Dexmedetomidine intravesical instillation reduces postoperative catheter-related bladder discomfort in male patients under general anesthesia: a randomized controlled study

Background The catheter-related bladder discomfort (CRBD) of male patients is a common clinical problem, albeit lacking effective solutions. The present study aimed to investigate whether dexmedetomidine intravesical instillation alleviates the postoperative urinary discomfort in male patients with catheter under general anesthesia. Methods This single-blinded, prospective, randomized study included a total of 167 male patients American Society of Anesthesiologists (ASA) physical status I-II scheduled for surgery under general anesthesia were allocated to two groups: 84 in the dexmedetomidine (Dex) group and 83 in the control group. Dex group patients received intravesical instillation of the drug 0.5 μg/kg and normal saline 20 mL, while the control group received intravesical instillation of 20 mL normal saline. The catheter was clamped for 30 min after intravesical instillation for all patients. Bladder stimulation scales and urethra pain numerical rating scale (NRS) scores were measured at admittance to post-anesthesia care unit (PACU) (T0), intravesical instillation (T1), 30 min (T2), 60 min (T3), 2 h (T4) after intravesical instillation, discharged from PACU (T5), and 6 h (T6) and 24 h (T7) after the operation. Patient satisfaction at discharge from PACU and 24 h post-operation were compared between the two groups. Results Bladder stimulation scales and urethra pain NRS scores after 30 min of dexmedetomidine intravesical instillation to 24 h post-operation were signicantly lower than the control group (p<0.001), and patient satisfaction was higher at discharge from PACU and 24 h post-operation (p<0.001). No di ﬀ erences were detected in Steward score out of PACU (p=0.213) and from the time of the end of operation to fully awake (p=0.417). Conclusion Dex intravesical instillation reduces postoperative urinary discomfort and urethra pain and improves satisfaction in male patients under general anesthesia. and no catheter drainage bag traction, catheter obstruction, hemorrhagic pseudopolyps were observed. we the main for the difference in the urethral pain between the two groups was the tolerance of catheter stimulation of the bladder wall and the difference in the and psychological rejection of the catheter. Dex is a solution to bladder irritation and psychological maladjustment of patients, thereby reducing the catheter-induced urethral pain. Systematic pain NRS score decreased at T4, and there was no signicant change at other time points. The possible reason is that dextromethorphan was absorbed by bladder and played a systemic role, which need further study.


Patient randomization
Male patients with CRBD into PACU were randomly divided into two groups with an allocation ratio of 1:1 according to the computerized randomization table in a blinded manner. Random numbers to each patient while the nurses collected postoperative data from the patients.

Anesthesia application
The surgery and anesthesia program of the patient was similar to that of the other patients. Electrocardiography (ECG), peripheral oxygen saturation (SpO 2 ), non-invasive blood pressure (NBP), and respiratory rate (RR) were monitored routinely after the patients were admitted to the operating room. The vein channel was established with a 22-gauge indwelling needle. Oxygen was inhaled by mask (oxygen ow rate was 4-5 L/min). Midazolam 0.025 mg/kg, sufentanil 2-4 μg/kg, etomidate 1-2 mg/kg, and rocuronium 0.9 mg/kg were injected intravenously for anesthesia induction. After intubation, a ureteral catheter was used for catheterization, followed by anesthesia maintenance propofol 2-4 mg/kg/h, remifentanil 10-20 μg/kg/h, and continued addition of cisatracurium to maintain muscle relaxation. At the end of the operation, the muscle relaxation and consciousness of the patient were restored, the tracheal tube was removed and sent to PACU for observation.

Catheterization
After induction of anesthesia, 16F latex ureteral catheter (Huaxing Medical Equipment Co., Ltd, China) was used for all participants. Catheterization was performed by surgeons with more than 5 years experience. The operation process must be as gentle as possible, and the whole process was sterile. Before catheterization, para n oil fully lubricated the catheter. After the successful placement of the catheter, 10 mL of normal saline was injected into the cuff balloon to prevent catheter slippage. After catheterization, the catheter was xed on the inside of the thigh to prevent urinary tract injury caused by catheter pulling.

Interventions
As a safe and widely used drug, Dex intravesical instillation method has been approved by the Institutional Review Board and Hospital Research Ethics Committee of the Second A liated Hospital of Anhui Medical University. In the Dex group, 0.5 μg/kg Dex was solubilized in 20 mL normal saline infused from the ureteral catheter to bladder for Dex intravesical instillation. In the control group, 20 mL of normal saline was infused from the ureteral catheter to the bladder. After instillation, the ureteral catheter was clipped for 30 min and then unclipped.

Assessments
The primary outcome endpoint was CRBD grade, and the second outcome endpoint was urethra pain NRS score and patient's satisfaction. The duration of anesthesia, the time length of operation, the time from the end of the operation to full consciousness, and patient characteristics were recorded. Mean arterial pressure (MAP), heart rate (HR), RR, SpO 2 , CRBD grade, and urethra pain NRS score were recorded when the patient was sent to PACU (T0) , the time of intravesical instillation with Dex or normal saline (T1), 30 min after intravesical instillation (T2), 1 h after intravesical instillation (T3), 2 h after intravesical instillation (T4), the time point of leaving PACU (T5), 6 h after operation (T6), and 24 h after opertaion (T7). The NRS score of urethra pain and the complications after intravesical instillation were also recorded. The patient satisfaction score were recorded when leaving PACU and 24 h after the operation. The NRS score was used for the assessment of urethra pain in both groups. CRBD grade: grade 0, patients have no discomfort at all; grade 1, patients have slight discomfort, only when asked to show discomfort; grade 2, patients have moderate discomfort, frequency of urination, the urgency of urination, feeling of lower abdominal distension, which is not easy to bear; grade; 3, the patient had severe discomfort, intolerable distension, urethral pain, frequent urination with strong restlessness, and needed to be removed. Ramsay score: 1 point, the patient is restless and dgety; 2 points, the patient is quiet and cooperative; 3 points, the patient is sleepy and can follow the instructions; 4 points, the patient is in a sleep state and can wake up; 5 points, the respiratory response of the patient is slow; 6 points, the patient is deep asleep and has no response to stimulation. Patient satisfaction score is consisting of integers from 1 point to 5 points: 1 point means dissatis ed and 5 points mean very satis ed. The urethra pain NRS scores consists of integers from 0-10 points; 0 point means no urethra pain, and 10 points indicate intense urethra pain. Subsequently, the patients selected an integer to describe the intensity of their urethra pain while using a ureteral catheter.
Statistical analysis SPSS software (version 22.0, Chicago, USA) and were used for statistical analysis. The age, weight, blood, and other measurement data of patients were presented as mean±standard deviation. The ASA classi cation data were expressed as counts. Student's t-test or the Mann-Whitney U test was used for continuous variables, such as age and weight. The c 2 or Fisher's exact tests were assessed for categorical variables, such as ASA grade and patient satisfaction score. ANOVA was used for the comparison of MAP, HR, SpO 2 , and other data at different time points. pvalue <0.05 was accepted as statistically signi cant.

Study demographics
A total of 289 male patients were screened in this study, of which, 109 cases were excluded; among them, 96 did not present CRBD, 6 were did not meeting the other inculsion criteria, 5 refused to participate in the study, and 2 were excluded for other reasons. A total of 180 male patients with CRBD were randomly and equally divided into both groups when into PACU. Six cases in the Dex group and 7 cases in the control group did not complete the experiment. None of the patients were lost follow-up. Finally, 84 patients in the Dex group and 83 patients in the control group were included in the analysis (Fig. 1). A total of 276 patients were enrolled in PACU, including 180 patients with CRBD, and 96 patients were excluded from this study due to the absence of CRBD. The incidence of CRBD was 65.2%.
No signi cant difference was detected between the two groups in age, weight, ASA grade, duration of operation, duration of anesthesia, Steward's score when leaving PACU, the time length of operation end to fully awake, catheter removal time ( Table 1) and type of operation. There was no signi cant difference was observed in HR, RR, MAP, and SpO 2 in the two groups from T0 to T7 (Table 2), as well as no complications, occurred in either of the groups.
Systematic pain NRS score decreased at T4.

Discussion
In the present study, we observed that 0.5 μg/kg Dexmedetomidine intravesical instillation can signi cantly reduce the symptoms of postoperative catheter-related bladder discomfort and the urethral pain caused by catheter in male patients who received general anesthesia, and consequently, their satisfaction was improved. The improvement of these symptoms can sustain from 0.5-24 h after Dex intravesical instillation.
CRBD is common in PACU, especially male patients [26]. Therefore, in this study, we included male patients as the study subject, and the incidence of CRBD was 65.2%, which was consistent with that reported previously [1,2,26]. The high incidence of CRBD in male patients might be related to the anatomical characteristics, such as the long urethra and large catheter [26]. Because several urological operations need to operate on the urethra, which markedly impacts this study, and the degree of impact is different, so this study was not included in the urological patients.
In this study, we observed that Dex intravesical instillation can signi cantly reduce the symptoms of postoperative CRBD according to the following underlying mechanism. Alpha 2-adrenoceptor, i.e., the α2A-subtype, is expressed in the bladder, urethra, and prostate. The intra-arterial administration of an α-2 agonist reduced the micturition pressure, bladder capacity, and micturition volume [27,28]. Dex is a high selective adrenergic α-2 receptor agonist which may reduce the micturition pressure, bladder capacity, and micturition volume. There are several muscarinic receptors in bladder epithelium and efferent nerves, including M2 and M3. The M3 receptor is mainly responsible for bladder contraction [29]. The catheter can stimulate the afferent nerves of the bladder to release acetylcholine, which leads to the contraction of detrusor mediated by muscarinic receptors. Therefore, muscarinic antagonists alleviate CRBD in different degrees. [1] Some studies showed that Dex might reduce bladder contractility via α-2 receptor and M3 muscarinic receptor antagonism. [16,17] On the other hand, catheter stimulation can cause in ammation and increase prostaglandin secretion, which is one of the plausible reasons for CRBD. [30] Therefore, some antiin ammatory drugs can also alleviate CRBD. Another study showed that Dex reduces the release of prostaglandins of in ammation, and hence, relieves CRBD [31]. In addition, Dex exerts a sedative effect and relieves CRBD [10].
In the current study, Dex plays a role in intravesical instillation. The off-label method of dexmedetomidine is often used in clinical research, which has proved to be safe and effective. For example, dexmedetomidine is safely used in subarachnoid and epidural [32], neuraxial [33] and for children intranasal [34]. As a safe and widely used drug, Dex intravesical instillation method has been approved by the Institutional Review Board and Hospital Research Ethics Committee. Several studies [23][24][25] showed that intravesical instillation is an effective way of administration of drugs, which had an obvious effect on the treatment of bladder-related diseases and reduce the systemic response. Dex is well absorbed through the mucous membrane. Iirola et al. [35] reported that peak plasma concentrations of Dex were 38 min after intranasal administration, and the pharmacological effects were similar to the intravenous administration but with a later onset time. In the current study, Dex was able to work through the bladder mucosa, with a signi cant effect at half an hour after administration.
In this study, Dex intravesical instillation alleviates the pain caused by catheter while in situ and on removal. The main causes of the pain during catheter in situ were as follows: the material and size of the catheter, the traction of the catheter drainage bag, the urethral discomfort, the stimulation of the bladder wall by the catheter, the obstruction of the catheter, catheter blockage, the hemorrhagic pseudopolyps, the fear of the catheter, and the psychological rejection [36]. In the present study, all patients were observed and nursed closely, and the material and size of the catheter were identical, and no catheter drainage bag traction, catheter obstruction, hemorrhagic pseudopolyps were observed. Therefore, we speculated that the main reason for the difference in the urethral pain between the two groups was the tolerance of catheter stimulation of the bladder wall and the difference in the fear and psychological rejection of the catheter. Dex is a solution to bladder irritation and psychological maladjustment of patients, thereby reducing the catheter-induced urethral pain. Systematic pain NRS score decreased at T4, and there was no signi cant change at other time points. The possible reason is that dextromethorphan was absorbed by bladder and played a systemic role, which need further study.
Patients' satisfaction at the time point out of PACU and 24 h after the operation was signi cantly improved after Dex intravesical instillation because there were reductions in CRBD and catheter-induced urethral pain and patient satisfaction is closely related to the postoperative outcomes [37]. The improvement in the patients' satisfaction might reduce their CRBD and urethral pain.
No complications were detected in the control and experimental groups. Since the sample size of this study is small, and the patients selected are ASA I-II, their basic conditions are well. Clinically, we will encounter CRBD to aggravate the condition of patients with coronary heart disease, and Dex might also lead to arrhythmia and other risks.
Nevertheless, the present study has some limitations. The number of cases is small as only 167 patients were included in this single-center study. In the future, large sample and multi-center clinical veri cation is essential. The patients included in this study were male patients with catheter placement under general anesthesia. The type of operation is not uniform, and the duration of operation is varied. Further subgroup study can be carried out after expanding the sample size in the future. All the patients included in this study were ASA I-II patients with elective surgery, and the basic condition of the patients was good. Also, critical patients have not been analyzed previously. Moreover, the effect of different doses of Dex on CRBD was not assessed in this study. Ten milliliter normal saline was injected into the cuff balloon of catheter for all paitents to prevent slippage in our research. This may also be a potential cause of bladder wall irritation. It is regretful that we did not follow up with further research on the effect of reducing the balloon volume for reducing CRBD.

Conclusions
Dex 0.5 μg/kg intravesical instillation reduces postoperative urinary discomfort and urethra pain caused by catheter in male patients under general anesthesia and improves patient satisfaction after the operation.    Figure 1 Schematic of the study with a CONSORT diagram. CRBD, catheter-related bladder discomfort; group Dex, dexmedetomidine group.  Spine plot of patient satisfaction score out of PACU (Fig. 3A) and 24 h after the operation (Fig. 3B) in Dex and control groups. Patient satisfaction score: 5 points, very satis ed; 4 points, satis ed; 3 points, relatively satis ed; 2 points, basically satis ed; 1 point, dissatis ed.