Bladder dysfunction is the most common complication after radical hysterectomy. The incidence is approximately 10% to 80%, depending on the degree of surgical radicality and diagnostic methods.1 Radical hysterectomy is a major operative procedure that excises the uterus and the cervix, including parametrial tissue and upper vagina. It affects autonomic nerves innervating the bladder during resection of anterior, lateral, and posterior parametrium and vaginal cuff. The bladder dysfunction seems to be partial damage of parasympathetic denervation rather than a complete denervation. As a result, decreased bladder sensation and decreased detrusor muscle contraction are demonstrated, which interfere with bladder emptying.2
Generally, management of bladder dysfunction is continuous urethral catheterization or clean intermittent self-catheterization. Prolonged urethral catheterization may increase the risk of urinary tract infection (UTI) and decrease quality of life. Our previous study reported that up to 20% of patients required urethral catheterization more than 2 weeks and 15% required more than 4 weeks. Few patients (1.5%) required permanent urethral catheterization because of a neurogenic bladder.3
Bethanechol chloride is a cholinergic drug considered as a treatment in patients with high postvoid residual urine (PVR) without bladder outlet obstruction. Bethanechol chloride may enhance the detrusor muscle contraction, resulting in higher maximum flow rate, higher detrusor pressure at maximum flow, and lower PVR.4 The efficacy of this agent is unclear; there are both negative and positive reported outcomes.5 In 1 case-controlled study, they reported the efficacy of bethanechol chloride for the prophylaxis of detrusor underactivity after radical hysterectomy.6 Urethral catheterization could be discontinued significantly faster (9.6 vs 13.3 days), and residual urine returned to normal quicker (8.0 vs 13.0 days) than that in the control group. Furthermore, the incidence of UTI was lower (18.8% vs 25%).
This study was conducted to compare the efficacy of bethanechol chloride compared with placebo for the prevention bladder dysfunction after type III radical hysterectomy.
MATERIALS AND METHODS
Study Design and Patients
This was a randomized, double-blinded placebo-controlled study of bethanechol chloride versus placebo in patients with early-stage cervical cancer or endometrial cancer, who underwent standard type III radical hysterectomy during August 2007 to March 2010 at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Exclusion criteria were hypersensitivity to bethanechol chloride, active bronchial asthma, hyperthyroidism, hypotension, tachycardia, vasomotor instability, coronary artery disease, epilepsy, Parkinsonism, gastrointestinal obstruction, bladder neck obstruction, and recent urinary bladder surgery and gastrointestinal resection with anastomosis. All patients received complete physical examination and laboratory studies preoperatively. Operations were performed by 9 experienced gynecologic oncologists using similar techniques. The surgical techniques of type III radical hysterectomy are as follows. The uterine artery was ligated at its origin on the internal iliac artery, and the ureter was dissected from the pubovesical ligament. The ligament at the lower end of the ureter and superior vesical artery was preserved. The cardinal ligament and the uterosacral ligament were resected from the pelvic sidewall. The upper 25% of the vagina or an approximately 2-cm length was excised.
Baseline characteristics including age, parity, menopausal status, hormone treatment, body mass index, and type of cancers were recorded. Vaginal and parametrial length were measured from unfixed specimens. The other surgical outcomes such as operative time, estimated blood loss, and length of hospital stays were also recorded. Blood loss was estimated from the amount in the suction bag and numbers of swabs or gauzes. This study was approved by the institutional review board of the Faculty of Medicine, Chulalongkorn University, and all patients signed informed consents before randomization. This study was registered as ISRCTN92687416 (www.controlled-trials.com/ISRCTN92687416)
Randomization and Masking
After the patients were screened for eligibility by the investigators, they were randomized by computer-generated schedule to assign patients in a 1:1 ratio into 2 groups. Allocation concealment of the treatment drugs was assigned in sequential numbered, sealed packages that linked to the randomization numbers. Patients and physicians including the nursing staff were masked to the treatment allocation. Identification was made by standard code and revealed at the end of the study. Data analysts were also blinded from the treatment assignment.
The study procedures are shown in Figure 1. Patients were randomly assigned to receive bethanechol chloride (Ucholine, M&H Manufacturing Co., Ltd., Samutprakarn, Thailand) 20 mg 3 times a day, 1 hour before meals on the third to seventh postoperative day (POD), or placebo, which was identical in appearance to bethanechol chloride and was presented in the same packaging. Primary end point was the rate of urethral catheter removal at 1 week postoperatively. Secondary end point was duration of urethral catheterization, volume of PVR, adverse events, and UTI at 1 month postoperatively.
Vital signs were monitored every 30 minutes on the first 2 hours then every 4 hours on the first day. Any adverse events were recorded. Particular attention was paid to malaise, abdominal cramps or discomfort, colicky pain, nausea, and vomiting, diarrhea, salivation, urinary urgency, headache, flushing, lacrimation, miosis, hypotension with reflex tachycardia, bronchial constriction, and asthmatic attack. Atropine, which is an antidote, would be given to patients with severe adverse events.
The urethral catheter was inserted intraoperatively and removed on the eighth POD. Voided volume and PVR were recorded. Intermittent urethral catheterization was used to measure PVR. If PVR was more than 30% of the voided volume, the urethral catheter was reinserted, and medication would be continued until the catheter could be removed. However, if medication were not given for more than 1 month, then patients would be offered clean intermittent self-catheterization. PVR, urinalysis, and urine culture were evaluated at 1 month postoperatively.
The χ2 or Fisher exact test was used to analyze the categorical variables. The median values of continuous variables were compared by the Mann-Whitney U test. P values less than 0.05 were considered statistically significant.
There were 31 patients in each group without significant difference in baseline characteristics (Table 1). Twenty-one patients (67.7%) in the treatment group and 12 patients (38.7%) in the control group had the urethral catheter removed at the eighth POD. The treatment group had a significantly higher rate of urethral removal at the eighth POD (P = 0.04). The median duration of urethral catheterization was significantly shorter in the treatment group (7 and 14 days, respectively; P = 0.03). The cumulative number of patients who could remove urethral catheter according to different postoperative periods in both groups is shown in Figure 2. Higher cumulative percentage of patients who could remove urethral catheter was demonstrated in the treatment group. However, there was significant difference only at the first week postoperatively.
There were no significant differences in voided volume, PVR, and UTI at 1 month postoperatively between both groups (Table 2). All patients who discontinued the use of bethanechol chloride after urethral catheter removal had normal voiding function without high PVR at 1 month postoperatively. One third of patients in the treatment group had adverse events such as nausea, abdominal distension, and abdominal cramping, which were higher than the control group. (Table 3). However, all adverse events were mild, and no patient required any medical treatment.
Bladder dysfunction is the most common complication after radical hysterectomy. It can be classified as early and late dysfunction. Early bladder dysfunction consists of decreased bladder capacity, detrusor underactivity, and diminished bladder sensation, which causes voiding dysfunction and requires urethral catheterization. This is usually temporary and depends on the severity of damage to autonomic innervation. Late dysfunction such as voiding difficulty with abdominal straining, decreased bladder compliance, detrusor overactivity, and urinary incontinence could persist for longer times but usually resolve within 6 to 12 months.2 Early voiding dysfunction is associated with an increased risk of late bladder dysfunction. Bandy et al.7 reported that patients who required bladder drainage for more than 30 days after surgery had significantly worse PVR and bladder capacity. High prevalence of long-term voiding dysfunction after radical hysterectomy in patients with early postoperative voiding dysfunction was also demonstrated in our previous report. High residual urine and abdominal straining increased significantly in these patients.8 Any strategies to eliminate the risk of early voiding dysfunction might decrease long-term voiding dysfunction.
The extent of bladder dysfunction after radical hysterectomy is associated with the extent of surgical resection. Several reports suggest that the most damaging step for bladder function was vaginal and paravaginal tissue resection.9 The proprioceptive sensory pathway arises from tension receptors in the bladder wall and traverses via thin myelinated fibers. These fibers pass mainly through the parasympathetic nerve. Damage to the autonomic afferent neurons that traverse the parametrium, cardinal ligament, and uterosacral ligaments during radical hysterectomy may cause motor and sensory impairment of the detrusor muscle. This might be the most plausible explanation for the bladder dysfunction.
Bethanechol chloride is a parasympathomimetic drug that has proved to be the most widely used pharmacological agent to promote bladder emptying. It is considered for treatment of urinary retention, high PVR, and neurogenic bladder without infravesical obstruction.5 However, the efficacy of bethanechol chloride in promoting bladder emptying is controversial. Autonomic denervation may preclude the pharmacological action of this drug. However, in animal models, bethanechol chloride proved to be efficient in promoting urinary frequency in rats subjected to bilateral pelvic nerve transection.10 Bethanechol chloride may enhance the detrusor muscle contraction by stimulation of muscarinic receptor, resulting in increased detrusor pressure. Furthermore, it may improve afferent signals in the pelvic nerves, resulting in increased bladder sensation.11 Kemp et al.6 performed a comparative study on the efficacy of bethanechol chloride for prophylaxis of detrusor hypotonia after the Wertheim-Meigs operation. Shorter hospital stay, earlier removal of a suprapubic catheter, lower PVR, and decreased rates of cystitis were reported in patients receiving bethanechol chloride. Madeiro et al.4 evaluated the effects of bethanechol chloride and cisapride on urodynamic parameters in patients undergoing radical hysterectomy. They found that early use of bethanechol and cisapride after radical hysterectomy positively modified urodynamic parameters, resulting in more efficient detrusor function. Significantly lower maximum cystometric capacity, lower cystometric capacity at first desire to void, higher maximum flow rates, higher detrusor pressure at maximum flow, and lower PVR were reported. However, there was higher incidence of detrusor overactivity in patients who received a combination of bethanechol and cisapride compared with patients who received bethanechol or cisapride alone. In contrast, others reported the clinical ineffectiveness of bethanechol chloride to promote bladder emptying. Barrett et al.12 reported that bethanechol chloride failed to treat patients with bladder atony associated with excessive residual urine. Chronic bladder overdistension may damage the smooth muscle, which causes an inability of nerve stimulation to induce detrusor muscle contraction. Furthermore, bethanechol chloride may be ineffective in patients with complete lower motor neuron lesion.13 Autonomic denervation after radical hysterectomy is usually partial or incomplete; therefore, bethanechol chloride may have some benefit.
Our study reported that bethanechol chloride reduces the duration of urethral catheterization in patients undergoing type III radical hysterectomy. A significantly higher number of patients in the bethanechol-treated group had their urethral catheters removed at 1 week postoperatively. Median duration of urethral catheterization was significantly shorter in the bethanechol-treated group. Although bethanechol chloride was discontinued in patients who could remove their urethral catheter, there was no effect on further voiding function. Voided volume and PVR were reevaluated at 1 month postoperatively. All patients could complete emptying of bladder without high PVR. Therefore, this confirmed that the effectiveness of bethanechol chloride does not occur only when the drug was prescribed. It may normalize the voiding function permanently.
Optimal dosage, time schedule, route, and duration of administration remain unclear. Various dosages of bethanechol chloride were reported from 30 to 150 mg daily every 6 to 8 hours.4,6,13 Route of administration may be orally or subcutaneously. Although the subcutaneous route was reported to be more efficient than the oral route, it is not available in Thailand.13 Therefore, we used 60 mg oral dose daily, 3 times a day in this study. This dosage was similar to one study, and it was the recommended dosage in Japan.13 It can be started immediately within the first 3 days postoperatively without serious adverse events.4,6 Higher cumulative percentage of patients who could remove their urethral catheter was demonstrated in the bethanechol-treated group. However, this benefit was demonstrated only before 1 month postoperatively. The patients who could not remove their urethral catheter after 1 month may have extensive or complete damage to autonomic innervation. Bethanechol chloride may be ineffective in these patients. Therefore, we chose the 1-month period as a maximum duration of administration.
The extent of radicality relates with lower urinary tract (LUT) dysfunction. Resected parametrial length more than 2 cm and vaginal length more than 3 cm associated with significant LUT dysfunction.9,14 Less radicality (type II radically hysterectomy) was proposed aiming to reduce LUT dysfunction without any effect on survival.15 Recently, nerve-sparing radical hysterectomy has been developed. Type III nerve-sparing radical hysterectomy seems to be comparable with type II radical hysterectomy and superior to type III radical hysterectomy in terms of early bladder dysfunctions.16 However, it lacked large randomized controlled trials and long-term follow-up. To our knowledge, there has been no study reporting the efficacy of bethanechol chloride in patients treated with type II or nerve-sparing radical hysterectomy. A comparative study should be conducted to compare the incidence of early voiding dysfunction between less radicality or nerve-sparing technique and conventional technique with bethanechol chloride treatment.
In conclusion, bethanechol chloride may be used early in the prophylaxis of bladder dysfunction in patients who underwent type III radical hysterectomy. It decreases the duration of urethral catheterization with manageable adverse events. However, a larger randomized controlled trial with quality of life measurements using validated questionnaires should be conducted to prove the clinical significance of our findings.
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Keywords:Copyright © 2011 by IGCS and ESGO
Bladder dysfunction; Bethanechol chloride; Gynecologic cancer; Radical hysterectomy