Variable response to intracavernous prostaglandin E1 testing for erectile dysfunction

ADULT UROLOGY

VARIABLE RESPONSE TO INTRACAVERNOUS PROSTAGLANDIN E1 TESTING FOR ERECTILE DYSFUNCTION KURT LEHMANN, HUBERT JOHN, GEORG KACL, DIETER HAURI,

AND

THOMAS C. GASSER

ABSTRACT Objectives. Anxiety and apprehension may negatively influence the erectile response to the first intracavernous injection with vasoactive agents. This may result in too many false-positive diagnoses of vascular insufficiency if the first injection ever made in a patient is used for color Doppler duplex sonography (CDS) evaluation. Methods. One hundred sixty-eight consecutive patients (aged 18 to 75 years) with erectile dysfunction underwent a standardized evaluation, including the intracavernous injection test (ICIT) stimulated with 10 ␮g prostaglandin E1. Responses were recorded on a four-point scale: no response ⫽ 0, tumescence ⫽ 1, rigidity sufficient for intercourse ⫽ 2, full erection ⫽ 3. ICIT was repeated after 10 days and combined with CDS. The clinically assessed response to ICIT was correlated with end-diastolic flow velocity. Results. Of 168 patients, 114 (68%) responded equally to the first and second ICIT, but 45 (27%) had an improved response, from tumescence to full erection in the second test (P ⬍0.0001); in 9 (5%), the response deteriorated. The overall mean response was 1.6 (95% confidence interval 1.5 to 1.7) and 1.9 (95% confidence interval 1.7 to 2.0) (P ⬍0.0001) for the first and second test, respectively. Of 168 patients, 89 (53%) responded with erections sufficient for intercourse when tested the first time and 104 (62%) did so after the second injection. Conclusions. Erectile response to diagnostic intracavernous injection of prostaglandin E1 significantly improved in the second compared with the first test. Therefore, cautious interpretation of CDS is advised when patients are injected for the first time because too many false-positive tests may result. UROLOGY 54: 539–543, 1999. © 1999, Elsevier Science Inc.

I

n patients with erectile dysfunction (ED), a precise etiologic diagnosis is important for those who might have surgically correctable lesions. The evaluation of ED has improved greatly since the introduction of intracavernous injection and color Doppler duplex sonography (CDS).1,2 CDS of the cavernous arteries provides functional and quantifiable assessment of penile arterial flow during pharmacologic erection. Problems with CDS include variations in anatomy and sympathetic response to pain and unfamiliarity with staff memFrom the Urologic Clinic, University of Basel, Kantonsspital, Basel, Switzerland; and Urologic Clinic and Department of Radiology, University of Zurich, Universita¨tsspital, Zurich, Switzerland Reprint requests: Kurt Lehmann, M.D., Urologic Clinic, Kontonsspital Baden, CH-5404 Baden, Switzerland Submitted: October 5, 1998, accepted (with revisions): March 29, 1999 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

bers, the environment, and the evaluation procedure itself.3,4 To minimize these effects, the procedure should be carefully explained to the patient and conducted in a quiet environment. Pharmacologic erections may be induced by a standardized dosage of 10 ␮g5,6 prostaglandin E1 (PGE1). Repeating the dose with the same or an alternative agent is recommended to better achieve complete smooth muscle relaxation.7–9 Another approach is an age-referenced standard dosage.10 In addition, there may be a potential benefit to standard dosages with the addition of self-stimulation11 or visual sexual stimulation.12 We do not use either of these two techniques routinely. Repeating the dose is time-consuming and requires pharmacologic reversal of the erection after completion of the test in many patients.13 Therefore, this approach for CDS seems less useful for a standard clinical evaluation. Probably the most practical ap0090-4295/99/$20.00 PII S0090-4295(99)00260-5 539

TABLE I. Number of men in each category of clinically assessed response to 10 ␮g prostaglandin E1 Response to Intracavernous Prostaglandin E1

First Test Summary

No response Tumescence Sufficient for intercourse Full erection Total

8 71 65 24 168

No Change in Second Test

Improved in Second Test

Deteriorated in Second Test

5 50 37 22 114

3 20 22 — 45

— 1 6 2 9

(5) (42) (39) (14)

Second Test Summary 6 58 56 48 168

(4) (34) (33) (29)

Numbers in parentheses are percentages.

proach for clinical use is a standardized dosage of the vasodilating pharmacologic agent.5,6 We have used a standardized intracavernous injection test (ICIT) with 10 ␮g PGE1 for many years.5 We have often observed a diverging response to a repeated dose of the same agent. We speculated that the response to intracavernous injection of a vasoactive agent is partly dependent on a learning process for the patient. This may have important implications on the results and interpretation of CDS, depending on how familiar the patient is with pharmacologic erections. MATERIAL AND METHODS One hundred sixty-eight consecutive patients (mean age ⫾ SD 49 ⫾ 12 years, range 18 to 75) with difficulty in obtaining and/or maintaining an erection sufficient for satisfactory sexual intercourse14 underwent a standardized evaluation. The evaluation included an ICIT at two time points. Both tests were performed with 10 ␮g PGE1. The second test was combined with CDS.5,15 Patients had not undergone any intervention for evaluation or treatment of ED before entry into the study.

INTRACAVERNOUS INJECTION TEST

A volume of 0.5 mL with 10 ␮g PGE1 was injected into the right corpus cavernosum. The patient compressed the injection site for 1 minute. This test was performed at the first evaluation and repeated in the same way at least 10 days later when CDS was added. The erectile response was recorded and clinically classified 15 minutes after injection with the patient upright using the criteria following: no response (0), tumescence (1), an erection at ⫾90° not firm to palpation but sufficient for vaginal intromission (2), and a full erection firm to palpation (3).16 These criteria were clear, and for training and accordance they were applied to the same patients by the two examiners involved before the study began.

COLOR DOPPLER DUPLEX SONOGRAPHY CDS was performed with the second ICIT at least 10 days after the first ICIT. The examiner was unaware of the first ICIT result and independently rated the response to the second test when doing the CDS. CDS was performed with a linear array, 5 to 10-MHz broadband transducer and with a pulsed Doppler probe with a frequency of 5 MHz (Ultramark 9 HDI system, Bothwell, Atlanta, Ga). The internal structure of the penile tissues was assessed with B mode imaging. Pulsed-wave Doppler studies of each cavernosal artery were performed. Spectral Doppler signals with angle correction were measured. 540

The patient was placed in the supine position with the penis dorsiflexed. The deep cavernosal arteries were imaged as proximally as possible with the probe longitudinally positioned.2,17,18 CDS was begun with the penis flaccid. Peak-systolic flow and end-diastolic flow velocities were assessed. After baseline examinations, 10 ␮g PGE1 was injected into the corpus cavernosum, and digital compression was exerted to the injection site for 1 minute. Flow parameters and the internal diameter of the cavernosal arteries were measured 5, 10, and 20 minutes thereafter. At 15 minutes after stimulation, the response was graded clinically by the above-mentioned criteria. A peak flow of less than 30 cm/s 10 minutes after injection of PGE1 suggested evidence of arterial deficiency17,18 and an end-diastolic flow velocity of more than 5 cm/s 20 minutes after injection suggested evidence of venous leakage.19 The end-diastolic flow velocity 20 minutes after intracavernous stimulation with 10 ␮g PGE1 was correlated with the clinically assessed response to the first and second ICIT. For statistical analysis, the paired t test and Spearman correlation test were used, with P ⬍0.05 considered significant.

RESULTS Of 168 patients injected with 10 ␮g PGE1, 79 (47%) achieved erections insufficient for intercourse when tested the first time. When tested the second time, this proportion decreased to 64 of the men (38%). A detailed overview is given in Table I. Overall, the response to the second injection significantly improved, from 1.6 (95% confidence interval 1.5 to 1.7) to 1.9 (95% confidence interval 1.7 to 2.0) (P ⬍0.0001) (Table II). Of 168 men, 45 (27%) of those whose response to PGE1 was tumescence (median value) when tested the first time responded with a full erection (median value) in the second test. The details of these 45 men (Table III) reveal that only 2 men improved from no response to tumescence, and 26 men improved to full erection and 17 to rigid erections good enough for intercourse. Twenty-three men were from the group whose response to PGE1 was not hard enough for intercourse in the first test. The other 22 responded with a rigid erection in the first test and improved to a full erection in the second test. Nine patients had a lesser response to PGE1 in the second test. Of these 9 men, 1 patient did not UROLOGY 54 (3), 1999

TABLE II. Clinically assessed response to prostaglandin E1 (median values) Clinically Assessed Response

Response to Intracavernous Prostaglandin E1 Equal in both tests Improved in second test Deteriorated in second test

Patients (n)

First Test

Second Test

114 45 9

2 1 2

2 3 1

KEY: 0 ⫽ no response; 1 ⫽ tumescence; 2 ⫽ strong enough for intercourse; 3 ⫽ full erection.

respond at all, 6 had some enlargement (tumescence), and 2 deteriorated to incomplete erections (Table II). The flow parameters of the 79 men who responded with erections insufficient for intercourse in the first test are summarized in Table IV. The erectile response in 21 men improved in the second test to a degree that was clinically rated sufficient for intercourse. They showed no vascular pathologic features. Of the 58 men whose erectile response did not improve to a level allowing intercourse, 47 were proved to have vascular pathologic features (7 mixed, 9 arterial, and 31 venous leakage). The flow parameters were normal in 11 patients, although the pharmacologically-induced erections were rated insufficient for intercourse. The flow parameters and the clinically assessed response in the first and second test in the patients who initially responded with erections good enough for intercourse are summarized in Table V. They showed normal flow parameters, with the exception of the men whose second response deteriorated. The correlation (Spearman) between the clinically assessed response to the first and second ICIT and the end-diastolic flow velocity in CDS was ⫺0.48 and ⫺0.62, respectively. COMMENT Despite a growing trend toward cost containment and use of a therapy-oriented approach for the diagnosis and treatment of ED, a precise etiologic diagnosis is important for those patients who might have correctable lesions.20,21 Many patients with ED do not receive a proper evaluation because currently available treatments are so effective. The challenge, however, is to select the best, most appropriate therapy with the least side effects and greatest long-term benefit.22 When the diagnosis is uncertain after history, physical examination, and ICIT and the patient wishes an accurate diagnosis, we add CDS. However, the technique and interpretation of CDS have UROLOGY 54 (3), 1999

many pitfalls. The reproducibility of CDS strongly depends on both the operator’s and patient’s experience.23 As we have no single reproducible method to establish a firm diagnosis, we have no normative reference test.24 The sensitivity and specificity of CDS are difficult to assess. For operators, the learning curve is steep, but we do not know about the patient’s learning curve. The pharmacologic action of vasodilating intracavernous agents might be dependent on the patient’s anxiety status. Therefore, the same dosage of a specific vasodilating agent might not have the same effect on an individual patient at a second injection on another day. This circumstance may have profound effects on the results of CDS. In the present study, a remarkable 27% of men showed a dramatically improved response to the second ICIT. At the first test, they responded with tumescence only. When tested the second time, they had full erections. The evaluation with CDS largely depends on changes effectuated by the action of the vasodilating agent. This action might be counterbalanced by the heightened sympathetic response to anxiety and/or stress in some patients due to lack of privacy, fear of injection, and the nonsexual setting. Thus, CDS performed on a patient injected for the first time may not be representative. Recently, it has been shown that repeating the dose did not have significant implications on the parameters evaluated by CDS.6 However, that study did not overcome nor exclude adverse effects from sympathetic tone. In our study, we demonstrated that prior experience with the injection procedure itself may have profound effects on the pharmacologic erection in up to one third of patients. Therefore, it seems essential to perform CDS on patients only if they are prepared for the intracavernosal injection so as to induce the least sympathetic response possible. We found that 5.4% of men responded less to the second injection. The characteristics of these men were younger age and important psychological factors such as anxiety, fetishism, and depression as evaluated by a psychiatrist. There are limits to the interpretation and reproducibility of the evaluation if the protocols are based on the effects of intracavernosal injections of vasoactive agents.23 These disadvantages may be overcome by repeating the dose of the vasoactive agent to achieve complete smooth muscle relaxation within cavernous bodies.7,25 This regimen is time-consuming and has the disadvantage that the test is performed in supramaximal stimulation not necessarily required for adequate sexual performance. It cannot be recommended for the average patient who wants to regain the ability to achieve erections sufficient for satisfactory sexual performance. As an alternative, additional manual self541

TABLE III. Forty-five patients improving in response to prostaglandin E1 in the second test

Rigid Erection

Full Erection

Duplex Demonstrating Vascular Pathology

17

1 3 22

0 5 2

Clinically Assessed Response to Prostaglandin E1 at Second Test

First Test*

n

Tumescence

0 1 2

3 20 22

2

*0 ⫽ no response; 1 ⫽ tumescence; 2 ⫽ strong enough for intercourse but not full erection.

TABLE IV. Flow parameters of men whose response to prostaglandin E1 in the first test was not good enough to allow sexual intercourse* Subgroups in Patients with Incomplete Response to First Test Improved to rigid or normal erections in second test Second test Vascular pathology Normal flow parameters

n

Peak Flow Velocity at 10 min

End-Diastolic Flow Velocity at 20 min

Resistance Index at 10 min

21

46 (23–92)

0 (⫺15 to ⫹10)

0.95 (0.66–1.2)

58 47 11

40 (10–91) 37 (10–91) 43 (38–80)

7 (⫺6 to ⫹20) 8 (⫺6 to ⫹20) 0 (⫺3 to ⫹4)

0.82 (0.57–1.2) 0.80 (0.57–1.2) 0.95 (0.66–1.0)

* Of these men, 32 (41%) had normal flow parameters in the second test.

TABLE V. Patients who responded with an erection rigid enough for sexual intercourse in the first test First Test

Second Test

n

3 2 2 2/3*

3 3 2 1/2*

23 21 37 8

Peak Flow Velocity at 10 min 53 51 44 39.5

(30–110) (26–108) (14–100) (26–50)

End-diastolic Flow Velocity at 20 min ⫺5 ⫺4 0 6.5

(⫺17 (⫺13 (⫺16 (⫺11

to to to to

0) ⫹10) ⫹12) ⫹18)

Resistance Index at 10 min 1.06 1.06 1.0 0.82

(0.57–1.28) (0.67–1.29) (0.68–1.28) (0.6–1.0)

Normal Duplex Results (n) 23 16 25 2

* Deteriorated in second test.

stimulation11 or video-based stimulation12 may be used to further increase the response to intracavernous vasoactive agents. Interpatient reproducibility of these additional stimulations is questionable in an artificial setting and, furthermore, they might have medicolegal implications, if the patients were to suggest voyeurism by the examiner. Patients may profit from an evaluation that includes CDS performed with a standardized dosage, preferably age related,10 if testing is performed in an adequate environment. The alternative to complete smooth muscle relaxation attained by repeated dosing is to perform CDS on a relaxed and fully informed patient. He will be under less stress if he knows the procedure and is experienced with the pharmacologic erection. CONCLUSIONS We do not recommend performing CDS on patients who are injected with vasoactive agents for the first time. The injection itself, the unusual sur542

roundings, and the unknown personnel may induce stress and heightened adrenergic response, with too many false-positive CDS measurements resulting. ACKNOWLEDGMENT. To Gabriel P. Haas, M.D., Professor of Urology, SUNY Health Science Center at Syracuse, New York, for his help in preparation of this manuscript. REFERENCES 1. Virag R: Intracavernous injection of papaverine for erectile failure (letter). Lancet 2: 938, 1982. 2. Lue TF, Hricek H, Marich KW, et al: Evaluation of vaculogenic impotence with high resolution ultrasonography and pulsed Doppler spectrum analysis. Radiology 155: 777–781, 1985. 3. Meuleman EJ, and Diemont WL: Investigation of erectile dysfunction. Urol Clin North Am 22: 803– 819, 1995. 4. Diederichs W, Stief CG, Lue TF, et al: Sympathetic inhibition of papaverine induced erection. J Urol 146: 195–198, 1991. 5. Lehmann K, Kacl G, Hagspiel K, et al: Die Wertigkeit der farbcodierten Duplexsonographie als Standardabkla¨rung bei erektiler Dysfunktion. Urologe A 35: 456 – 462, 1996. UROLOGY 54 (3), 1999

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