Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(3):12576 1 REVIEW an episode of priapism, O2 partial pressure decreases as the closed compartment prevents the supply of fresh, oxygenated blood, resulting in initial thickening and interstitial edema without smooth muscle necrosis (3, 5). Necrosis of the corpus cavernosum muscle was seen after 24 hours. After 24 hours, the risk of irreversible compre- hensive smooth muscle changes leading to refractory erectile dysfunction is over 90%, and after 72 hours, there is no hope for recovery of erectile function (2, 3, 6). Failure to respond to aspiration and instillation of a-ago- nists suggests that irreversible changes have occurred in the smooth muscle of the corpus cavernosum. At this stage, shunt surgery may successfully induce deconges- tion but will not reverse the ischemic damage, and refrac- tory erectile dysfunction will persist in the long term (1, 4, 7). Refractory erectile dysfunction cannot be treated conservatively, and penile prosthesis implantation is the only way to achieve the stiffness required for penetrative intercourse. Penile prosthesis implantation at this stage can be very difficult due to diffuse corporal fibrosis, which complicates corporal dilation and is associated with an increased risk of distal/proximal cross-over com- plications and urethral perforation or injury (4, 8-10). In addition, the duration of the procedure significantly increases the risk of postoperative infection. In addition, fibrosis results in some shortening of the penis. After implantation, most patients still complain of penile short- ening, which is one of the reasons for men's dissatisfac- tion with penile prostheses (11, 12). Immediate implantation of a penile prosthesis is usually simple, reduces pain, and allows an earlier return to sexu- al activity. Despite the above advantages, immediate implantation of penile prostheses is associated with penile edema, increased risk of infection, and distal perforation, especially in patients with a history of shunt surgery (7, 13, 14). Delayed implantation of penile prostheses is now considered a surgical challenge with a high complication rate. Delayed implantation is also associated with subopti- mal satisfaction. Several studies suggest that penile pros- theses should be implanted in patients with refractory ischemic priapism at the acute stage when irreversible erectile smooth muscle damage has occurred (11, 15). Currently, there is no general agreement on the timing of Background: This study determined pooled estimates of short- and long-term complica- tions of early versus delayed implantation of penile prosthesis in patients with ischemic priapism. Methods: We searched Pubmed, ProQuest, Scopus, EBSCOHost, and other sources from January 1, 2013, to March 2023. All study designs were included except animal studies, review arti- cles, and consensus documents. Of the 214 articles, four studies were included in the systematic review, and further meta-analy- sis included three studies (PROSPERO CRD42023411005). Results: The short-term complication rate was lower with early implantation than with later implantation (β= -2.08; 95% Confidence Interval [CI] = -3.54, -0.6; p = < 0.05). A similar value was also found in the pooled analysis for long-term out- comes, defined as overall satisfaction rate, which is better with early implantation than later (β = 2.18; 95% CI = 1.35, 3.02; p = < 0.05). Conclusions: The results of the pooled analysis confirmed that short-term complications were significantly lower with early implantation than with delayed implantation. Overall satisfac- tion rates were higher in early implantation than in delayed implantation of penile prostheses. KEY WORDS: Penile prosthesis; Early implantation; Delayed implantation; Ischemic priapism; Priapism. Submitted 16 March 2024; Accepted 30 April 2024 BACKGROUND "Priapism" describes a pathological condition characterized by a prolonged erection of more than four hours without sexual stimulation. This condition can be divided into sub- types of low, high, and intermittent flow (1). Ischemic pri- apism is the most common form of priapism and accounts for 90-95% of all cases. Although a common form, ischemic priapism is rare, with an overall incidence of 1.5 cases per 100.000 person-years (1, 2). Most cases of pri- apism have an idiopathic etiology; others may be related to hematologic abnormalities, intracavernosal injection of vasoactive drugs, illicit drug use, or malignancy (3, 4). Ischemic priapism is considered a form of compartment syndrome caused by hypoxia, hypercapnia, acidosis, and glucopenia in the erectile tissue. In the first 12 hours after A systematic review and meta-analysis of short- and long-term complications of early versus delayed penile prosthesis implantation in patients with ischemic priapism Agustin J. Nanda De Niro 1, Gede Wirya Kusuma Duarsa 2, Marshal Harvy Wicaksono 1, Pande Made Wisnu Tirtayasa 2, Kadek Budi Santosa 2, I Wayan Yudiana 2, Nyoman Gede Prayudi 2 1 Intern Doctor of Urology Surgery Department Prof. dr. I.G.N.G Ngoerah General Hospital, Bali, Indonesia; 2 Urology staff of Urology Surgery Department Prof. dr. I.G.N.G Ngoerah General Hospital, Bali, Indonesia. DOI: 10.4081/aiua.2024.12576 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(3):12576 A.J. Nanda De Niro, G. Wirya Kusuma Duarsa, M. Harvy Wicaksono, et al. 2 penile prosthesis implantation in patients with ischemic priapism, as outcomes are variable. This review examines the current literature on priapism, with a focus on evalu- ating short-term and long-term outcomes in adult men undergoing direct implantation of a penile prosthesis for the treatment of acute ischemic priapism unresponsive to medical therapy or shunt surgery. METHODS Search strategy and selection criteria Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for conducting meta-analyses (http://www.prisma-statement.org/), two independent reviewers performed data extraction (AJ, GW). Disagreements were resolved in a discussion among all investigators, and if necessary, they were analyzed and clarified by IW. For the literature search, we used the PubMed, EbscoHost, Scopus, and ProQuest databases from January 1, 2023, to March 2023. We also reviewed and manually searched the references and identified the possi- ble dates from the conferences. The systematic search for terms and combinations used the following terms: "penile prosthesis"; "priapism"; "early"; "delayed"; "graft"; "satisfac- tion"; "complications". Original research articles were included if they met the fol- lowing criteria: (a) diagnosis of acute priapism, (b) com- parison of penile prosthesis implantation: early vs. delayed, and (c) if the study provided information on clinical char- acteristics and outcomes of the two techniques. We exclud- ed animal studies, review articles, and consensus docu- ments. The exclusion criteria were as follows: (a) the study was a review article, letter to the editor, animal study, com- mentary, or consensus document; (b) the study did not focus on priapism patients or the diagnosis was unclear. If the patients were from the same hospital and the cases over- lapped, we selected only the publication with the largest number of cases. The protocol was registered with the international prospective register of systematic reviews (PROSPERO), in accordance with PRISMA-P guidelines (PROSPERO CRD42023411005) (16). The protocol for this systematic review has been previously described (17). All identified stud- ies are included in this review. Quality assessment and Risk of Bias The five authors of the review classified each of the included studies as 'risk of bias’. Risk of bias in Randomized Controlled Trial (RCT) was assessed using the tools recommended in the Cochrane Handbook for Systematic Review of Interventions. Additional items were included to determine the risk that confounding factors may explain the results. ROBINS-1 quality ratings for non-random- ized studies were used to assess the quality of observational studies. For each study, a pragmatic approach was used to assess the risk of confounding. Statistical analysis The primary outcomes of interest in the study were short- and long-term complications of penile prostheses at early and late implantation. Short-term complications included pain, palpable nodules, residual curvature, infection, and erosion of the prosthesis, while long-term complications included quality of life, overall satisfaction, sexual satis- faction, penetration ability, erectile dysfunction, and increased curvature. I2 was used to assess heterogeneity between studies. A fixed-effects model was used when I2 was < 50%, and when I2 was > 50%, a random-effects model was chosen. In the fixed-effects model, population effect sizes were assumed to be the same for all studies. In contrast, the random-effects model attempted to generalize the results beyond the included studies by assuming that the select- ed studies were random samples from a larger popula- tion. If there was statistical heterogeneity in the results, a further sensitivity analysis was performed to determine the source of heterogeneity. Sensitivity analyses were performed only for meta-analy- ses that evaluated primary/main outcomes (including outliers). Sensitivity analyses were performed in three dif- ferent ways by excluding (1) each study individually, (2) studies identified as outliers, and (3) studies with a mod- erate and high risk of bias. After each analysis, the con- sistency and significance of the meta-analysis results are reassessed. A study is considered an outlier if the 95% Confidence Interval (CI) of the study is outside the 95% CI of the combined effect when the Forest Plot is viewed visually. The Forest plot shown refers only to the meta- analysis with outliers. After excluding significant clinical heterogeneity, the random-effects model with coefficient estimation (b) was used as the effect size for the meta- Figure 1. Flow diagram of study selection. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12576 3 Penile prosthesis implantation in patients with ischemic priapism analysis (ES). When p was < 0.05, the result was consid- ered statistically significant (2-sided). All data were analysed using STATA ver. 15 software. Overview of the study selection The PRISMA diagram for the entire study selection process is shown in Figure 1. An initial search of four databases yielded 212 studies, while additional records identified through references and conferences included two studies. Subsequently, 154 studies were excluded because they did not meet the requirements of the automation tool, and 48 duplicate studies were also excluded. Of the remaining 12 studies, a total of 6 studies were identified as reviews, and 2 studies did not compare early and delayed penile pros- theses. Ultimately, four studies were selected and includ- ed in this systematic review and three studies were includ- ed in the meta-analysis. Studies characteristics The characteristics of the included studies are summarized in Table 1. All included studies were retrospective studies using medical records. The total number of ischemic pri- apism patients from four studies was 287, with 187 patients undergoing early penile prosthesis implantation and 100 patients undergoing delayed penile prosthesis implantation. The operational definition for categorizing patients as "early" or "delayed" was different in each study. The time from onset of priapism to implantation was 31 hours to less than three weeks in the early group. In the delayed group, it was 3 weeks to more than 6 months. Three studies reported initial treatment before implantation in the form of physical aspiration, irrigation, instillation of a-agonists, and T-shunt surgery (open distal and percuta- neous). In patients with early implantation, 178 patients were treated with malleable implants and 9 others with inflatable implants. In patients with delayed implantation, 66 patients used malleable implants and 34 others used inflatable implants. Most studies stated that deformable implants were preferred because they are less expensive. Risk of Bias The risk of bias assessment is presented using two summa- ry figures (Figures 2, 3) for each study according to all risk of bias domains. Two studies have a low risk of bias, and the other two studies have a potentially moderate risk of bias. When assessing the risk of confounding, all studies had a moderate risk of bias, mainly due to the type of penile prostheses that may have influenced study results. There is a moderate risk of bias in participant selection, with the exception of one study that did not include complete infor- mation on patient selection (published as a conference pro- ceeding at a symposium). All studies have a moderate risk Table 1. Study characteristics. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12576 A.J. Nanda De Niro, G. Wirya Kusuma Duarsa, M. Harvy Wicaksono, et al. 4 of bias in the classification of interventions, while the remaining domains have a low risk, except for one study that has a moderate risk of selection bias in outcome report- ing. This study does not explain exactly how many patients in each group experienced complications but only reports the frequency of complications present, and more than one complication may occur in each patient. Short-term complications In the meta-analysis of short-term complications, all stud- ies were included in the analysis. Nevertheless, the results of heterogeneity analysis using I2 showed a high hetero- geneity of 82.6%. Sensitivity analysis using Forest plots revealed that two studies were outliers. In the follow-up analysis, one outlier study was excluded due to the small sample size. The results of a random-effects meta-analysis on short- term complications showed that complications were sig- nificantly lower with early implantation of penile pros- thesis than with delayed implantation (b = -2.08 (-3.54, -0.61); p = < 0.05) (Figure 4). Funnel plot results are in Figure 5. shows asymmetric results, highlighting the potential for publication bias. Long-term complications The meta-analysis of long-term complications showed that Figure 2. Risk of bias summary: review authors' assessment of each risk of bias for each included study. Figure 3. Risk of bias chart: review authors' assessment of each risk of bias item, presented as a percentage of all included studies. Figure 4. Forest plot short-term complications. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12576 5 Penile prosthesis implantation in patients with ischemic priapism patients were satisfied with the outcome of the prosthesis, including sexual intercourse and overall comfort. This analysis included three studies. In this case, there was no clear assessment of overall satisfaction in one study. The results of the meta-analysis on satisfaction rate showed that early implantation of the penile prosthesis had significant- ly better satisfaction than delayed implantation (b = 2.18 (1.35, 3.02); p = < 0.05) (Figure 6). The results of the fun- nel plot show that there is no outliers (Figure 7). DISCUSSION The decision about penile prosthesis in an acute episode of ischemic priapism is still based on expert opinion that referred to small or retrospective studies, hence decision- making should be discussed between the patient and the urologist (11, 18). This study is the first systematic review and meta-analysis to exclusively include a comparative study of the short- and long-term complications of early and delayed penile prosthesis implantation. According to a retrospective study conducted by Palmisano et al., the immediate implantation of a soft penile prosthesis for patients with refractory ischemic pri- apism leads to instant pain alleviation, preservation of sex- ual function, and penile size, as well as higher surgical reproducibility in an emergency. Furthermore, ischemic priapism's financial and resource burden on the healthcare system may be decreased (19). The previous systematic review by Capece et al. showed that all studies found supe- riority of early versus delayed penile prosthesis implanta- tion in patients with ischemic priapism; however, this superiority was merely speculative because none of the studies were designed to compare the outcome of early versus delayed implantation (20). In this study, however, the pool effect size from a meta-analysis provided better certainty about the outcome of penile prosthesis implan- tation in the 287 patients with ischemic priapism. For both short-term and long-term complications, the pooled analysis showed significantly better outcomes for early implantation (p< 0.05) than for delayed implantation. Infection is the most common complication after early implantation of penile prostheses, especially in patients with postoperative aspiration, injection, or shunt (12, 21, 22). It can be caused by the penetration of bacteria through the skin into the sterile compartment and by cav- ernous edema, which prevents antibiotics from penetrat- ing the cavernous tissue (1, 10, 21). Nevertheless, post- operative infections are generally treatable. The most challenging aspect of penile prosthesis implantation in delayed cases is existing corpus cavernosum fibrosis. Difficult physical dilatation with Hegars dilators can be replaced with cavernotomes to cover difficult dilatations, called corporal drilling (23, 24). This difficult situation can be complicated by urethral injuries, lateral or distal perforations, or cylindrical branches. Extensive corporal fibrosis and difficult dilation have resulted in the penile prosthesis being reduced in size to accommodate the cor- poral compartment (7, 20). This condition results in decreased penile length and is ultimately associated with lower overall patient satisfaction (7, 24). Indeed, in the study by Salman et al., satisfaction after penile prostheses were found to reach 100% in patients with delayed Figure 6. Forest Plot long-term complications. Figure 5. Funnel Plot short-term complications. Figure 7. Funnel Plot long-term complications. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12576 A.J. Nanda De Niro, G. Wirya Kusuma Duarsa, M. Harvy Wicaksono, et al. 6 implantation, although this was also based on the base- line condition of the patient, who had a long history of penile fibrosis, shortening, and impotence (12). To date, the exact timing of prosthesis insertion when fibrosis has occurred is not known with certainty. The timing of complete fibrosis after an acute attack of pri- apism is also unknown. Sedigh et al. described mild dilata- tion after one week of priapism (25), similar to the study performed by Salman et al. in which mild dilatation was performed within 5 days of establishing a diagnosis of priapism (12). Conflicting results were presented by Hebert et al., who indicated a greater benefit in reducing the rate of severe complications when penile prosthesis implantation and reimplantation were performed within the first 4 months after the onset of corporal fibrosis (24). Although the benefits of early penile prosthesis surgery are well documented and continue to be studied, the psy- chological impact on patients with ischemic priapism who must make an urgent decision to undergo penile prosthesis surgery and then receive the results is an inter- esting topic. In the four studies included in this review, patients undergoing delayed penile prosthesis implanta- tion were mostly unprepared for the surgery to be per- formed. From a psychological perspective, the impact of penile prosthesis implantation on patients' overall quality of life has not been studied. Currently, some reports rec- ommend delaying the procedure for up to a week to give patients more time to understand their situation (11, 25). Although delayed treatment increases endogenous fibro- sis, a delay may be justified if the psychological benefits of a longer duration outweigh the negative effects. Further studies on this topic should be initiated. This study has some limitations. Studies comparing early and delayed penile prosthesis implantation are very lim- ited; moreover, all study designs performed are retro- spective studies, which have their limitations in influenc- ing confounding factors. The relatively large heterogene- ity in short-term complications remains a limitation of the study. The differences may be due to patient demograph- ic characteristics, surgeon experience, a technique used, type of implant, and timing of prosthesis insertion. CONCLUSIONS This systematic review and meta-analysis is the first study to include a comparative examination of the short-term and long-term complications of early and delayed penile prosthesis implantation. The results of the pooled analy- sis confirmed that short-term and long-term complica- tions were significantly lower with early implantation than with delayed implantation. Studies on the psycho- logical impact of early penile prosthesis implantation are suggested for further investigation to optimize treatment outcomes for patients with ischemic priapism. REFERENCES 1. Mishra K, Loeb A, Bukavina L, et al. Management of Priapism: A Contemporary Review. Sex Med Rev 2020; 8:131-9. 2. Biebel MG, Gross MS, Munarriz R. 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Nanda De Niro, MD deniro_nanda@yahoo.co.id Gede Wirya Kusuma Duarsa gwkduarsa@gmail.com Marshal Harvy Wicaksono marshalharvy@gmail.com Pande Made Wisnu Tirtayasa wisnu.tirtayasa@gmail.com Kadek Budi Santosa busanbsa@gmail.com I Wayan Yudiana yanyud@yahoo.com Nyoman Gede Prayudi prayudi_blonx@yahoo.com Prof. I.G.N.G. Ngoerah General Hospital Jl. Diponegoro, Dauh Puri Kelod, Denpasar, Bali Conflict of interest: The authors declare no potential conflict of interest.