primarily responsible for the changes in penile volume and rigidity.3• 5• With this assumption Schwartz et al obtained meaningful results by using the 99mTc time activity curve in the evaluation of arterial inflow disorders. 15 When we examined the changes in the average 99mTc time activity curve of our control group, it was observed that the maximum increase occurs within the first few minutes after papaverine injection (fig. 4). The marked increase in the time activity curve might be the result of the increase in arterial inflow at the initial phase of penile erection. This finding was in agreement with the literature. 15• 1 Also, the gradual increase in the time activity curve of the patients with arterial insuffi ciency supported this suggestion (fig. 4). 1
1
1
ARTEROGENIC
FIG. 4.
99
10
15
20
25
30
35
40
45
so
55
60
mTc time activity curve of control and arteriogenic groups y =
70
.18x + 9.407,
A-squared:
.819
u
I Cl. ::, 0
30
1
17
60 50
1
0
40
20
Io 0 50
I 00
150
TPI
200
250
1
300
350
FIG. 5. Regression analysis of 99mTc penogram index (TPI) and mean peak flow velocity of cavernous artery.
17
7
45
DUAL Rl.DI0l801I'1 0PIC ST-UDY IN VASCULOGENIC IIv1POTEI\JCE
TP! 350
- --------------�-------
-
-----------------------
---
--
300 250 200 150 100 50 0
A
C
111111
V
I
PATIENTS A Patient
·--· climit of normal (93)
FIG. 6. 99mTc penogram index (TPI) values of patients in control (C), venogenic impotence (V) and arteriogenic impotence (A) groups 90000 80000
B
I
:::?� A 50000
� PAPAVERINE
40000 30000 20000
Conlrol
10000
Venous 1O
15
20
25
30
35
40
45
50
55
60
FIG. 7. Xe washout curves of control and venogenic impotence groups. A, sharp decline indicates increased venous outflow due to increased arterial inflow during early phase of erection. B, gentle decline and plateau during maintenance period of erection. 133
"��1 '
11 40
35
/;:/<�
/71
/
11 0� � 20
30
40
50 60 Cavernosometry
70
80
90
I
FIG. 8. Regression analysis of 133Xe penogram index (XPI) and maintenance rate of erection in cavernosometry.
According to these findings we described 99mTc penogram index from the 99mTc time activity curve, which was assumed to be an indicator of increase in arterial inflow during the initial 3 minutes after papaverine injection. Also, the meaningful difference of 99mTc penogram index results between the control and arterial impotence groups supports this suggestion (see table). The significant correlation between duplex ultrasonog raphy measurements, considered to be among the most relia ble, 18 and 99mTc penogram index results suggests that the 99mTc
phase of the dual radioisotopic study may be as useful and noninvasive a method to evaluate arterial sufficiency as the former method (fig. 5, r = 0.905). Three volunteers in our control group had 99mTc penogram index values of less than the lower limits of normal subjects (fig. 6). The duplex ultrasonographic measurements of these patients were on the lower border. Also, the erectile responses to papaverine were subnormal. We believe that these 3 false positive results might be due to relative insensitivity to papav erine, which has been reported by other investigators as well. 17 On the other hand, the 133Xe washout method originally de scribed by Conn in 195519 has been used to measure blood flow in a number of organs. Several investigators, especially Shirai et al, have used this method providing an absolute value for penile blood flow.1 1 Haden20 and Nseyo 13 et al performed ra dioisotopic evaluations during the flaccid phase and determined the penile blood flow rate in their groups. Recently, hemodynamic studies have shown that a normal venous closure mechanism, which occurs during erection, is essential not only to initiate but also to maintain erection.7 It has been demonstrated that venous outflow increases because of increased arterial inflow, especially in the early period of erection.3 In our study this was shown as a sharp decline in the 133 Xe washout curve (fig. 7, A). We did not find a significant difference between the normal and venogenic im potent patients in the early period of erection (fig. 7, A). The maintenance period of erection, which occurred only in the control group, was determined with palpation and inspection. During this period there was a gentle decline and a plateau (fig. 7, B), indicating low venous outflow as proposed by Tanagho et al.3 This phase corresponds to the plateau phase of a 99 mTc study. A steady state is obtained by the 99mTc study, which means that the inflow is equal to the outflow. We described the 133 Xe penogram index as a parameter to obtain information about the venous outflow in the maintenance period of erection. Statistically different 133Xe penogram index results of the con trol and venogenic incompetence groups, and the meaningful correlation between 133Xe penogram index results and caver nosometric findings suggest that the 133Xe penogram index will be a useful parameter in the diagnosis of vasculogenic impo tence. Insufficient arterial inflow causes inadequate compression of venous channels and venous leakage continues after papaverine
46
ESEN AND ASSOCIATES
XPI -----1 0 0 _ 80 -- 5 0
V
C lllllm A Pat i e n t
A PAT I E N TS
· --":l i m i t o f n o r m al ( - 3 8 . 4 5 )
FIG. 9.
133
Xe penogram index (XPI) values o fpatients i n control ( C), venogenic impotence ( V ) and arteriogenic impotence (A ) groups
injection in the arteriogenic group. The severity of venous leakage may differ greatly according to arterial inflow. This may explain why the 133Xe penogram index results of the arteriogenic impotence group were not significantly different from those of the other groups (see table). We suggest that if a patient has an arterial pathological condition determination of the venogenic component is inconclusive in this technique. The findings that the 3 volunteers in the control group had lower 133 Xe and 99mTc penogram index levels (figs. 6 and 9) also suggested papaverine insensitivity. To minimize the papaverine insensitivity we decided to combine phentolamine and papav erine in further studies. The dual radioisotopic study proposed is unable to detect a venous pathological condition in patients with arterial plus venous disorders. Although the dual radiois otopic study could differentiate between venous and arterial pathological conditions, it also might be useful to evaluate the long-term results of vascular procedures, such as revasculari zation or venous ligation. However, it could not determine the site of the vascular pathological conditions. In conclusion, although the results are preliminary the ability to evaluate the arterial and venous systems in a noninvasive manner makes the dual radioisotopic study a valuable screening test in the evaluation of vasculogenic impotence. Prof. Meral T. Ercan reviewed and evaluated the manuscript.
7. 8.
9. 10.
11.
12. 13. 14.
REFERENCES
1. Lue, T. F., Takamura, T., Schmidt, R. A., Palubinskas, A. J. and Tanagho, E. A.: Hemodynamics of erection in the monkey. J. Urol., 1 3 0 : 1237, 1983. 2. Lue, T. F., Takamura, T., Umraiya, M., Schmidt, R. A. and Tanagho, E. A.: Hemodynamics of canine corpora cavernosa during erection. Urology, 24: 347, 1984. 3. Tanagho, E. A., Lue, T. F. and McClure, R. D.: Contemporary Management of Impotence and Infertility. Baltimore: Williams & Wilkins, 1988. 4. Vickers, M. A., Jr., Benson, C. B. and Richie, J. P.: High resolution ultrasonography and pulsed wave Doppler for detection of cor porovenous incompetence in erectile dysfunction. J. Urol., 1 4 3 : 1125, 1990. 5. Moore, R. D., Steinberg, E. P., Powe, N. R., White, R. I., Jr., Brinker, J. A., Fishman, E. K., Zinreich, S. J. and Smith, C. R.: Frequency and determinants of adverse reactions induced by high-osmolality contrast media. Radiology, 170: 727, 1989. 6. Virag, R., Frydman, D., Legman, M. and Virag, H.: Intracavernous
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injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology, 35: 79, 1984. Aboseif, S. R., Breza, J., Lue, T. F. and Tanagho, E. A.: Penile venous drainage in erectile dysfunction. Anatomical, radiological and functional considerations. Brit. J. Urol. , 64: 183, 1989. Bekdik, C. F., Ercan, M. T., Bernay, I., Caner, B. E. and Turguter, S.: An improved method for the in vivo labelling of red blood cells with 99mTc in gated cardiac imaging. Eur. J. Nucl. Med., 14: 408, 1988. Srivastava, S. C. and Chervu, L. R.: Radionuclide-labeled red blood cells: current status and future prospects. Sem. Nucl. Med., 14: 68, 1984. Lue, T. F., Hricak, H., Marich, K. W. and Tanagho, E. A.: Vascu logenic impotence evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Radiology, 1 5 5 : 777, 1985. Shirai, M., Nakamura, M., Ishii, N., Mitsukawa, S. and Yoshikazu, S.: Determination of intrapenile blood volume using 99mTc labeled autologous red blood cells. Tohoku J. Exp. Med., 120: 377, 1976. Fanous, H. N., Jevtich, M. J., Chen, D . C. P. and Edson, M.: Radioisotope penogram in diagnosis of vasculogenic impotence. Urology, 20: 499, 1982. Nseyo, U. 0., Wilbur, H. J., Kang, S. A., Flesh, L. and Bennett, A. H.: Penile xenon ( 133Xe) washout: a rapid method of screening for vasculogenic impotence. Urology, 2 3 : 31, 1984. Lin, S. N., Liu, R. S., Yu, P. C., Chang, L. S., Yeh, S. H. and Kuo, J. S.: Diagnosis ofvasculogenic impotence: combination ofpenile xenon-133 washout and papaverine tests. Urology, 34: 28, 1989. Schwartz, A. N., Graham, M. M., Ferency, G. F. and Miura, R. S.: Radioisotope penile plethysmography: a technique for evaluating corpora cavernosal blood flow during early tumesence. J. Nucl. Med., 30: 466, 1989. Miraldi, F., Nelson, A. D., Jones, W. T. and Kursh, E. D.: A non invasive technique for the evaluation of male impotence. J. Nucl. Med., 30: 29, abstract 231, 1989. Schwartz, A. N., Wang, K. Y., Mack, L. A., Lowe, M., Berger, R. E., Cyr, D. R. and Feldman, M.: Evaluation of normal erectile function with color flow Doppler sonography. AJR, 1 5 3 : 1155, 1989. Lue, T. F., Mueller, S. C., Jow, Y. R. and Hwang, T. 1-S.: Functional evaluation of penile arteries with duplex ultrasound in vasodi lator-induced erection. Urol. Clin. N. Amer., 16: 799, 1989. Conn, H. L., Jr.: Measurement of organ blood flow without blood sampling. J. Clin. Invest., 3 4 : 916, 1955. Haden, H. T., Katz, P. G., Mulligan, T. and Zasler, N. D.: Penile blood flow by xenon-133 washout. J. Nucl. Med., 30: 1032, 1989.