- Email: [email protected]
Is There a Point to Performing a Penile Duplex Ultrasound?
ORIGINAL RESEARCH & REVIEWS
Is There a Point to Performing a Penile Duplex Ultrasound? Afonso Morgado,1,2 Paulo Diniz, PhD,1,3 and Carlos Martins Silva, PhD1,3
ABSTRACT
Introduction: Specialized diagnostic evaluation of erectile dysfunction (ED) may require an intracavernous injection test (IIT) or penile duplex ultrasound (PDU). Aim: Our primary objective was to compare the prognostic value of IIT and PDU for treatment efficacy and patient satisfaction with first-line sildenafil citrate. Methods: After 200 patients were screened, a total of 77 patients with ED had a standardized PDU by a blinded third party, and peak systolic velocity (PSV), end diastolic flow (EDF), and resistive index (RI) in timely intervals were recorded. The erection hardness score (EHS) was used to score erection rigidity during the test and was also noted. Patients also completed a briefed International Index of Erectile Function (IIEF-5) questionnaire and were started on open-label 100 mg sildenafil citrate at baseline. The IIEF-5 and erectile dysfunction inventory of treatment satisfaction (EDITS) questionnaires were repeated and completed at 6 months’ follow-up. Improvement, cure, and satisfaction were defined as an increase of 4 points in IIEF-5 with an IIEF-5 score higher than 21 points and EDITS score higher than 50, respectively. Receiver operating characteristic curves were drawn and the area under the curve (AUC) was calculated and compared. Main Outcome Measure: EHS did not have a different or larger AUC than PSV, EDF, and RI for improvement, cure, and satisfaction with sildenafil citrate. Results: The patient’s mean age was 58.76 ± 10.27 years and almost half of the patients had moderate ED according to the IIEF-5 (42.8%). Improvement, cure, and satisfaction were high among participants (77.9%, 64.9%, and 67.5%, respectively). The erection rigidity EHS also showed an excellent-to-good ability to predict improvement, cure, and patient satisfaction (AUC ¼ 0.921, 0.873, and 0.898, respectively) with sildenafil citrate. Clinical Implications: There is no point in performing more than an IIT when a specialized diagnostic evaluation is required for diagnostic or medico-legal reasons because PDU is time-consuming and requires both hardware and ultrasound skills with no added prognostic value. Strengths and Limitations: This is the first prospective study to directly compare IIT with PDU, and validated disease-specific questionnaires were used to assess both clinical efficacy and satisfaction. Moreover, the PDU was performed by a blinded third party. However, this was a single-center study and the population included was small. Conclusion: PDU parameters add no prognostic value to determining erection rigidity during a standard IIT. Erection rigidity during IIT, as assessed with the EHS, suffices as a prognostic tool. Morgado A, Diniz P, Silva CM. Is There a Point to Performing a Penile Duplex Ultrasound? J Sex Med 2019;XX:XXXLXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Penile Doppler Ultrasound; Intracavernous Injection Test; Erection Hardness Score; Erectile Dysfunction; Prognostic; Satisfaction
INTRODUCTION Erectile dysfunction (ED) is a prevalent age-related disease worldwide, with 26.0% of men aged over 60 years reporting erection problems.1 The diagnostic evaluation of ED may require Received June 16, 2019. Accepted July 12, 2019. 1
Serviço de Urologia, Centro Hospitalar Universitário São João, Porto, Portugal;
2
Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal;
J Sex Med 2019;-:1e7
a minimally invasive procedure, such as the intracavernous injection test (IIT) or the penile duplex ultrasound (PDU), to assess penile vascular hemodynamics. However, since PDU’s first introduction by Lue et al2 in 1985, IIT has been largely replaced
3
Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.07.010
1
2
by PDU because ITT yields limited diagnostic information regarding vascular status, and it is often considered inconclusive as a diagnostic procedure. The added information from the PDU may provide a clear diagnosis and allow for targeted treatment, which could increase treatment efficacy and patient satisfaction. However, there is no generalized agreement on the interpretation of common PDU parameter measurements,2e4 such as peak systolic velocity (PSV), end diastolic flow (EDF), and resistive index (RI). Additionally, there is also known intra- and inter-observer variation in terms of PDU results.5 Moreover, effective targeted treatment remains elusive in the current era because most, if not all, patients will adhere to the same treatment algorithms with little to no individual variations. Our group doubts the added value of common PDU parameter measurement and its diagnostic value in predicting improvement, cure, or satisfaction with ED treatment, which are the primary end points in patient care. Moreover, simple scores and scales, such as the Erection Hardness Score (EHS), do not require ultrasound or Doppler measurements and can be easily applied during IIT. The former is a simple 1-item method to grade erection quality, and it has been demonstrated to be able to reliably predict successful sexual intercourse with both oral sildenafil citrate and intracavernous alprostadil treatment.68 Our primary objective was to compare the prognostic value of common PDU parameters—PSV, EDF, and RI—with EHS during IIT in predicting improvement, cure, and satisfaction with first-line ED treatment featuring sildenafil citrate.
MATERIALS AND METHODS After approval by the hospital’s ethical committee, 200 consecutive male patients referred for ED were screened between January 2016 and December 2018. After consent was obtained, a full standardized medical and sexual history was taken, and if a diagnosis of ED was not confirmed or male hypogonadism was diagnosed, the patients were excluded. Male hypogonadismscreening methods are further described in a previous article. Patients had a standardized PDU with 15 ug of intracavernous injection (ICI) alprostadil by a blinded third party. Alprostadil redosing or repeating PDU were not exclusion criteria and were allowed to achieve the best quality erection (BQE). The detailed list of exclusion criteria is depicted in Table 1. A total of 77 patients were included and further completed a translated validated version of the brief International Index of Erectile Function (IIEF-5) at baseline9 and started ondemand treatment with open-label oral sildenafil citrate 100 mg. Two programmed follow-up appointments were scheduled at 3 and 6 months, at which point IIEF-5 questionnaires were repeated to assess clinical improvement and cure. The erectile dysfunction inventory of treatment satisfaction (EDITS) questionnaire was also completed at 6 months to assess treatment satisfaction.10
Morgado et al
Table 1. Exclusion criteria Unconfirmed main diagnosis of ED ED with < 12 months of duration Failure to achieve BQE with PDU Male hypogonadism Peyronie’s disease Premature ejaculation Unstable or no relationship Absolute contraindication for ED treatment with sildenafil or alprostadil Radical pelvic surgery History of penile surgery other than circumcision were excluded BQE ¼ best quality erection; ED ¼ erectile dysfunction; PDU ¼ penile duplex ultrasound.
ED severity was evaluated according to IIEF-5 scores as follows: 2225 ¼ no ED; 1721 ¼ mild ED; 1216 ¼ mild-tomoderate ED; 811 ¼ moderate ED; and 57 ¼ severe ED.11 Regarding the primary objective, clinical improvement was defined as an increase of 4 points in IIEF-5 score between the baseline and the last valid follow-up visit, and cure was defined as an IIEF-5 higher than 21 points at the last valid follow-up visit.12 Satisfaction was defined as an EDITS score higher than 50.
Penile Doppler Ultrasound Patients followed a standardized protocol by a blinded radiologist using a color duplex ultrasound device and a 7.5 MHz superficial probe. First, a penile evaluation was performed to exclude corporeal fibrosis or Peyronie’s plaques, and the bilateral cavernous artery diameter was measured. An ICI of 15 ug alprostadil was performed on one side. Bilateral PSV and EDF were then recorded at timed 5-minute intervals. The highest PSV and lowest EDF were noted. An erection equivalent to the best erection obtainable at home was required for the test to count. Alprostadil redosing or repeating the PDU were permitted to achieve a BQE. A normal PDU was defined as the highest PSV > 30 cm/s, an EDF < 5 cm/s, and RI higher than 0.8.13
Erection Rigidity Erection rigidity was assessed during PDU by the radiologist at the point of maximal erection using the EHS. This score is a single-item Likert scale that rates the hardness of an erection according to 5 grades: 0 ¼ penis does not enlarge; 1 ¼ penis enlarges but not is hard; 2 ¼ penis is hard but not hard enough for penetration; 3 ¼ penis is hard enough for penetration but not completely rigid; and 4 ¼ penis is completely hard and fully rigid.7 A normal EHS was defined as a score equal to or higher than 3.
Sildenafil Citrate Administration The pharmacologic intervention was carried out by an openlabel administration of 100 mg sildenafil citrate at least 30 J Sex Med 2019;-:1e7
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Is There a Point to Penile Duplex Ultrasound?
Table 2. Patient characteristics (n ¼ 77 patients)
Table 3. PDU hemodynamic characteristics and EHS absolute Mean ± SD
Age, yr Body mass index, kg/m2 Comorbidities Arterial hypertension Diabetes mellitus Dyslipidemia Coronary artery disease Stroke Peripheral artery disease Active smoking Baseline IIEF-5 Mild ED Mild-to-moderate ED Moderate ED Severe ED Previously treated for ED
58.76 ± 10.27 28.79 ± 3.33 % of N total 45.5% 33.8% 41.6% 6.5% 6.5% 2.6% 22.0% % of N total 14.2% 23.6% 42.8% 19.4% % of N total 40.3%
ED ¼ erectile dysfunction; IIEF ¼ International Index of Erectile Function; P25 ¼ 25th percentile; P75 ¼ 75th percentile.
minutes before intercourse on an empty stomach (1 hour before or 2 hours after the last meal), and patients were informed of its 6-hour clinical effect. Patients were counseled to try at least 8 attempts before quitting and at the 3-month follow-up appointment, re-education about the drug and its effects was provided to nonresponders who did not comply. If positive results were accomplished, a dosage reduction to 50 or 25 mg was carried out.
Statistical Analysis All data were collected and assessed using the Statistical Package for the Social Sciences version 24 (IBM, Chicago, IL). The Shapiro-Wilk test was applied to assess parameter distribution. All continuous variables with normal distribution are expressed as the mean ± SD, and non-normally distributed variables are expressed as the median (25the75th quartiles). Pearson’s correlation was applied to assess the correlation between IIEF-5 and EDITS at 6 months of follow-up and for PSV, EDF, RI, and EHS during PDU. Chi-square testing was used to assess the distribution between groups. Receiver operating characteristic (ROC) curves were drawn for PSV, EDF, RI, and EHS using improvement, cure, and satisfaction at 6 months of treatment with sildenafil citrate as dichotomic variables, and the area under the curves (AUCs) were calculated and compared to assess test power. EDF was interpreted as if a lower test value was a more positive test because a negative correlation was verified, and DeLong’s empirical method was used to compare the AUCs. All tests were 2-sided and statistical significance was considered at a P value < .05.
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frequencies Mean ± SD Highest PSV, mL/s Lowest EDF, mL/s Resistive index EHS I II III IV
56.57 ± 19.27 0.37 ± 6.63 Median [P25; P75] 1.00 [0.90; 1.00] % of N total 1.3% 27.2% 35.1% 36.4%
EDF ¼ end diastolic flow; EHS ¼ erection hardness score; P25 ¼ 25th percentile; P75 ¼ 75th percentile; PDU ¼ penile duplex ultrasound; PSV ¼ peak systolic velocity.
RESULTS A total of 77 patients were included and underwent the methods because only 115 patients had a confirmed diagnosis of ED, and from those patients, 38 had a diagnosis of male hypogonadism, and were excluded. Only 2 patients required alprostadil redosing or a repeated PDU for failure to achieve a BQE upon first ICI. No patient was excluded for failure to achieve a BQE, and no patient presented a clinically significant complication related to the PDU, namely priapism. The patients’ mean age was 58.76 ± 10.27 years, and arterial hypertension, diabetes mellitus, and dyslipidemia were common among participants (45.5%, 33.8%, and 41.6%, respectively). Almost half of the patients had previously been treated for ED and had moderate ED according to the IIEF-5 (40.3% and 42.8%, respectively). Other patient’s characteristics are described in Table 2, and PDU characteristics, namely penile hemodynamic measures PSV, EDF, and RI, as well as EHS, are described in Table 3. There was a weak to moderate correlation between IIEF-5 and EDITS at 6 months of follow-up and PSV, EDF, and RI during PDU, whereas the correlation was moderate to strong with EHS during PDU (Table 4). Improvement, cure, and satisfaction were high among participants (77.9%, 64.9%, and 67.5%, respectively), and there were differences in improvement, cure, and satisfaction regarding PDU or EHS status (P > .001 for all), as shown in Table 5.
Primary End Point The ROC curves for EHS, RI, and PSV are displayed in Figure 1. The EHS has a larger AUC than PSV, EDF, and RI for treatment satisfaction, whereas it was not smaller than PSV, EDF, or RI for neither improvement nor cure with sildenafil citrate (Table 6). The EHS has also shown an excellent to good ability to predict improvement, cure, and satisfaction (AUC ¼ 0.921, 0.873, and 0.898, respectively) with sildenafil citrate treatment.
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Table 4. Correlation (r) between IIEF-5 and EDITS at 6 months’ follow-up, and PSV, EDF, RI, and EHS during PDU
IIEF-5 at 6 mo, r P value EDITS at 6 mo, r P value
PSV
EDF
RI
EHS
0.334 .007* 0.321 .010*
-0.376 .002* -0.439 > .001*
0.625 > .001* 0.670 > .001*
0.403 .001* 0.402 .001*
Pearson’s test was applied to assess significance. EDF ¼ end diastolic flow; EDITS ¼ Erectile Dysfunction Inventory of Treatment Satisfaction; EHS ¼ erection hardness score; IIEF ¼ International Index of Erectile Function; PDU ¼ penile duplex ultrasound; PSV ¼ peak systolic velocity; RI ¼ resistive index. *Denotes statistical significance.
DISCUSSION Although PDU is an established specialized diagnostic test in ED, its real-life impact in clinical practice is still unknown. In the past, several authors assessed PDU’s role as a predictor of treatment response or satisfaction,14e17 and none has shown a positive contribution that would allow or facilitate targeted ED treatment. As shown in past research, PDU hemodynamic parameters— PSV, EDV, or RI—and the usual classifications (normal, arterial insufficiency, and veno-occlusive dysfunction), can significantly predict ED treatment response,14,16e18 and even satisfaction,17 with sildenafil citrate. Moreover, the degree of association seems to be consistent between authors and methodologies. However, 1 group did not find PDU hemodynamic parameters to be clinical predictors of treatment response or satisfaction,19 whereas another group did not observe a correlation between erection rigidity during IIT and sildenafil citrate treatment.20 Our group believes that in the first case, forward stepwise binary regression statistical analysis performed may not have been the best approach to assess a continuous variable, such as PSV, EDF, and RI, diminishing its values when dichotomy cutoffs are attributed. In the second case, patients who are known to have a worse response to sildenafil citrate compared to ICI, such as male hypogonadism20,21 or radical pelvic surgery,22 were not excluded and most likely biased the results. The clinical utility of PDU hemodynamic parameters has never before been formally compared to erection rigidity during
an IIT, yet only PDU is often recommended to document endstage ED for medico-legal reasons.23 Moreover, there are no universally agreed upon diagnostic thresholds for PDU categories,24 and the distinction between arterial insufficiency and veno-occlusive dysfunction in an abnormal PDU has yet to have a clinical impact; hence, targeted treatment is still an illusion.23 Only Elhanbly et al19 have compared PDU hemodynamic parameters and erection rigidity because the latter factor, although assessed with a nonvalidated score, was a clinical predictor of treatment improvement/satisfaction, whereas the former factor was not. Thus, no formal comparison was performed between PDU and IIT. Although the Elhanbly et al19 research served as a pioneer effort and was the first study to doubt the added value of PDU as a clinical predictor of treatment response, our work is the first to directly compare IIT with PDU using validated questionnaires in a standardized, prospective manner. Although PSV, EDF, and RI are fair-to-good predictors of clinical response on their own, erection rigidity as assessed using the EHS was either a better or nondifferent test than PSV, EDF, and RI for improvement, cure, and satisfaction with sildenafil citrate treatment (Table 6 and Figure 1). Moreover, erection rigidity may be a better predictor of treatment response, as indicated by the consistently larger AUC with treatment satisfaction, which is the most important end point in patient care. The present study shows that in the case of need for a specialized diagnostic test for ED, there may be no reason to perform more than a simple IIT with alprostadil, a process that can be easily performed by health care professionals and does not require ultrasonography skills or hardware—our study clearly demonstrates that there is no difference in the ability of PSV, EDV, or RI and EHS to predict treatment improvement, cure, or satisfaction with first-line therapy featuring sildenafil citrate. Moreover, the EHS may even be a better predictor than the former 3 approaches. This finding could be explained by the fact that erection rigidity and the EHS score depend on the total combined effect of both arteries and veins, whereas with PDU, PSV, and EDF are expressed singly, and EDF is an indirect measure of the venous side, RI being only an indirect and imperfect measure of erection rigidity. Our study has certain limitations. It was a single-center analysis, and the population included was rather small when compared to previous research articles in this field. Methods were
Table 5. Improvement, cure, and satisfaction regarding PDU and EHS status PDU
Improvement Cure Satisfaction
EHS
Normal (n ¼ 46)
Abnormal (n ¼ 31)
P value
Normal (n ¼ 57)
Abnormal (n ¼ 20)
P value
100.0% 95.6% 97.8%
74.1% 45.1% 54.8%
> .001* > .001* > .001*
100.0% 91.2% 96.4%
55.0% 30.0% 35.0%
> .001* > .001* > .001*
Percentages are described as % of N row total. Chi-square testing was used to assess distribution. EHS ¼ erection hardness score; PDU ¼ penile duplex ultrasound. *Denotes statistical significance. J Sex Med 2019;-:1e7
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Is There a Point to Penile Duplex Ultrasound?
Figure 1. Peak systolic velocity, end diastolic flow (EDF), resistive index, and erection hardness score receiver operating characteristic curves are depicted. EDF was interpreted as if a lower test value was a more positive test.
initially drawn up to allow similar recruitment with 200 patients screened, but misdiagnosis and male hypogonadism diagnoses limited final inclusion to 77 patients25—half the initial intended number. However, our study presented a similar correlation among PSV, EDF, and RI and the clinical efficacy questionnaires in previous studies,14 thus reducing the possibility of a type 1 error. The complete IIEF was not used because only the IIEF-5 was available in our native language at the time of study design.9 However, our group utilized the same translation in 2 previous research articles with success.26,27 On the other hand, this is the first study to directly compare IIT and PDU. It is prospective, and validated disease-specific questionnaires were used to assess both clinical efficacy and satisfaction. There were strict inclusion and exclusion criteria, and a rigorous protocol was followed. Moreover, PDU was conducted by a blinded third party following a standardized protocol to avoid suggestion bias. Table 6. AUC for PSV, EDF, RI, and EHS for improvement, cure, and satisfaction
Improvement P value Cure P value Satisfaction P value
EHS
PSV
EDF
RI
0.921 Reference 0.873 Reference 0.898 Reference
0.837 .237 0.687 .022* 0.729 .029*
0.625 .006* 0.798 .285 0.748 .045*
0.638 .008* 0.792 .253 0.746 0.045*
Comparison was performed with DeLong’s empirical method taking the EHS AUCs as reference. AUC ¼ area under the curve; EDF ¼ end diastolic flow; EHS ¼ erection hardness score; PSV ¼ peak systolic velocity; RI ¼ resistive index. *Denotes statistical significance.
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CONCLUSION PDU does not offer any added value as a specialized ED diagnostic tool when compared with IIT, as penile hemodynamic parameters add no prognostic value to improvement, cure, or satisfaction with first-line sildenafil citrate for ED treatment. Assessment of erectile rigidity during IIT, using the EHS, may suffice and even surpass PDU as a prognostic tool, and, thus, IIT could replace PDU for medico-legal reasons. Corresponding Author: Afonso Morgado, Centro Hospitalar Universitário São João, Serviço de Urologia, Porto, Portugal. Tel: 351 22 551 21 00; Fax: 351 22 502 57 66; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Afonso Morgado (b) Acquisition of Data Afonso Morgado (c) Analysis and Interpretation of Data Afonso Morgado; Paulo Diniz; Carlos Martins Silva Category 2 (a) Drafting the Article Afonso Morgado (b) Revising It for Intellectual Content Afonso Morgado; Paulo Diniz; Carlos Martins Silva
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Category 3 (a) Final Approval of the Completed Article Afonso Morgado; Paulo Diniz; Carlos Martins Silva
Corresponding Author: Afonso Morgado, Centro Hospitalar Universitário São João, Serviço de Urologia, Porto, Portugal. Tel: 351 22 551 21 00; Fax: 351 22 502 57 66; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
STATEMENT OF AUTHORSHIP: Statement of Authorship: Conceptualization, A. M.; Methodology, A.M. and C. S.; Investigation, A. M. and C. S.; Writing e Original Draft, A. M.; Writing e Review & Editing, C. S..; Funding Acquisition, P.D.; Resources, P.D.; Supervision, P.D. and C.S.
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16. Xuan XJ, Bai G, Zhang CX, et al. The application of color Doppler flow imaging in the diagnosis and therapeutic effect evaluation of erectile dysfunction. Asian J Androl 2016; 18:118-122.
2. Lue TF, Hricak H, Marich KW, et al. Evaluation of arteriogenic impotence with intracorporeal injection of papaverine and the duplex ultrasound scanner. Semin Urol 1985;3:43-48.
17. Morgado A, Dinis P, Silva CM. Is there a role for bilateral peak systolic velocity readings in a penile duplex ultrasound? Andrologia 2019:e13297.
3. Lee B, Sikka SC, Randrup ER, et al. Standardization of penile blood flow parameters in normal men using intracavernous prostaglandin E1 and visual sexual stimulation. J Urol 1993; 149:49-52.
18. Mahon A, Sidhu PS, Muir G, et al. The efficacy of sildenafil for the treatment of erectile dysfunction in male peritoneal dialysis patients. Am J Kidney Dis 2005;45:381-387.
4. Sikka SC, Hellstrom WJ, Brock G, et al. Standardization of vascular assessment of erectile dysfunction: Standard operating procedures for duplex ultrasound. J Sex Med 2013; 10:120-129. 5. Pagano MJ, Stahl PJ. Variation in penile hemodynamics by anatomic location of cavernosal artery imaging in penile duplex Doppler ultrasound. J Sex Med 2015;12:1911-1919. 6. Mulhall JP, Goldstein I, Bushmakin AG, et al. Validation of the erection hardness score. J Sex Med 2007;4:1626-1634. 7. Goldstein I, Mulhall JP, Bushmakin AG, et al. The erection hardness score and its relationship to successful sexual intercourse. J Sex Med 2008;5:2374-2380. 8. Parisot J, Yiou R, Salomon L, et al. Erection hardness score for the evaluation of erectile dysfunction: Further psychometric assessment in patients treated by intracavernous prostaglandins injections after radical prostatectomy. J Sex Med 2014;11:2109-2118. 9. Pechorro PS, Calvinho AM, Pereira NM, et al. Validação de uma versão portuguesa do Índice Internacional de Função Eréctil-5 (IIEF-5). Rev Int Androl 2011;9:3-9.
19. Elhanbly SM, Elkholy AA, Alghobary M, et al. Clinical predictive factors of sildenafil response: A penile hemodynamic study. Andrology 2015;3:241-246. 20. Park K, Ku JH, Kim SW, et al. Risk factors in predicting a poor response to sildenafil citrate in elderly men with erectile dysfunction. BJU Int 2005;95:366-370. 21. Efesoy O, Ҫayan S, Akbay E. The effect of testosterone replacement therapy on penile hemodynamics in hypogonadal men with erectile dysfunction, having veno-occlusive dysfunction. Am J Mens Health 2018;12:634-638. 22. Baniel J, Israilov S, Segenreich E, et al. Comparative evaluation of treatments for erectile dysfunction in patients with prostate cancer after radical retropubic prostatectomy. BJU Int 2001; 88:58-62. 23. Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation. Eur Urol 2010;57:804-814. 24. Butaney M, Thirumavalavan N, Hockenberry MS, et al. Variability in penile duplex ultrasound international practice patterns, technique, and interpretation: An anonymous survey of ISSM members. Int J Impot Res 2018;30:237-242.
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Is There a Point to Penile Duplex Ultrasound? 25. Morgado A, Moura ML, Dinis P, et al. Misdiagnosis and undertreatment of erectile dysfunction in the Portuguese primary health care. Sex Med 2019;7:177-183. 26. Morgado A, Cavadas AS, Pacheco Figueiredo L, et al. Longterm patient-reported satisfaction with different inflatable
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7 penile prosthesis: Comparison between AMS 700CX and Coloplast Titan. Rev Int Androl 2018;16:112-118. 27. Morgado A, Morgado MR, Tomada N. Penile lengthening with porcine small intestinal submucosa grafting in Peyronie’s disease treatment: Long-term surgical outcomes, patients’ satisfaction and dissatisfaction predictors. Andrology 2018;6:909-915.
Is There a Point to Performing a Penile Duplex Ultrasound? Afonso Morgado,1,2 Paulo Diniz, PhD,1,3 and Carlos Martins Silva, PhD1,3
ABSTRACT
Introduction: Specialized diagnostic evaluation of erectile dysfunction (ED) may require an intracavernous injection test (IIT) or penile duplex ultrasound (PDU). Aim: Our primary objective was to compare the prognostic value of IIT and PDU for treatment efficacy and patient satisfaction with first-line sildenafil citrate. Methods: After 200 patients were screened, a total of 77 patients with ED had a standardized PDU by a blinded third party, and peak systolic velocity (PSV), end diastolic flow (EDF), and resistive index (RI) in timely intervals were recorded. The erection hardness score (EHS) was used to score erection rigidity during the test and was also noted. Patients also completed a briefed International Index of Erectile Function (IIEF-5) questionnaire and were started on open-label 100 mg sildenafil citrate at baseline. The IIEF-5 and erectile dysfunction inventory of treatment satisfaction (EDITS) questionnaires were repeated and completed at 6 months’ follow-up. Improvement, cure, and satisfaction were defined as an increase of 4 points in IIEF-5 with an IIEF-5 score higher than 21 points and EDITS score higher than 50, respectively. Receiver operating characteristic curves were drawn and the area under the curve (AUC) was calculated and compared. Main Outcome Measure: EHS did not have a different or larger AUC than PSV, EDF, and RI for improvement, cure, and satisfaction with sildenafil citrate. Results: The patient’s mean age was 58.76 ± 10.27 years and almost half of the patients had moderate ED according to the IIEF-5 (42.8%). Improvement, cure, and satisfaction were high among participants (77.9%, 64.9%, and 67.5%, respectively). The erection rigidity EHS also showed an excellent-to-good ability to predict improvement, cure, and patient satisfaction (AUC ¼ 0.921, 0.873, and 0.898, respectively) with sildenafil citrate. Clinical Implications: There is no point in performing more than an IIT when a specialized diagnostic evaluation is required for diagnostic or medico-legal reasons because PDU is time-consuming and requires both hardware and ultrasound skills with no added prognostic value. Strengths and Limitations: This is the first prospective study to directly compare IIT with PDU, and validated disease-specific questionnaires were used to assess both clinical efficacy and satisfaction. Moreover, the PDU was performed by a blinded third party. However, this was a single-center study and the population included was small. Conclusion: PDU parameters add no prognostic value to determining erection rigidity during a standard IIT. Erection rigidity during IIT, as assessed with the EHS, suffices as a prognostic tool. Morgado A, Diniz P, Silva CM. Is There a Point to Performing a Penile Duplex Ultrasound? J Sex Med 2019;XX:XXXLXXX. Copyright 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Penile Doppler Ultrasound; Intracavernous Injection Test; Erection Hardness Score; Erectile Dysfunction; Prognostic; Satisfaction
INTRODUCTION Erectile dysfunction (ED) is a prevalent age-related disease worldwide, with 26.0% of men aged over 60 years reporting erection problems.1 The diagnostic evaluation of ED may require Received June 16, 2019. Accepted July 12, 2019. 1
Serviço de Urologia, Centro Hospitalar Universitário São João, Porto, Portugal;
2
Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal;
J Sex Med 2019;-:1e7
a minimally invasive procedure, such as the intracavernous injection test (IIT) or the penile duplex ultrasound (PDU), to assess penile vascular hemodynamics. However, since PDU’s first introduction by Lue et al2 in 1985, IIT has been largely replaced
3
Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
Copyright ª 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jsxm.2019.07.010
1
2
by PDU because ITT yields limited diagnostic information regarding vascular status, and it is often considered inconclusive as a diagnostic procedure. The added information from the PDU may provide a clear diagnosis and allow for targeted treatment, which could increase treatment efficacy and patient satisfaction. However, there is no generalized agreement on the interpretation of common PDU parameter measurements,2e4 such as peak systolic velocity (PSV), end diastolic flow (EDF), and resistive index (RI). Additionally, there is also known intra- and inter-observer variation in terms of PDU results.5 Moreover, effective targeted treatment remains elusive in the current era because most, if not all, patients will adhere to the same treatment algorithms with little to no individual variations. Our group doubts the added value of common PDU parameter measurement and its diagnostic value in predicting improvement, cure, or satisfaction with ED treatment, which are the primary end points in patient care. Moreover, simple scores and scales, such as the Erection Hardness Score (EHS), do not require ultrasound or Doppler measurements and can be easily applied during IIT. The former is a simple 1-item method to grade erection quality, and it has been demonstrated to be able to reliably predict successful sexual intercourse with both oral sildenafil citrate and intracavernous alprostadil treatment.68 Our primary objective was to compare the prognostic value of common PDU parameters—PSV, EDF, and RI—with EHS during IIT in predicting improvement, cure, and satisfaction with first-line ED treatment featuring sildenafil citrate.
MATERIALS AND METHODS After approval by the hospital’s ethical committee, 200 consecutive male patients referred for ED were screened between January 2016 and December 2018. After consent was obtained, a full standardized medical and sexual history was taken, and if a diagnosis of ED was not confirmed or male hypogonadism was diagnosed, the patients were excluded. Male hypogonadismscreening methods are further described in a previous article. Patients had a standardized PDU with 15 ug of intracavernous injection (ICI) alprostadil by a blinded third party. Alprostadil redosing or repeating PDU were not exclusion criteria and were allowed to achieve the best quality erection (BQE). The detailed list of exclusion criteria is depicted in Table 1. A total of 77 patients were included and further completed a translated validated version of the brief International Index of Erectile Function (IIEF-5) at baseline9 and started ondemand treatment with open-label oral sildenafil citrate 100 mg. Two programmed follow-up appointments were scheduled at 3 and 6 months, at which point IIEF-5 questionnaires were repeated to assess clinical improvement and cure. The erectile dysfunction inventory of treatment satisfaction (EDITS) questionnaire was also completed at 6 months to assess treatment satisfaction.10
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Table 1. Exclusion criteria Unconfirmed main diagnosis of ED ED with < 12 months of duration Failure to achieve BQE with PDU Male hypogonadism Peyronie’s disease Premature ejaculation Unstable or no relationship Absolute contraindication for ED treatment with sildenafil or alprostadil Radical pelvic surgery History of penile surgery other than circumcision were excluded BQE ¼ best quality erection; ED ¼ erectile dysfunction; PDU ¼ penile duplex ultrasound.
ED severity was evaluated according to IIEF-5 scores as follows: 2225 ¼ no ED; 1721 ¼ mild ED; 1216 ¼ mild-tomoderate ED; 811 ¼ moderate ED; and 57 ¼ severe ED.11 Regarding the primary objective, clinical improvement was defined as an increase of 4 points in IIEF-5 score between the baseline and the last valid follow-up visit, and cure was defined as an IIEF-5 higher than 21 points at the last valid follow-up visit.12 Satisfaction was defined as an EDITS score higher than 50.
Penile Doppler Ultrasound Patients followed a standardized protocol by a blinded radiologist using a color duplex ultrasound device and a 7.5 MHz superficial probe. First, a penile evaluation was performed to exclude corporeal fibrosis or Peyronie’s plaques, and the bilateral cavernous artery diameter was measured. An ICI of 15 ug alprostadil was performed on one side. Bilateral PSV and EDF were then recorded at timed 5-minute intervals. The highest PSV and lowest EDF were noted. An erection equivalent to the best erection obtainable at home was required for the test to count. Alprostadil redosing or repeating the PDU were permitted to achieve a BQE. A normal PDU was defined as the highest PSV > 30 cm/s, an EDF < 5 cm/s, and RI higher than 0.8.13
Erection Rigidity Erection rigidity was assessed during PDU by the radiologist at the point of maximal erection using the EHS. This score is a single-item Likert scale that rates the hardness of an erection according to 5 grades: 0 ¼ penis does not enlarge; 1 ¼ penis enlarges but not is hard; 2 ¼ penis is hard but not hard enough for penetration; 3 ¼ penis is hard enough for penetration but not completely rigid; and 4 ¼ penis is completely hard and fully rigid.7 A normal EHS was defined as a score equal to or higher than 3.
Sildenafil Citrate Administration The pharmacologic intervention was carried out by an openlabel administration of 100 mg sildenafil citrate at least 30 J Sex Med 2019;-:1e7
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Table 2. Patient characteristics (n ¼ 77 patients)
Table 3. PDU hemodynamic characteristics and EHS absolute Mean ± SD
Age, yr Body mass index, kg/m2 Comorbidities Arterial hypertension Diabetes mellitus Dyslipidemia Coronary artery disease Stroke Peripheral artery disease Active smoking Baseline IIEF-5 Mild ED Mild-to-moderate ED Moderate ED Severe ED Previously treated for ED
58.76 ± 10.27 28.79 ± 3.33 % of N total 45.5% 33.8% 41.6% 6.5% 6.5% 2.6% 22.0% % of N total 14.2% 23.6% 42.8% 19.4% % of N total 40.3%
ED ¼ erectile dysfunction; IIEF ¼ International Index of Erectile Function; P25 ¼ 25th percentile; P75 ¼ 75th percentile.
minutes before intercourse on an empty stomach (1 hour before or 2 hours after the last meal), and patients were informed of its 6-hour clinical effect. Patients were counseled to try at least 8 attempts before quitting and at the 3-month follow-up appointment, re-education about the drug and its effects was provided to nonresponders who did not comply. If positive results were accomplished, a dosage reduction to 50 or 25 mg was carried out.
Statistical Analysis All data were collected and assessed using the Statistical Package for the Social Sciences version 24 (IBM, Chicago, IL). The Shapiro-Wilk test was applied to assess parameter distribution. All continuous variables with normal distribution are expressed as the mean ± SD, and non-normally distributed variables are expressed as the median (25the75th quartiles). Pearson’s correlation was applied to assess the correlation between IIEF-5 and EDITS at 6 months of follow-up and for PSV, EDF, RI, and EHS during PDU. Chi-square testing was used to assess the distribution between groups. Receiver operating characteristic (ROC) curves were drawn for PSV, EDF, RI, and EHS using improvement, cure, and satisfaction at 6 months of treatment with sildenafil citrate as dichotomic variables, and the area under the curves (AUCs) were calculated and compared to assess test power. EDF was interpreted as if a lower test value was a more positive test because a negative correlation was verified, and DeLong’s empirical method was used to compare the AUCs. All tests were 2-sided and statistical significance was considered at a P value < .05.
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frequencies Mean ± SD Highest PSV, mL/s Lowest EDF, mL/s Resistive index EHS I II III IV
56.57 ± 19.27 0.37 ± 6.63 Median [P25; P75] 1.00 [0.90; 1.00] % of N total 1.3% 27.2% 35.1% 36.4%
EDF ¼ end diastolic flow; EHS ¼ erection hardness score; P25 ¼ 25th percentile; P75 ¼ 75th percentile; PDU ¼ penile duplex ultrasound; PSV ¼ peak systolic velocity.
RESULTS A total of 77 patients were included and underwent the methods because only 115 patients had a confirmed diagnosis of ED, and from those patients, 38 had a diagnosis of male hypogonadism, and were excluded. Only 2 patients required alprostadil redosing or a repeated PDU for failure to achieve a BQE upon first ICI. No patient was excluded for failure to achieve a BQE, and no patient presented a clinically significant complication related to the PDU, namely priapism. The patients’ mean age was 58.76 ± 10.27 years, and arterial hypertension, diabetes mellitus, and dyslipidemia were common among participants (45.5%, 33.8%, and 41.6%, respectively). Almost half of the patients had previously been treated for ED and had moderate ED according to the IIEF-5 (40.3% and 42.8%, respectively). Other patient’s characteristics are described in Table 2, and PDU characteristics, namely penile hemodynamic measures PSV, EDF, and RI, as well as EHS, are described in Table 3. There was a weak to moderate correlation between IIEF-5 and EDITS at 6 months of follow-up and PSV, EDF, and RI during PDU, whereas the correlation was moderate to strong with EHS during PDU (Table 4). Improvement, cure, and satisfaction were high among participants (77.9%, 64.9%, and 67.5%, respectively), and there were differences in improvement, cure, and satisfaction regarding PDU or EHS status (P > .001 for all), as shown in Table 5.
Primary End Point The ROC curves for EHS, RI, and PSV are displayed in Figure 1. The EHS has a larger AUC than PSV, EDF, and RI for treatment satisfaction, whereas it was not smaller than PSV, EDF, or RI for neither improvement nor cure with sildenafil citrate (Table 6). The EHS has also shown an excellent to good ability to predict improvement, cure, and satisfaction (AUC ¼ 0.921, 0.873, and 0.898, respectively) with sildenafil citrate treatment.
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Table 4. Correlation (r) between IIEF-5 and EDITS at 6 months’ follow-up, and PSV, EDF, RI, and EHS during PDU
IIEF-5 at 6 mo, r P value EDITS at 6 mo, r P value
PSV
EDF
RI
EHS
0.334 .007* 0.321 .010*
-0.376 .002* -0.439 > .001*
0.625 > .001* 0.670 > .001*
0.403 .001* 0.402 .001*
Pearson’s test was applied to assess significance. EDF ¼ end diastolic flow; EDITS ¼ Erectile Dysfunction Inventory of Treatment Satisfaction; EHS ¼ erection hardness score; IIEF ¼ International Index of Erectile Function; PDU ¼ penile duplex ultrasound; PSV ¼ peak systolic velocity; RI ¼ resistive index. *Denotes statistical significance.
DISCUSSION Although PDU is an established specialized diagnostic test in ED, its real-life impact in clinical practice is still unknown. In the past, several authors assessed PDU’s role as a predictor of treatment response or satisfaction,14e17 and none has shown a positive contribution that would allow or facilitate targeted ED treatment. As shown in past research, PDU hemodynamic parameters— PSV, EDV, or RI—and the usual classifications (normal, arterial insufficiency, and veno-occlusive dysfunction), can significantly predict ED treatment response,14,16e18 and even satisfaction,17 with sildenafil citrate. Moreover, the degree of association seems to be consistent between authors and methodologies. However, 1 group did not find PDU hemodynamic parameters to be clinical predictors of treatment response or satisfaction,19 whereas another group did not observe a correlation between erection rigidity during IIT and sildenafil citrate treatment.20 Our group believes that in the first case, forward stepwise binary regression statistical analysis performed may not have been the best approach to assess a continuous variable, such as PSV, EDF, and RI, diminishing its values when dichotomy cutoffs are attributed. In the second case, patients who are known to have a worse response to sildenafil citrate compared to ICI, such as male hypogonadism20,21 or radical pelvic surgery,22 were not excluded and most likely biased the results. The clinical utility of PDU hemodynamic parameters has never before been formally compared to erection rigidity during
an IIT, yet only PDU is often recommended to document endstage ED for medico-legal reasons.23 Moreover, there are no universally agreed upon diagnostic thresholds for PDU categories,24 and the distinction between arterial insufficiency and veno-occlusive dysfunction in an abnormal PDU has yet to have a clinical impact; hence, targeted treatment is still an illusion.23 Only Elhanbly et al19 have compared PDU hemodynamic parameters and erection rigidity because the latter factor, although assessed with a nonvalidated score, was a clinical predictor of treatment improvement/satisfaction, whereas the former factor was not. Thus, no formal comparison was performed between PDU and IIT. Although the Elhanbly et al19 research served as a pioneer effort and was the first study to doubt the added value of PDU as a clinical predictor of treatment response, our work is the first to directly compare IIT with PDU using validated questionnaires in a standardized, prospective manner. Although PSV, EDF, and RI are fair-to-good predictors of clinical response on their own, erection rigidity as assessed using the EHS was either a better or nondifferent test than PSV, EDF, and RI for improvement, cure, and satisfaction with sildenafil citrate treatment (Table 6 and Figure 1). Moreover, erection rigidity may be a better predictor of treatment response, as indicated by the consistently larger AUC with treatment satisfaction, which is the most important end point in patient care. The present study shows that in the case of need for a specialized diagnostic test for ED, there may be no reason to perform more than a simple IIT with alprostadil, a process that can be easily performed by health care professionals and does not require ultrasonography skills or hardware—our study clearly demonstrates that there is no difference in the ability of PSV, EDV, or RI and EHS to predict treatment improvement, cure, or satisfaction with first-line therapy featuring sildenafil citrate. Moreover, the EHS may even be a better predictor than the former 3 approaches. This finding could be explained by the fact that erection rigidity and the EHS score depend on the total combined effect of both arteries and veins, whereas with PDU, PSV, and EDF are expressed singly, and EDF is an indirect measure of the venous side, RI being only an indirect and imperfect measure of erection rigidity. Our study has certain limitations. It was a single-center analysis, and the population included was rather small when compared to previous research articles in this field. Methods were
Table 5. Improvement, cure, and satisfaction regarding PDU and EHS status PDU
Improvement Cure Satisfaction
EHS
Normal (n ¼ 46)
Abnormal (n ¼ 31)
P value
Normal (n ¼ 57)
Abnormal (n ¼ 20)
P value
100.0% 95.6% 97.8%
74.1% 45.1% 54.8%
> .001* > .001* > .001*
100.0% 91.2% 96.4%
55.0% 30.0% 35.0%
> .001* > .001* > .001*
Percentages are described as % of N row total. Chi-square testing was used to assess distribution. EHS ¼ erection hardness score; PDU ¼ penile duplex ultrasound. *Denotes statistical significance. J Sex Med 2019;-:1e7
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Figure 1. Peak systolic velocity, end diastolic flow (EDF), resistive index, and erection hardness score receiver operating characteristic curves are depicted. EDF was interpreted as if a lower test value was a more positive test.
initially drawn up to allow similar recruitment with 200 patients screened, but misdiagnosis and male hypogonadism diagnoses limited final inclusion to 77 patients25—half the initial intended number. However, our study presented a similar correlation among PSV, EDF, and RI and the clinical efficacy questionnaires in previous studies,14 thus reducing the possibility of a type 1 error. The complete IIEF was not used because only the IIEF-5 was available in our native language at the time of study design.9 However, our group utilized the same translation in 2 previous research articles with success.26,27 On the other hand, this is the first study to directly compare IIT and PDU. It is prospective, and validated disease-specific questionnaires were used to assess both clinical efficacy and satisfaction. There were strict inclusion and exclusion criteria, and a rigorous protocol was followed. Moreover, PDU was conducted by a blinded third party following a standardized protocol to avoid suggestion bias. Table 6. AUC for PSV, EDF, RI, and EHS for improvement, cure, and satisfaction
Improvement P value Cure P value Satisfaction P value
EHS
PSV
EDF
RI
0.921 Reference 0.873 Reference 0.898 Reference
0.837 .237 0.687 .022* 0.729 .029*
0.625 .006* 0.798 .285 0.748 .045*
0.638 .008* 0.792 .253 0.746 0.045*
Comparison was performed with DeLong’s empirical method taking the EHS AUCs as reference. AUC ¼ area under the curve; EDF ¼ end diastolic flow; EHS ¼ erection hardness score; PSV ¼ peak systolic velocity; RI ¼ resistive index. *Denotes statistical significance.
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CONCLUSION PDU does not offer any added value as a specialized ED diagnostic tool when compared with IIT, as penile hemodynamic parameters add no prognostic value to improvement, cure, or satisfaction with first-line sildenafil citrate for ED treatment. Assessment of erectile rigidity during IIT, using the EHS, may suffice and even surpass PDU as a prognostic tool, and, thus, IIT could replace PDU for medico-legal reasons. Corresponding Author: Afonso Morgado, Centro Hospitalar Universitário São João, Serviço de Urologia, Porto, Portugal. Tel: 351 22 551 21 00; Fax: 351 22 502 57 66; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Afonso Morgado (b) Acquisition of Data Afonso Morgado (c) Analysis and Interpretation of Data Afonso Morgado; Paulo Diniz; Carlos Martins Silva Category 2 (a) Drafting the Article Afonso Morgado (b) Revising It for Intellectual Content Afonso Morgado; Paulo Diniz; Carlos Martins Silva
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Category 3 (a) Final Approval of the Completed Article Afonso Morgado; Paulo Diniz; Carlos Martins Silva
Corresponding Author: Afonso Morgado, Centro Hospitalar Universitário São João, Serviço de Urologia, Porto, Portugal. Tel: 351 22 551 21 00; Fax: 351 22 502 57 66; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
STATEMENT OF AUTHORSHIP: Statement of Authorship: Conceptualization, A. M.; Methodology, A.M. and C. S.; Investigation, A. M. and C. S.; Writing e Original Draft, A. M.; Writing e Review & Editing, C. S..; Funding Acquisition, P.D.; Resources, P.D.; Supervision, P.D. and C.S.
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