Ahmed Abulfotooh Eid Assistant Lecturer of Genitourinary Surgery, Department of Urology, Faculty of Medicine, University of Alexandria, 15 Rakotees Street, Camp Cesar 21321, Alexandria, Egypt. Email: email@example.com
Objective: Evaluating long-term (50 months) efficacy of transurethral intraprostatic injection of absolute ethanol to treat benign prostatic hyperplasia (BPH).
Methods: A prospective study was conducted to evaluate 35 patients with BPH treated by transurethral injection of dehydrated ethanol. Mean age was 66.3 years. Endoscopic injection of 6–12 mL ethanol was carried out at 5–10 sites in the prostate. International Prostate Symptom Score (IPSS), maximum flow rate, prostate volume, postvoid residual and side effects or complications incidence were logged.
Results: Mean IPSS ± standard deviation improved significantly from 22.0 ± 3.89 preoperatively to 9.85 ± 2.23 at 50 months follow-up. Mean peak urinary flow rate increased from 5.87 ± 3.69 mL/s to 16.89 ± 4.12 after 4 years. Mean residual urine volume had decreased from 68.6 ± 49.98 mL to 36.02 ± 20.87 after 4 years (P < 0.05). The prostate volume decreased from 52.67 ± 20.43 g preoperatively to 49.94 ± 21.28 g after 4 years (statistically significant). There were no intra-operative complications but post-operative urine retention occurred in all patients requiring catheterization for a mean 6.7 days. Acute epididymitis and chronic prostatitis occurred in two patients. Urethral stricture occurred in one patient.
Conclusions: This technique appears to be safe and cost effective. No occurrence of retrograde ejaculation was detected. The long-term effects of ethanol injection of the prostate were satisfactory and acceptable as a minimally invasive therapeutic modality of selected patients.
Benign prostatic hyperplasia (BPH) is the most common benign prostatic lesion in men; its incidence and symptomatology are age-related. It is a pathologic process that contributes to lower urinary tract symptoms (LUTS) in aging men, but it is not the sole cause as it is now clear that a significant portion of LUTS is the result of age-related detrusor dysfunction.1,2
Prostatectomy was the most widely accepted intervention for managing BPH before the 1980s; morbidity and mortality due to surgery were the motive for the development of medical therapy. Since then the trend has shifted towards medical treatment, leaving surgery only to those with absolute indication for surgery, as a result, the total number of men undergoing prostatectomy has decreased over the last two decades despite the fact that more men are diagnosed with BPH.3
During the last two decades the number of patients undergoing transurethral resection of the prostate (TURP) has annually decreased significantly as the treatment of BPH continues to shift toward medical and minimally invasive surgical therapies.
Although pharmacological therapy with alpha-blockers and 5 alpha-reductase inhibitors have gained widespread acceptance in urology, a significant number of patients with symptomatic BPH inevitably require definitive surgical intervention. Numerous minimally invasive techniques have been developed within the last decade, but most have been rapidly abandoned due to their ineffectiveness, lack of reproducible results and unacceptably high levels of morbidity.4
The method of local injection in the prostate for treatment of BPH was first practiced at the beginning of the last century by sir James Roberts (1909–16).5
In 1995 Mori et al. used absolute ethanol injection transurethrally before TURP to prevent preoperative blood loss.5 Littrup et al.6 in 1988 described their experience with canine models injected percutaneously in their prostates with absolute ethanol and reported extraprostatic tissue necrosis due to backflow of the ethanol and the same was reported by Plante et al.7
Goya et al. in 1999 were the first to report the results of ethanol injection in the prostate using a straight needle through a cystoscope.8
By that time, ethanol injection was a well-established treatment for many lesions and tumors, and was gaining more ground in the medical field. Ditrolio et al. in 2002 reported also that ethanol injection was very effective in the treatment of BPH.9
The aim of the present study is to evaluate the efficacy and safety of ethanol injection in the prostate as well as the long-term (50 months) efficacy of minimally invasive treatment for benign prostatic hyperplasia involving direct injection of dehydrated ethanol.
This study was conducted on 35 patients admitted to the Urology Department, Faculty of Medicine; University of Alexandria, Egypt, between May 2003 to December 2003. These patients were followed from the time of injection in May 2003 until November 2007. The duration of follow-up ranged from 47 to 56 months (mean: 50 ± 2.1 months). The age of the patients ranged from 51 to 81 years; with a mean of 66.3 ± 9.0 years.
All of the patients in the present study had concomitant medical conditions such previous intra cranial hemorrhage, severe hypertension, total hip replacement, myocardial infarction, and cerebrovascular stroke. The concomitant medical conditions were irrelevant to BPH, but imposed additional care before and after the procedure.
All patients had obstruction according to the International Prostate Symptom Score (IPSS) (>7) and low flow rate (<10 mL/s). The patients failed medical therapy with no prior minimally invasive treatment for BPH or were in retention with failed response to medical treatment and/or failed to micturate after one trial of catheter removal.
Patients with suspicious prostates on digital rectal examination (DRE) or by ultrasound (US), chronic retention with bilateral hydroureteronephrosis (significant renal insufficiency), bladder stones, bladder tumors, neurogenic bladder, urethral stricture, active urinary tract infection, epididymitis, prostatitis, patients with systemic neurological disorder such as diabetic neuropathy, previous pelvic surgery or trauma were excluded from this study.
All patients were subjected preoperatively to the following:
1A full history taken from patients including duration of symptoms, diabetes, use of medications for ‘common cold’ (alpha sympathomimetic), history of previous lower urinary tract surgery or catheterization, and medical treatment for BPH.
2IPSS was used to assess the symptoms severity.
3General examination including neurological assessment.
4Urological examination: to assess the suprapubic area (chronic retention) and DRE.
5Routine laboratory investigations: urine analysis and culture, complete blood picture, bleeding and clotting time, prothrombin activity, partial thrombin time, blood urea and serum creatinine.
6Radiological investigations: Transrectal ultrasound (TRUS) to assess prostate size, detect any abnormality and pelvic US to assess post-void residual (PVR) and detect any stones.
7Uroflowmetry: Except those in acute retention.
Ethanol injection therapy of the prostate was carried out under spinal anaesthesia, using commercially available dehydrated ethanol (at least 99.5%) and an endoscopic Karl Storz (Tuttlingen, Germany) flexible injection 6-Fr. needle (50 cm long with a 1-cm long injection tip), a 19-Fr continuous flow cystoscope (Karl Storz) and a short bridge with a side channel and a 30° lens (Karl Storz).
Cystourethroscopy was carried out to visualize the urethra and rule out the presence of a urethral stricture or urethral stones. The bladder was thoroughly examined to exclude the presence of stones or tumors and finally to assess the length of the prostatic urethra. The injection needle was advanced through the side channel while the tip of the cystoscope was still in the bladder until the injection tip was seen in the field. The needle was then withdrawn slowly until it disappeared and then the cystoscope was withdrawn slowly to the verumontanum.
In the first four cases; it was noticed that when ethanol injection was started in the median lobe or near the bladder neck first (i.e. from proximal to distal), the swelling caused by the ethanol injection obstructed the urethra and hindered the flow of the irrigant fluid obscuring the vision and causing difficulty in completing the procedure. So a modification was made, and ethanol injection was first carried out at a level just above the level of the verumontanum, then 1 cm closer to the bladder neck and finally in the median lobe if it was enlarged. This sequence gave almost continuous clear vision throughout the procedure (starting distal and going proximal towards the bladder neck) and this is the preferred technique of ethanol injection. Injection sites are kept away from the bladder neck to avoid retrograde ejaculation later.
The needle was advanced until the injection tip was seen in the field, then it was directed to the targeted area. It was advanced at an acute angle to the surface of the prostate, pushed until the shoulder of the needle reached the base of the injection tip (Fig. 1). Two milliliters of absolute ethanol (99.5%) per site is then slowly injected to allow for diffusion.
After finishing the injection, to avoid backflow of ethanol, the needle is left in place for a few seconds before removal, and then the needle is slowly withdrawn.
Injection was carried out in one or two planes according to the length of the prostatic urethra. If the length of the prostatic urethra was less than 2 cm, injection was carried out in one plane and if it was more than 2 cm, injection was carried out in two planes. Injections were carried out at the 2, 4, 8, 10 o'clock positions. The first plane was just above the level of the verumontanum and the other was 1 cm nearer to the bladder neck. Median lobe (if enlarged) was injected in one or two sites.
After completion of the procedure, the color of the prostate surface appeared paler than before, (Fig. 2) and the prostate was markedly swollen by the injected ethanol.
A 20-F urethral Foley urethral catheter was then inserted and fixed and all patients were given two parenteral ampoules of 80 mg gentamicin intraoperatively.
All patients were discharged on the following morning with the catheter fixed and prescribed an oral antibiotic (500 mg oral quinolone twice daily for 10 days). The catheter was removed one week after injection.
The patients were followed for a period that ranged from May 2003 to November 2007. The average follow-up period was 4.1 years.
All patients were examined at the outpatient clinic every 2 weeks for the first 3 months and then every 3 months in the first year. The patients were then examined every year for the remaining period.
During the follow-up period: the rate of patients who did not require any treatment other than ethanol injection was recorded.
1IPSS to assess the change in the symptom score.
3Routine laboratory investigations
4Pelvic US to assess PVR and TRUS to assess the prostate volume.
Statistics were carried out using the SPSS statistical program on an IBM compatible computer and the appropriate statistical test was used according to the type of data. The level of significance was less than 0.05.
Intraprostatic ethanol injection was carried out under spinal anaesthesia in all patients.
The number of sites injected varied from four to 10; the mean was 5.8 ± 2.2. The amount of ethanol injected ranged from 8 to 20 mL and the mean was 11.9 ± 4.4 mL; about 23% of the pre-injection prostate volume. The average procedure time was 15 min.
Postoperatively, the catheter was removed in 33 patients (94.29%) after 7 days. In one patient the catheter was accidentally removed after 3 days and there was no need to re-insert it. In another patient the catheter was removed after 14 days as the patient developed retention on removal of the catheter on the seventh day and the patient was able to void when the catheter was removed after 14 days. The mean time for catheter removal was 7.2 ± 1.8 days.
Effect of ethanol injection on the IPSS
It was noticed that the mean IPSS decreased from 22.00 to 5.45 after injection, and then slightly increased to 9.85 ± 2.23 after 4 years (t = 19.45, P = 0.001). The difference of means is statistically significant (Table 1).
Table 1. Statistically significant improvement in the four parameters analyzed in the study, IPSS, Qmax, PVR, and prostate volume
Pre-injection mean ± SD
3 months post-injection mean ± SD
1 year post-injection mean ± SD
2 years post-injection mean ± SD
3 years post-injection mean ± SD
4 years post-injection mean ± SD
IPSS, International Prostate Symptom Score; PVR, post-void residual.
22.0 ± 3.89
5.45 ± 1.93
6.37 ± 1.82
7.46 ± 2.13
8.74 ± 2.08
9.85 ± 2.23
5.875 ± 3.69
20.4 ± 4.68
18.67 ± 3.92
18.15 ± 3.82
17.13 ± 3.91
16.89 ± 4.12
68.6 ± 49.98
29.72 ± 16.65
31.85 ± 19.03
32.54 ± 18.12
34.72 ± 15.34
36.02 ± 20.87
52.67 ± 20.43
42.21 ± 22.56
43.91 ± 18.73
44.78 ± 20.56
46.62 ± 19.52
49.94 ± 21.28
Effect of ethanol injection on Qmax
It was found that the mean Qmax increased from 5.875 mL/s to 20.445 mL/s after injection, and then decreased throughout follow up, reaching 16.89 ± 4.12 after 4 years (t = 14.010, P = 0.001). The difference of means is statistically significant (Table 1).
Effect of ethanol injection on PVR
Before ethanol injection, three patients (15%) presented with retention; in the remaining 32 patients the PVR ranged from 20 mL to more than 160 mL with a mean of 42.4 mL.
Following ethanol injection the PVR ranged from 5 mL to 60 mL with a mean of 29.72 mL (Table 1). It was noticed that the mean of PVR had decreased from 68.6 mL to 29.72 mL after injection, and then increased during the follow up to 36.02 ± 20.87 after 4 years (t = 3.641, P = 0.002). The difference of means is statistically significant (Table 1).
Effect of ethanol injection on the prostate size
Prior to injection the size of prostates ranged from 30.0 gm to 104.3 gm, with a mean of 52.67 gm. Following ethanol injection, the prostate size ranged from 10.0 gm to 90.0 gm with a mean of 42.21 gm. It was noticed that the mean for prostate volume had decreased from 52.67 ± 20.43 to 42.21 ± 22.56 after injection, but the prostate volume increased again during follow-up, reaching 49.94 ± 21.28 after 4 years (t = 7.723, P = 0.001). The difference of means is statistically significant (Table 1).
In the present study, it was found that there was a negative correlation between post-injection Qmax and the post-injection IPSS (i.e. the more the Qmax, the less was the IPSS after ethanol injection) (r = 0.613, P = 0.004), and this is statistically significant.
It was also noticed that there was a positive correlation between post-injection prostate volume and post-injection PVR (r = 0.733, P = 0.000), which is statistically significant. Both were decreased after injection.
Post-injection PVR was noticed to have a positive correlation with the number of sites injected (r = 0.616, P = 0.004), and total amount of ethanol injected (r = 0.635, P = 0.003); both are statistically significant (Fig. 3).
The age of patients was found to have a positive statistical correlation with pre-injection IPSS (r = 0.511, P = 0.21), post-injection PVR (r = 0.494, P = 0.027) and pre-injection prostate volume (r = 0.478, P = 0.33) Therefore, the older the patient, the higher the IPSS, and with increased PVR the volume of the prostate was higher.
Pre-injection prostate volume was noticed to show a significant statistical correlation with the number of sites injected (r = 0.768, P = 0.001), total amount of ethanol injected (r = 0.778, P = 0.001) and the time of removal of the catheter (r = 0.447, P = 0.048). Therefore, the larger the prostate before injection, the higher the number of sites injected, and with increased ethanol used, longer amounts of time were needed before catheter removal.
Postoperative complications were encountered in five patients (14.3%). These were urinary tract infection (UTI) and epididymo-orchitis in two patients (treated with oral quinolone and analgesics), and urethral stricture in one patient (treated by endoscopic visual urethrotomy). Stress incontinence occurred in one patient. Mild hematuria occurred in one patient. Another patient had urge incontinence due to cerebrovascular stroke. None of the patients in this study complained of any change in their potency state or retrograde ejaculation.
During the follow-up period no further treatment other than ethanol injection was necessary in 32 patients (91. 4%) after 1 year, 30 patients (85.7%) after 2 years, 27 patients (77. 1%) after 3 years and 26 patients (74.3%) after 4.1 years.
During follow up until 4 years there was no mortality from the procedure. Nine patients showed an insufficient response and required further treatment. The patients chose their subsequent treatment. Surgical treatment was carried out on four patients (TURP), ethanol injection was repeated in three patients and drug treatment was given to two patients (Table 2).
Table 2. Number of patients who required further treatment
TURP, transurethral resection of the prostate.
Benign prostatic hyperplasia (BPH) is the commonest benign prostatic lesion. It contributes largely – among other factors – to LUTS in aged men.1
Treatment modalities of BPH are many and varied and include watchful waiting, which carries a risk of 47% failure with increased post-void residual urine and/or symptom score; medical treatment, which necessitates a life-time commitment and the cooperation of the patient;10 minimally invasive surgical procedures;5,11–13 and surgery, which carries the disadvantage of bleeding, TUR syndrome and retrograde ejaculation.14,15
Various new approaches are being developed for the treatment of BPH. Taking into consideration that the incidence of BPH is increasing with an aging society, the search for an effective and minimally invasive method for treatment of BPH, especially when BPH is associated with co-morbid high-risk conditions, is mandatory.8,11,12
The first and most commonly used substance was phenol.13 Its use showed that intraprostatic injection for the treatment of BPH is a simple, effective and safe technique that can be used for high-risk patients. Phenol injected in the prostate caused necrosis in the prostate and softening,13 which explains relief of the obstruction after injection. The injection was carried out through a percutaneous, transperineal route. The main drawback of this technique was that sometimes several injections were needed to obtain an adequate response,13 and the associated perineal pain persisted for more than one month.17 Other substances were tried for injection into the prostate in animal models and seemed to be safe, but they are still in the experimental stage (e.g. sodium bicarbonate and enzymes).18
In the present study absolute ethanol was injected in the prostate as a treatment for BPH. Ethanol injection therapy has been successfully used in the medical field for nerve blockade, ablation of hepatic cysts, small hepatic and abdominal tumors,19 ablation of solid thyroid nodules,20 ablation of parathyroid gland,21 treatment of vertebral hemangiomas,22 closure of bronchopleural fistulae23 and ablation of renal cysts and renal tumors.24
Ethanol, as a treatment agent, combines the benefits of being widely available, inexpensive, efficient and relatively easy to administer.24
Local infiltration or intravascular injection of absolute ethanol causes coagulative necrosis of the tissues through a rapid dehydration and tissue fixation.8 On the cellular level, it was found to cause cell membrane lysis, protein denaturation and vascular occlusion ending in scar formation.25
In the prostate, it also causes destruction of the nerve endings and alpha receptors, thus decreasing the tone of the prostatic urethra, all of these actions explain the improvement of obstruction.8,16
Ethanol injection in the prostate could be done via a transurethral or a percutaneous route. The transurethral route is preferred to the percutaneous route, as in the animal model trials, extra-capsular leak of ethanol and periprostatic tissue damage occurred in some of the injected models via the percutaneous route in contrast to transurethral injection, in which no leak occurred.5–7
However some authors like Savoca et al. used the percutaneous route and reported that it was less painful, safe, and effective.16
Preliminary results with transurethral ethanol injection showed a significant improvement of the IPSS, maximum flow rate and PVR and a significant decrease in the volume of the prostate with no major intraoperative complications like bleeding or TUR syndrome.8
In the present study, the mean IPSS improved from 22.00 before injection to 5.45 after injection. This was in accordance with the results obtained by Goya et al.8 where the mean of IPSS improved from 23.1 to 12.2, and by Ditrolio et al.9 where the mean IPSS improved from 22.4 to 5.6 and by Savoca et al.16 where the mean IPSS improved from 21.0 to 10.0.
Ditrolio et al. carried out transurethral ethanol injection therapy in 15 patients and reported on the one-year outcome for 13 patients.9 They observed improvement of the American Urological Association symptom score, maximum urine flow rate and prostatic volume compared with baseline.
A significant improvement in the maximum flow rate was seen in the present study, the mean of Qmax increased from 5.9 mL/s to 20.45 mL/s after injection. Other authors had comparable results.8,9,16
Also in the present study, a significant decrease in the PVR occurred from 68 mL to 29 mL. This was in accordance with the results of other authors, who found statistically significant decrease in the post-voiding residual.8,9,16
Regarding the change in prostatic volume, a significant decrease in the mean prostatic volume from 52.7 gm to 42.2 gm has occurred after injection. This was in accordance with the results of Ditrolio et al.9 who found a decrease in the mean prostatic volume from 48 gm to 23.3 gm and Plante et al.25 where the mean volume of the prostate decreased from 53.0 gm to 37.2 gm.
In contrast, Savoca et al.16 found no significant change in the volume of the prostate, the mean decreased from 40 gm to 37 gm and the same finding was noticed by Goya et al.8 where the mean prostate volume that decreased from 50.7 gm to 48.6 gm was not statistically significant.
There was a significant decrease in prostate volume after 1 year but no significant decrease was seen during the following 3 years. The reason for this finding appeared to be progressive growth of the prostate tissue, which was probably not prevented by ethanol because of the relatively small doses used or it may need repeated injections.
During follow up, voiding cysto-urethrogram after 3 months showed dilatation of the prostatic urethra, and urethro-cystoscopy showed regression of the prostatic lobes with widening of the supra montanal prostatic urethra. These findings were also noted by Goya et al.,8 proving the decrease in the prostatic volume and its efficacy.
Ethanol injection, in the present study, was carried out under spinal analgesia in all patients. Goya et al.8 used spinal analgesia or sacral and urethral anaesthesia. The most essential advantage of this procedure is that it can be done under light or local anaesthesia.
In the present study, there was a significant negative correlation between post-injection Qmax and the post-injection IPSS (i.e. the greater the Qmax, the lower the IPSS after ethanol injection, which reflects the improvements after ethanol injection).
It was also noticed that there was a significant positive correlation between post-injection prostate volume and post-injection PVR. Both are decreased after injection which reflects the beneficial effect of ethanol therapy.
In addition, a significant statistical correlation was found between pre-injection prostate volume and pre-injection IPSS and post-injection PVR indicating a less favorable outcome in severe BPH cases.
Our results suggested that ethanol injection therapy of the prostate is safe and relatively effective as 71.5% of patients did not need medication or further treatment after 4 years and were satisfied with the outcome.
The total ethanol volume injected was small, a mean of 23.3% of prostate volume. A small dose of ethanol was injected early during this work because no clinical data on the safety of injecting dehydrated ethanol into the prostate were available at the time. Its safety has subsequently been established and the total volume injected can be up to 20% to 30% of the prostate volume.
Detrolio et al. injected 2–5 mL per site with the total dose not exceeding 25 mL.9
Savoca et al. used the transperineal approach and injected 6 mL of ethanol, representing 8.5% to 25.0% of the prostate volume.16
It is of utmost importance to avoid injection outside the prostate. However, the risk of leakage becomes greater with either an increase in the volume of ethanol injected or introducing the needle deep in the prostate, so determining the optimum amount and the depth of the needle is an issue for the future.
Postoperative complications are less common than those following other surgical techniques. Retrograde ejaculation did not occur in any of the patients and no patient complained of a change in his potency state; those are very important issues to be addressed when managing a sexually active patient. Similar results were noted by Goya et al.,8 Ditrolio et al.,9 Plante et al.25 and by Savoca et al.16
Others reported adverse events as bothersome or irritative voiding symptoms (26%), urinary retention/recatheterization (17%) and hematuria (16%), urinary tract infection, pain and discomfort in less than 7% and were easily managed with pharmacotherapy.
Incontinence was reported at a rate of 3% and was primarily urgency in nature. Events that occurred at a rate of less than 3% included hemospermia, erectile dysfunction, anejaculation, meatal stenosis, blocked catheter and hypotension. Two patients experienced serious adverse events after treatment, such as bladder necrosis and distal ureteral stenosis, and underwent open surgery that included urinary diversion and ureteral implantation26.
The data obtained in this study are encouraging. They show that ethanol injection seems to be a safe, useful and effective way to manage BPH.
The efficiency of ethanol injection as a treatment for BPH was shown in studies comparing ethanol injection to other modalities used to manage cases of BPH. Ethanol injection showed a lower re-treatment rate and statistically significant decrease in the prostate volume when compared with the results of the use of radio-frequency energy as shown by Plante et al.25 The improvement in IPSS, Qmax, prostate volume and post-voiding residual after using ethanol injection when compared with TURP are comparable.27
This study proved that ethanol injection therapy can be carried out for BPH with standard endoscopic equipment at an outpatient clinic. This method is safe, and results in prostate symptom score improvement and an increased peak urine flow that persists after 4 years.
The long term effects of ethanol injection in the prostate is safe, feasible, efficacious, with a short hospital stay, minimal perioperative or postoperative complications, improvement of the urinary symptoms, maintenance of sexual function and quality of life, and with light or local anaesthesia. This technique provides a promising option for managing BPH in the future.
Nevertheless, long-term follow up of a large series of patients is mandatory. Also, further comparison of the results of ethanol injection in the prostate to the results of other intervention modalities used in management of BPH is recommended.
Ethanol injection may be considered an effective minimally invasive treatment option for lower urinary tract symptoms secondary to BPH.
It can be done as an outpatient procedure under local anaesthesia, with a short hospital stay, minimal complications, maintenance of sexual function, and a good long-term result.
The procedure of transurethral ethanol injection is an easy, available, inexpensive, safe and rapid procedure; it is of importance in managing high risk patients who are not candidates for other surgical modalities. It has a low incidence of complications and no mortality due to treatment itself versus 1.6–6.4% mortality in operative series. The treatment response is not predictable, but if injection fails, surgery can be done at any time without increasing risk. It is a financially cost-effective procedure and can decrease the burden on general hospitals. Further long-term investigations and follow up to confirm these results are recommended.