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Introduction
The incidence of urethral stricture (US) is estimated to be 0.3%, and it is more common in men over 55 years of age1,2. The development of iatrogenic US took the first place with a high rate of 45% as a result of the increase and widespread use of diagnostic and therapeutic endourological approaches to urological diseases in recent years3.
Transurethral prostate resection (TURP) is the most important of these endoscopic urethral approaches. TURP is the most well-known, common, and gold-standard surgical treatment of benign prostatic hyperplasia4. US is one of the most common late complications of TURP, and its incidence has been reported as 13% in the literature5. According to the results of the patient follow-ups in the studies, most of the patients who developed US after transurethral surgery were observed to make a visit within the first 6 months, and the localization of the stricture was generally reported as the bulbar urethra6,7.
When we look at the pathogenesis of stricture, leakage of urine into the subepithelial area after damage to the urethral epithelium for any reason has prognostic importance. Urine leaking into the subepithelial area triggers fibrotic processes through corpus spongiosum sinusoids and dense connective tissue intermediates8.
Oxygen is required as a precursor in all stages of wound healing. Moreover, the hypoxic state is a factor that plays a role in the execution of all of these processes through the hypoxia-inducible factor-1 (HIF-1) signaling pathway9. Abnormal wound healing caused by excessive accumulation of extracellular matrix elements by fibroblasts and myofibroblasts in the wound area is called fibrosis. In tissues where fibrotic healing begins to be observed, the tissue becomes hypoxic as a result of decreased vascular density. Studies indicate that the development and progression of fibrosis are associated with hypoxia, that is, profibrotic genes activated by HIF-1α10,11.
There should be a balance between the need for oxygen and its transmission to maintain physiological events in the body. The two main organ systems responsible for the delivery of oxygen to the body and maintaining homeostasis are the respiratory and the cardiovascular systems. Abnormal functions of either of these two would lead to the development of hypoxemia and its harmful consequences12.
Heart failure (HF), chronic obstructive pulmonary disease (COPD), and smoking are comorbidities that cause ventilation/perfusion mismatch systemically. These conditions can cause hypoxemia in systemic arterial blood and microvascular areas. The negative effects of smoking on wound healing were first shown in a study conducted in 197713. In a retrospective study in which 3500 cases were examined, COPD has been emphasized to be a potential risk factor for wound dehiscence14. Especially in the older adult patient population, HF is considered responsible for the development of complicated wounds15.
US which develops in patients who underwent TURP for bladder outlet obstruction is an important complication. We could not come across any study in the literature drawing attention to the relationship between this condition and HF, COPD, and smoking. However, studies show that smoking after surgeries such as radical prostatectomy and urethroplasty is a factor that leads up to the development of stricture16,17. Similarly, COPD and cardiac pathologies were shown to increase the relapse rate of it after internal urethrotomy18.
Based on all this information, it was aimed to evaluate the relationship between HF, COPD, and smoking with the development of US by examining the patients who underwent TURP procedure, with and without the development of US in their follow-ups.
Materials and methods
Study population
This study was conducted in the urology and chest diseases department of Afyonkarahisar Health Sciences University Hospital between February 2021 and August 2021. The study data were collected retrospectively after obtaining the ethical approval (2011-KAEK-2 2021/2) for the study from the Clinical Research Ethics Committee of Afyonkarahisar Health Sciences University. It was conducted in accordance with the principles of the Declaration of Helsinki. The purpose and the study process were explained to the patients in detail, and then written informed consent was obtained from each patient.
Among the 834 patients who underwent TUR-P between 2017 and 2021, 102 patients did not attend their follow-up visits for at least 6 months after the operation. Seventy-eight patients were excluded from the study considering the stated exclusion criteria. During the follow-up, 32 patients who underwent traumatic catheterization due to urinary retention or severe low urinary tract symptoms (LUTS), urethra dilatation, percutaneous cystostomy, complicated urethral stenosis, and prostatic urethra or meatus stenosis were excluded from the study. Among the remaining 622 patients, penile or bulbar urethral stenosis was detected in 63 patients as a result of diagnostic evaluations performed with cystoscopy during their follow-up. Our stenosis rate was found to be 10.1% in patients who had regular check-ups and had a known medical history. Among these patients, 50 patients were selected using the randomizer.org system. Among the remaining 559 patients, 50 patients were randomly selected as the control group, again using the randomizer.org system.
History of following conditions as pelvic radiotherapy, neurogenic bladder, bladder cancer, US before TURP, bladder stones, urethritis with a definitive diagnosis, lichen sclerosus, high-energy pelvic trauma/fracture and urethral anomaly (Hipospadias etc.), and malignancy in TURP pathology and diagnosis of prostate cancer were the exclusion criteria.
Application
Anamnesis, detailed physical examination, DRM, UFM, PVR and prostate volume measurement with transabdominal ultrasonography, serum PSA, TIT, urine culture, chest X-ray, electrocardiography, complete blood count, blood biochemistry analysis, coagulation tests, and viral marker tests were evaluated preoperatively for all patients who underwent transurethral resection of the prostate. Anaesthesia, cardiology, and pulmonology consultation reports in which patients were consulted for pre-operative evaluation purposes were noted.
Name-surname, age, height, weight, smoking status (packs/year), pre-operative UFM data, IPSS and QoL data for symptom severity, PVR, and prostate volumes (cm3) evaluated by transabdominal USG of the participants were recorded in the individual files of the patients. Furthermore, ACC/AHA stage, scores of mMRC scale, and COPD CAT were created in line with the verbal responses from the patient used to predict the level of comorbidities such as HF and COPD and information obtained from cardiology and chest diseases department consultation reports preoperatively. Pulmonary function testing (spirometry) and clinical evaluation results carried out by a pulmonologist were recorded.
All patients were selected from cases operated by three urologists, each with more than 100 TURP case experiences. In all operations, resection was routinely performed with an Olympus 26-Fr permanent current resectoscope and standard electrode (Olympus Winter and Ibe GmbH, Germany) under irrigation of saline (0.9% sodium chloride), and a bipolar plasma kinetic energy source was used. After the operation, a 22-Fr 3-way Rüsch brand catheter was inserted in all patients, and continuous bladder irrigation, started immediately with saline (0.9% sodium chloride) in a way that the urine color was clear, and was routinely continued until the morning of the 1st post-operative day. The catheters of the patients were removed between 3 to 6 days.
Patients´ data on post-operative follow-up, infection status, storage symptoms, US status, UFM, PVR, and IPSS-QoL were recorded on their files. Internal urethrotomy was performed using a cold knife with a Storz 21-Fr Sacshe model optical urethrotome as a standard on patients who were found to have penile or bulbar US according to the diagnostic evaluations during their follow-ups. All patients evaluated in the stenosis group in the study had stenoses shorter than 2 cm and uncomplicated.
While 50 patients in whom penile or bulbar US was detected at least once in their follow-ups after the TURP operation formed Study Group 1, 50 patients selected by lot among the patients in whom no stricture was detected formed Study Group 2.
Statistical analysis
Statistical analysis of the study data was performed using the IBM Statistical Package for the Social Sciences version 15.0 program. The Kolmogorov-Smirnov test was used to check whether the variables had a normal distribution. In the comparison of paired groups, Student´s t-test was used for normally distributed parameters and the Mann-Whitney U-test was used for the parameters which did not have normal distribution parameters. The Chi-square test or Fisher´s Exact test was used for the evaluation of multi-well crosstabs. In multivariate analysis, independent predictors of stricture development were examined with the enter method and binary logistic regression analysis using possible factors identified in previous analyzes. The Hosmer-Lemeshow test was used for model fit. Results with a type 1 error level of p < 0.05 were considered statistically significant.
Results
The quantitative parameters of the patients such as age, body mass index (BMI), and number of cigarettes smoked (packs/year) evaluated before the operation was given as mean and standard deviation, and were compared for Group 1 and Group 2, and the results are presented in Table. No statistically significant difference was found between the ages of the patients in both groups (p = 0.368). While the mean BMI value of the patients in group 1 was 27.43 ± 3.17 kg/m2, it was 25.95 ± 2.78 kg/m2 in group 2, and the mean BMI value was found to be statistically significantly higher in the group with stricture. Similarly, while the mean number of cigarettes smoked in group 1 was 23.78 ± 18.2 packs/year, it was 13.94 ± 19.94 packs/year in group 2 and the mean number of cigarettes smoked was found to be statistically significantly higher in the group with stricture (p = 0.007) (Table 1).
Table 1 Comparison of pre-operative and intraoperative data between groups
| Patient data | Group 1 (n = 50) | Group 2 (n = 50) | p-value |
|---|---|---|---|
| Mean ± SD | Mean ± SD | ||
| Age (years) | 67.94 ± 8.07 | 66.62 ± 8.16 | 0.368 |
| BMI (kg/m2) | 27.43 ± 3.17 | 25.95 ± 2.78 | 0.015 |
| Number of cigarettes (packs/year) | 23.78 ± 18.2 | 13.94 ± 19.94 | 0.007 |
| Prostate volume (cm3) | 63.68 ± 23.78 | 56.42 ± 23.19 | 0.126 |
| Qmax (ml/sec) | 7.88 ± 3.22 | 6.72 ± 2.75 | 0.059 |
| PVR(cm3) | 152.06 ± 83.51 | 112.78 ± 66.94 | 0.007 |
| IPSS | 20.4 ± 5.22 | 22.04 ± 4.7 | 0.102 |
| QoL | 3.5 ± 0.99 | 3.66 ± 0.87 | 0.555 |
| Duration of operation (min) | 49 ± 17.78 | 43 ± 17.14 | 0.102 |
| Duration of catheter stay (days) | 3.76 ± 0.79 | 3.66 ± 0.71 | 0.571 |
BMI: body mass ındex; Qmax: maximum urine flow rate; PVR: post-void residual; IPSS: ınternational prostate symptom score; QoL: quality of life; Mean ± SD: mean ± standard deviation.
Data that are considered to be predictors of LUTS such as prostate volume, Qmax, PVR, IPSS, and QoL evaluated preoperatively, and surgery-related variables such as duration of operation and duration post-operative catheter stay were given as mean and standard deviation and were compared for Group 1 and Group 2, and the results are presented in the Table. When the table is examined, there was no statistically significant difference between the two groups in terms of prostate volume, Qmax, IPSS, QoL, duration of operation, and post-operative catheter stay parameters (p = 0.126, p = 0.059, p = 0.102, p = 0.555, p = 0.102, and p = 0.571, respectively). The PVR value measured before the operation in group 1 was found to be significantly higher than in group 2 (p = 0.007) (Table 1).
The staging of patients in terms of HF was performed according to the ACC/AHA system, a classification based mainly on symptoms and exercise capacity. Eighteen patients with no abnormality in their cardiac structures and no risk factors for the development of HF were not included in this classification (Table 2). While Stage A and Stage B patients were asymptomatic patients in terms of HF, with 18 patients not included in this classification, HF symptoms were observed in Stage C and Stage D patients. Symptomatic and asymptomatic patient groups in terms of HF were examined in the crosstabs with Group 1 and Group 2. While the rate of symptomatic HF was 56% in Group 1, it was 26% in Group 2. The patients with symptomatic HF were determined to have a statistically significantly higher rate of stricture development, which was found with the Chi-square test (p = 0.002) (Table 3). The data obtained from the mMRC scale and CAT scores, which evaluate the pulmonary functions of the patients before the operation, and the pulmonary function testing parameters such as forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC were given as mean and standard deviation and were compared for Group 1 and Group 2, and the results are presented in the Table. The mean mMRC scale and CAT scores of the patients in group 1 were found to be statistically significantly higher than those in group 2 (p = 0.003, p = 0.002, respectively). FEV1, FVC, and FEV1/FVC values, on the other hand, were found to be statistically significantly lower in Group 1 compared to Group 2 (p < 0.001, p < 0.001, p = 0.008, respectively) (Table 4).
Table 2 ACC/AHA staging of patients
| Number of Patients | None | Stage A | Stage B | Stage C | Stage D | Total |
|---|---|---|---|---|---|---|
| Number of Patients | 18 | 26 | 15 | 32 | 9 | 100 |
Table 3 Distribution of two groups according to HF symptom status and Chi-square test
| HF symptom status | Group 1 (n = 50) | Group 2 (n = 50) | Total | p-value |
|---|---|---|---|---|
| No symptoms | 22 | 37 | 59 | 0.002 |
| With symptoms | 28 | 13 | 41 | |
| Total | 50 | 50 | 100 |
HF: heart failure.
Table 4 Comparison of data evaluating patients respiratory functions
| Respiratory function data | Group 1 (n = 50) | Group 2 (n = 50) | p-value |
|---|---|---|---|
| Mean ± SD | Mean ±SD | ||
| mMRC | 1.07 ± 1.54 | 0.68 ± 1.25 | 0.003 |
| CAT | 14.6 ± 10.06 | 8.66 ± 7.98 | 0.002 |
| FEV1 (%) | 71.02 ± 22.69 | 87.36 ± 15.19 | <0.001 |
| FVC (%) | 83.18 ± 16.31 | 95.84 ± 10.14 | <0.001 |
| FEV1/FVC (%) | 66.6 ± 10.84 | 72.5 ± 6.69 | 0.008 |
mMRC: modified medical research council; CAT: COPD assessment test; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; Mean ± SD: mean ± standard deviation.
When the PFT results were evaluated, 35 out of 100 patients were considered to have COPD due to the detection of FEV1/FVC <70% after bronchodilator. Groups of patients with and without COPD were examined in crosstabs with Group 1 and Group 2. While the rate of COPD was 48% in Group 1, it was 22% in Group 2. The patients with COPD were determined to have a statistically significantly higher rate of stricture development, which was found with the Chi-square test (p = 0.006) (Table 5).
Table 5 Distribution of two groups according to COPD status and Chi-square test
| COPD status | Group 1 (n = 50) | Group 2 (n = 50) | Total | p-value |
|---|---|---|---|---|
| No COPD | 26 | 39 | 65 | 0.006 |
| With COPD | 24 | 11 | 35 | |
| Total | 50 | 50 | 100 |
COPD: chronic obstructive pulmonary disease.
When the group that developed stricture in the post-operative follow-up was examined, the mean time to develop stricture was found to be 7.04 ± 3.75 months. When the relationship between being a smoker, HF symptom status, and the status of having COPD and the duration of stricture development was evaluated, no statistically significant finding was found.
Binary logistic regression analysis was used to identify the possible independent predictors of stricture development that contributed the most to the outcome. Being a smoker, the number of cigarettes smoked, BMI value, pre-operative PVR, symptomatic HF, scores of mMRC scale and CAT, FEV1/FVC, and COPD status were used as predictors. The model predicting the development of stricture was significant (χ2(8) = 4.26, p = 0.832) and explained 32.7% of the variance (Nagelkerke R2 = 0.327). The model correctly predicted 70% of non-relapsed and 72% of relapsed (71% overall). Smoking, the number of cigarettes smoked, and the pre-operative PVR value were important predictors for the development of stricture. Being a smoker was found to be the strongest predictor among these parameters in the model (p = 0.032). One unit increase in the number of cigarettes smoked increased the risk of stricture by 2 units (Table 6).
Table 6 Predictors for the development of stricture
| Risk factor | Development of stricture | |
|---|---|---|
| RR (95% CI) | p-value | |
| Smoking | 7.39 (1.18-46.18) | 0.032 |
| Number of cigarettes | 0.94 (0.88-0.99) | 0.042 |
| BMI | 1.18 (0.99-1.39) | 0.052 |
| PVR | 1.00(1.00-1.01) | 0.042 |
| Symptomatic HF | 4.66 (0.39-54.58) | 0.220 |
| mMRC | 0.79 (0.29-2.10) | 0.638 |
| CAT | 1.06 (0.93-1.21) | 0.335 |
| FEV1/FVC | 0.95 (0.85-1.06) | 0.377 |
| COPD | 1.11 (0.15-7.97) | 0.918 |
BMI: body mass ındex; PVR: post-void residual; HF: heart failure; mMRC: modified medical research council; CAT: COPD assessment test; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; COPD: chronic obstructive pulmonary disease.
Discussion
The development of US after TURP has been reported in the literature in recent years, in the range of approximately 9.8-13%5,19. Prevention of stricture development after diagnostic or therapeutic endourological procedures or reduction of high relapse rates after transurethral treatments such as internal urethrotomy carried out on advanced US is the main goal of the US approach, considering the high treatment costs20.
Both adequate oxygenation of tissue and hypoxia are necessary factors for normal wound healing21. The hypoxic environment at the beginning of wound healing plays an early stimulating role in tissue repair and angiogenesis through HIF-19,21. However, the finding that the proliferative rate of fibroblasts increases by 71% if the hypoxic environment lasts for more than 72 h is thought-provoking for fibrotic pathologies22. Recent studies have shown that profibrotic genes associated with HIF-1a, that is, hypoxia-induced, are effective in the development of fibrosis23. More studies are being conducted on HIF-1α inhibition for the treatment and prevention of fibrotic diseases24.
Hypoxia and hypoxemia describe different conditions. Hypoxemia refers to a decrease in partial oxygen pressure in the blood, while hypoxia refers to decreased tissue oxygenation. Hypoxemia might lead to hypoxia as a result. The most common cause of hypoxemia is ventilation/perfusion mismatch and it benefits from complementary oxygen therapies12,25.
Based on these considerations, in our study, we aimed to evaluate the relationship between HF, COPD, and smoking with the development of US by making a comparison between the patients with US development in their follow-ups after the TURP operation and those without. HF, COPD, and smoking are comorbidities that cause ventilation/perfusion mismatch systemically. These conditions can cause hypoxemia in systemic arterial blood and microvascular areas and thus hypoxia at the tissue level.
There are studies on medical treatment options that can prevent the development of US in the literature. However, there is no method that was accepted and included in the treatment routine yet.
In their study in 2014, Ateş et al. evaluated the effectiveness of hyperbaric oxygen therapy (HBOT) on hypospadias cases that they treated with the help of a buccal mucosal graft. The success rate was found to be significantly higher in the patient groups who were given HBOT after both the first surgery and the second surgery stages. They reported in their conclusion that HBOT can be used as an alternative method to increase the success of the procedure in these patients26.
In an experimental study conducted in Ankara, Turkiye, the early administration of dexpanthenol to rats with urethral damage has been shown to significantly reduce inflammation and spongiofibrosis and it was suggested that it would be beneficial in preventing the development of US after urethral damage27.
A US-based study suggested that the mechanism responsible for the development of US was urethral fibrosis resulting from altered or increased fibroblast activity within the tissue. In this study, the application of an antifibrotic agent mitomycin C in addition to internal urethrotomy was compared and it was resented as an alternative option for poor open surgery candidates and patients who require repeated multiple internal urethrotomy28.
In the study conducted by Dalkılınç et al. in 2018, the effect of low molecular weight heparin (LMWH), which is mainly used as an anticoagulant, on the incidence of US in patients who underwent TURP operation was investigated since it was presented to have antifibrotic effects. Given the relapse and urethroplasty rates, the incidence of developing severe US was concluded to be less in those receiving anticoagulant therapy with LMWH29.
In the literature review conducted, we did not come across any study that found a direct relationship between the development of US after TURP and smoking. In their study in which a total of 467 patients who underwent radical prostatectomy have been reviewed retrospectively, Borboroglu et al. indicated that smoking significantly increased the risk of vesico US development17.
There are studies with different opinions about smoking among studies evaluating which factors could be associated with stricture relapse after urethroplasty. Some studies suggest that smoking increases the rate of stricture relapse after urethroplasty16. One of the important studies is the study by Whitson et al. in 2008. They, in their study, concluded that smoking was a predictor of failure in patients who underwent fasciocutaneous flap urethroplasty30. On the other hand, many studies, especially Kinnaird et al.´s study in which they evaluated 604 urethroplasty cases retrospectively, state that smoking is not associated with relapse31.
There is also a similar difference of opinion on the relationship between relapse after internal urethrotomy and smoking. Aydemir et al., as a result of the retrospective analysis of the data of 94 patients, suggested that smoking increases relapse after internal urethrotomy32. On the contrary, Redon-Galvez et al. argued in a similar study that age, weight, smoking status, and cardiovascular risk factors did not have a significant effect on relapse after internal urethrotomy33.
The mean number of cigarettes smoked in the group with stricture was statistically significantly higher than the control group in our study (p = 0.007). In the logistic regression analysis carried out to identify the possible independent predictors of stricture development that contributed the most to the outcome, smoking was found to be the strongest predictor in the model (p = 0.032). One unit increase in the number of cigarettes smoked increased the risk of stricture by 2 units. The number of cigarettes smoked was also found to be high in patients with stricture who had a relapse after internal urethrotomy, but this difference was not statistically significant (p = 0.732).
Sinanoglu et al. suggested in their retrospective review of TURP data of 317 patients with different comorbidities that COPD was not a risk factor for the development of post-operative stricture34. In another study with a similar design, the minimum triple combinations of diabetes mellitus (DM), hypertension, coronary artery disease (CAD), and COPD comorbidities were determined to pose a risk in the development of stricture after internal urethrotomy18. The erectile dysfunction status of 41 patients with COPD was investigated in another study in which the severity of erectile dysfunction was observed to increase as the pulmonary function test parameters FEV1, FVC, and FEV1/FVC levels decreased35. Given that the penis and urethra are both supplied with blood by the internal pudendal artery, it was thought that there may be a connection between erectile perfusion and urethral ischemia.
In our study, COPD, as an independent comorbidity, was found in a higher number of patients in the group with stricture, which was statistically significant (p = 0.006). The mMRC scale and CAT test results evaluating the patients in terms of respiratory symptoms and severity of dyspnea were significantly higher in the stricture group (p = 0.003, p = 0.002, respectively). Levels of the pulmonary function test parameters FEV1, FVC, and FEV1/FVC levels were significantly lower in the stricture group (p < 0.001, p < 0.001, p = 0.008, respectively).
Sinanoglu et al. concluded in their study that comorbidities such as HT, DM, and CAD (Congenital Adrenal Hyperplasia) are risk factors for the development of US, especially in patients who underwent plasma kinetic TURP34. There are also studies showing that the same comorbidities are associated with the development of stricture after radical prostatectomy17,18,32 and relapse after internal urethrotomy. In a study conducted by Ruutu et al., among the patients who underwent open heart surgery and had a short-term urethral catheter and did not develop mortality in their 1-year follow-ups, 16.6% of them were found to have US developed36. In another study, the severity of CAD has been found to be associated with the US development in patients who underwent cardiac angiography for acute coronary syndrome and had a urethral catheter placed37.
In our study, patients were evaluated for HF using the ACC/AHA classification. After that, they were grouped as asymptomatic and symptomatic patients in terms of HF. The reason for this is that the hypoxemia picture, considered responsible for the pathogenesis in our study, was encountered only in symptomatic HF patients. When evaluated in this way, it was observed that there were many symptomatic HF patients at a statistically significant level in the group that developed stricture (p = 0.002).
In the literature, US has been observed to be detected in the first 6 months on average after TURP6. This period was 7.04 months in our study on average and was similar to the literature. There was no significant relationship between HF, COPD, smoking, and duration of stricture development.
Our study has some limitations. These include; the retrospective design of the study and the inability to perform histological examination because urethral tissue was not taken. In addition, smoking, COPD, and HF were evaluated using scales. Comorbidity studies detailed with physiometric and radiological imaging may contribute to the literature.
Conclusion
In our study, we concluded that smoking, HF, and COPD significantly increase the risk of stricture development after TURP. The symptom scores and each of the pulmonary function test parameters used in the diagnosis of COPD were determined to have a statistically significant relationship with stricture development. Among the possible independent predictors for stricture development, smoking was found to be the strongest predictor in the model.
Given these conclusions, it is believed that the hypoxemic picture should be closely monitored in the pre-operative, intraoperative, and post-operative periods in patients who would undergo TURP operation and remedial treatments and measures should be taken to reduce the rate of US development. Furthermore, patients who are planned for TURP and who are at high risk of developing US considering these factors can be provided more detailed information about the complications that might develop before the procedure, and they could be informed that they have a higher risk for this condition. Thus, despite the complications that might occur in the post-operative period, higher patient satisfaction and a conscious patient profile can be achieved.
The implications of our study need to be supported by more randomized controlled studies and meta-analyses as required by evidence-based science.
Authors´ contributions
K.T, A.D, O.G., and I.K. designed the study; K.T, K.U, A.B, and M.K. recruited the participants and collected the data; K.T, O.G., and I.K. performed the statistical analysis; K.T, A.D, and A.B interpreted the data; K.T. drafted the first manuscript; and all authors critically reviewed the paper.
