Catheter-related bladder discomfort (CRBD) is described as a burning sensation with an urge to void or as discomfort in the suprapubic area caused by irritation of the bladder due to a catheter.1 This discomfort may reduce the quality of life postoperatively and increase postoperative pain and agitation.2–4 Muscarinic receptors, particularly subtype 3, are closely related to CRBD.1 Many agents, including ketamine, tolterodine, tramadol and butylscopolamine, which commonly block the muscarinic receptor, have been investigated as approaches in the prevention or treatment of CRBD.1,5–7
Dexmedetomidine, a selective α2-adrenoceptor agonist, has analgesic, sympatholytic and sedative properties. Such characteristics make dexmedetomidine a useful anaesthetic adjuvant for general anaesthesia. Many reports have revealed the beneficial effects of dexmedetomidine in terms of reducing intraoperative anaesthetic requirements, postoperative analgesic demand and haemodynamic responses to noxious stimuli such as endotracheal intubation.8–12 Moreover, a previous experimental study13 demonstrated that dexmedetomidine inhibits muscarinic receptor subtype 3. The effect of dexmedetomidine on preventing postoperative CRBD, however, has not been studied when dexmedetomidine is used as anaesthetic adjuvant for general anaesthesia.
A previous study14 identified male sex and diameter of the Foley catheter as risk factors for CRBD. Transurethral resection of the bladder tumour (TURB) is the treatment of choice for many bladder cancers.15,16 Most patients undergoing TURB are high-risk for CRBD, as the majority are men and many will have a large diameter urinary catheter postoperatively.
In this study, we aimed to determine the ability of intraoperative dexmedetomidine administration to prevent CRBD in patients undergoing TURB by investigating the incidence of CRBD during the postoperative period.
Materials and methods
After receiving approval from the Institutional Review Board of Seoul National University Hospital (Chairperson Prof Jae-Seung Paick, number H-1309-047-519, date 31 October 2013) and acquiring written informed consent from the patients, we performed this randomised, double-blind, placebo-controlled study. The protocol for this clinical trial was registered at ClinicalTrials.gov (NCT01991223). Patients aged 18 to 80 years who were American Society of Anesthesiologists (ASA) physical status I and II and scheduled to undergo elective TURB were recruited from November 2013 to January 2014. Exclusion criteria were bladder outflow obstruction, overactive bladder (frequency greater than three times per night or more than eight times per 24 h), end-stage renal disease [serum creatinine >1.6 mg dl−1 (141 mmol l−1)], neurogenic bladder, heart failure, arrhythmia, morbid obesity, use of chronic analgesic medication and hepatic or psychiatric disease.
Patients were randomly assigned to one of two groups (control or dexmedetomidine) with the help of a computer-generated random number table. The randomisation was sequenced into blocks of 4 and 6. The assignments were concealed in opaque envelopes and opened immediately before induction by a nurse who was blinded to this study and was responsible for preparing the study drugs. After anaesthetic induction, the dexmedetomidine group was infused with dexmedetomidine (Predecex; Hospira Inc., Lake Forest, Illinois, USA) at a loading dose of 1 μg kg−1 over 10 min, followed by a continuous infusion of 0.5 μg kg−1 h−1 until the end of surgery. In the control group, an identical volume of 0.9% saline was infused in the same manner.
Patients were educated about the symptoms of CRBD (characterised as a burning sensation with an urge to void or as discomfort in the suprapubic area) during a preoperative visit. Anaesthesia was induced with 2 mg kg−1 propofol. Insertion of a supraglottic airway device (I-gel; Intersurgical Ltd., Berkshire, UK) was facilitated by intravenous administration of 0.6 mg kg−1 rocuronium bromide. Desflurane was used to maintain anaesthesia and the inhalational end-tidal concentration was adjusted to maintain SBP within ±20% of baseline and bispectral index 40 to 60. Intraoperative hypotension (20% reduction in baseline blood pressure) and bradycardia (heart rate <50 beats min−1) was treated with 5 to 10 mg ephedrine and 0.5 mg atropine, respectively, and the incidence was noted. At the end of the procedure, residual neuromuscular blockade was antagonised with neostigmine 0.05 mg kg−1 and atropine 0.02 mg kg−1. A urinary catheter was inserted and fixed to the leg without any traction using adhesive tape. The bladder was irrigated continuously with 0.9% saline through the urinary catheter. The Foley catheter was removed 24 h postoperatively. Time to extubation (the time from the end of the procedure to the removal of the airway device) was recorded. After removal of the I-gel, patients were transferred to the postanaesthesia care unit. Average desflurane concentration during surgery was noted.
Severity of CRBD was recorded as ‘none’ when patients did not complain of any CRBD on questioning, as ‘mild’ when reported by patients only on asking, as ‘moderate’ when reported by patients on their own (without asking and not accompanied by any behavioural response) and as ‘severe’ when reported by patients on their own along with behavioural responses (flailing limbs, strong vocal response and attempt to pull out the catheter).1,5,6,17 The incidence and severity of CRBD were assessed at 0, 1, 6 and 24 h postoperatively by a nurse or junior anaesthesiology resident who was blinded to the group assignments. When moderate or severe CRBD was reported, 50 to 100 mg tramadol was administrated intravenously as a rescue therapy. The postoperative pain was recorded using a numerical rating scale (NRS) (0: no pain, 10: worst imaginable pain) at 0, 1, 6 and 24 h. In the event of a NRS score more than 4, fentanyl 50 μg or demerol 25 mg was administrated as a rescue therapy. The presence of postoperative nausea and vomiting (PONV) and dry mouth were also recorded. The Ramsay Sedation Scale was measured postoperatively at 0, 1, 6 and 24 h and recorded as follows: 1 (anxious, agitated or restless); 2 (cooperative, oriented and tranquil); 3 (responds to commands, asleep); 4 (brisk response to light glabellar tap or loud noise); 5 (sluggish response to light glabellar taps or loud noise); or 6 (no response).18 Patients with a sedation scale score of at least 4 were considered sedated.18 The primary endpoint was a 30% reduction in the incidence of CRBD with the use of dexmedetomidine. Secondary endpoints were postoperative analgesic requirements and the incidence of analgesic side effects.
According to a previous study,7 70% of patients complain of CRBD postoperatively. Assuming that this incidence would decrease to 40% after treatment, we calculated that 48 patients would be needed in each group to achieve statistical significance (α = 0.05 and β = 0.20). Considering a 20% dropout rate, 57 patients per group were included. Statistical analysis was done using SPSS v19.0 (SPSS Inc., Chicago, Illinois, USA). The incidence of CRBD, PONV, dry mouth, intraoperative hypotension and bradycardia and the number of patients with receiving tramadol were compared using the Chi-square test or Fisher's exact test (if cell size ≤5). Intraoperative desflurane concentrations were compared using Student's t-test. Ramsay Sedation Score and postoperative pain score were analysed by repeated measures analysis of variance and the t-test was then used to compare values at each time point. A P value less than 0.05 was considered significant. Data are described as mean ± SD or number (proportion) as appropriate.
One hundred and twenty-eight patients were screened for inclusion in the study (Fig. 1). Nineteen patients were excluded [exclusion criteria (n = 14), refusal (n = 3), cancelled operation (n = 2)], leaving 109 patients for analysis. No differences in the demographic characteristics of the groups were observed (Table 1). The total dose of dexmedetomidine delivered was 77 ± 2 μg in the dexmedetomidine group.
The incidence of CRBD was significantly higher in the control group than in the dexmedetomidine group at 0 [43 (78%) vs. 27 (50%); P = 0.004], 1 [47 (85%) vs. 31 (57%); P = 0.002] and 6 h [45 (82%) vs. 34 (63%); P = 0.047] (Table 2). The incidence of moderate to severe CRBD at 0 [21 (38%) vs. 6 (11%); P = 0.002] and 1 h [16 (29%) vs. 4 (7%); P = 0.006] was higher in the control group than in the dexmedetomidine group. The number of patients who required treatment with tramadol for CRBD was 24 (44%) and 12 (22%) in the control and dexmedetomidine groups, respectively (P = 0.03).
The mean end-tidal desflurane concentration was higher in the control group than in the dexmedetomidine group (4.5 ± 1.7 vs. 3.9 ± 1.2%; P = 0.040). Time to extubation did not differ between the groups. The rates of intraoperative hypotension [12 (22%) vs. 18 (33%); P = 0.203] and bradycardia [5 (9%) vs. 6 (11%); P = 0.761] were similar in both groups.
The postoperative pain score was higher in the control group than in the dexmedetomidine group at 0 (4.6 ± 3.2 vs. 2.7 ± 3.0; P = 0.002), and 1 h (3.8 ± 2.4 vs. 2.7 ± 2.8; P = 0.041). After that time, the postoperative pain score was comparable between the control and dexmedetomidine groups at 6 (2.0 ± 1.7 vs. 2.0 ± 1.6) and 24 h (1.3 ± 1.3 vs. 1.7 ± 1.4). The number of patients who needed rescue analgesia with fentanyl or demerol for postoperative pain was 21 (38%) and 8 (15%) in the control and dexmedetomidine groups, respectively (P = 0.011).
No significant differences were observed in the rates of postoperative nausea [4 (7%) vs. 5 (9%); P = 0.742] and dry mouth [2 (4%) vs. 3 (6%); P = 0.679] between the control and dexmedetomidine groups. No patient in either group vomited postoperatively. The two groups did not differ in changes in Ramsay Sedation Score over time. No patient in either group desaturated (oxygen saturation <90%) or became very sedated (Ramsay sedation scale ≥4) during the entire study period.
We have demonstrated that intraoperative dexmedetomidine reduces the incidence and severity of postoperative CRBD as well as intraoperative desflurane and postoperative opioid requirements in patients undergoing TURB.
CRBD due to an indwelling urinary catheter is a common and distressing complication that often occurs in postanaesthetic recovery room. However, it is frequently neglected and left untreated, despite CRBD being a recognised risk factor for emergence agitation.19 Therefore, preventing or decreasing the severity of CRBD may be helpful in increasing patients’ quality of life and reducing postoperative emergence agitation. This is the first study to show that the intraoperative administration of dexmedetomidine, when used as an anaesthetic adjuvant for general anaesthesia in patients undergoing TURB, reduces the incidence of CRBD until 6 h postoperatively.
Unlike postoperative pain, CRBD may be resistant to conventional analgesic therapy such as opioids, because a different underlying mechanism is involved. Symptoms of CRBD, as in bladder overactivity, originate from involuntary contractions of the bladder muscle triggered by muscarinic receptors.20 Various agents such as tolterodine, oxybutynin, ketamine, tramadol and gabapentin have been investigated in the prevention or treatment of CRBD.1,2,5–7,17,21,22 The antimuscarinic actions of these drugs, particularly subtype 3 blockers, are considered to be responsible for the effective management of postoperative CRBD. In our study, intraoperative dexmedetomidine dramatically decreased the incidence and severity of CRBD, suggesting a beneficial effect of dexmedetomidine. A previous experimental study also demonstrated that dexmedetomidine significantly inhibited the muscarinic type 3 receptor expressed in Xenopus oocytes.13 Our results and previous findings suggest that the muscarinic type 3 receptor plays a key role in the development of CRBD.
In our investigation, 47 (85%) of 55 patients in the control group complained of CRBD at 1 h postoperatively. The incidence of CRBD in previous studies was reported with various ranges of 64 to 90%.6,7,17,21,22 A large diameter Foley catheter is a known risk factor for CRBD. A urinary catheter with a diameter of at least 18 Fr was inserted postoperatively in this study. Most patients with TURB are male, which is another risk factor for CRBD. Moreover, the bladders of our patients were irrigated for 24 h postoperatively to drain blood clots and prevent reimplantation of cancer cells. Thus, the bladder wall may have been continuously irritated by the irrigation fluid. These factors may explain the high incidence of CRBD in our study.
In our study, dexmedetomidine reduced the postoperative incidence of CRBD by 28, 28 and 19% at 0, 1 and 6 h, respectively. These results are consistent with those of other investigations that used antimuscarinic agents to prevent CRBD in which the incidence of CRBD was decreased by 19 to 30% until 6 h postoperatively.1,21 The context sensitive half-time of dexmedetomidine is approximately 30 min after a 30 min infusion.23 Considering our results, the duration of the antimuscarinic effect of dexmedetomidine may extend up to 6 h postoperatively.
Hypotension, bradycardia and hypertension are haemodynamic side effects of dexmedetomidine. However, we found no difference in the incidence of intraoperative hypotension or bradycardia between the two groups. Antimuscarinic agents, including tolterodine and oxybutynin, significantly reduced the incidence of CRBD but promoted a higher incidence of dry mouth (59%) in previous studies.1,22 A previous investigation using tramadol also demonstrated a reduction in the incidence of CRBD with side effects, including sedation (92%), nausea (56%) and vomiting (40%).6 Dry mouth, nausea and sedation have also been reported as side effects of dexmedetomidine. The incidence of dry mouth and nausea associated with dexmedetomidine were reported to be 3 and 11%, respectively.24 The incidence of nausea and dry mouth were 9 and 6% in our study, respectively. In addition, we found no differences between the two groups in the incidence of these side effects. Although dexmedetomidine has a sedative effect, we showed that the extubation times and Ramsay Sedation Scores in the dexmedetomidine group were similar to those in the control group. The delay between the end of the dexmedetomidine infusion and tracheal extubation may explain why the dexmedetomidine group was not sedated compared with the control group. As TURB usually takes a short time to perform, the infusion period for dexmedetomidine in our study was limited. This short infusion period may have contributed to the lower rates of side effects related to dexmedetomidine.
In this study, intraoperative dexmedetomidine administration decreased intraoperative desflurane requirements by about 13%. In accordance with our results, previous studies have showed that dexmedetomidine decreased the intraoperative isoflurane requirement in major spinal surgery and the total cumulative intraoperative consumption of sevoflurane in gynaecological surgery.25,26 This study also showed that intraoperative dexmedetomidine reduced postoperative opioid consumption. Similar to our results, many previous studies have showed the beneficial postoperative opioid-sparing effect of dexmedetomidine.27–29 A recent meta-analysis showed that perioperative dexmedetomidine or clonidine administration decreased postoperative opioid consumption and pain intensity.30 Our results confirm that dexmedetomidine is a useful and effective anaesthetic adjuvant for general anaesthesia.
Our study had several limitations. First, we did not evaluate the dose–response relationship between dexmedetomidine and CRBD. Second, TURB per se may cause CRBD. The effect of the surgery on CRBD was not considered in this study. Surgical time, however, did not differ between the groups. It also may be difficult to differentiate symptoms of CRBD from postoperative surgical pain in this study. Moreover, opioids used for postoperative pain control can mask symptoms of CRBD, although there is no report that opioids are effective in relieving postoperative CRBD. Third, intravesicular foreign bodies, cauterised bladder mucosa, intravesical chemotherapy and bladder sutures may represent different triggers for bladder spasms and pain of varying degrees and duration. All individuals in this study underwent TURB under general anaesthesia. Therefore, caution in the interpretation of our results is needed because the incidence, severity and duration of CRBD may vary in study populations with different triggers for CRBD. In addition, the use of regional anaesthetic techniques such as epidural analgesia for postoperative pain relief may influence the incidence and severity of postoperative CRBD. Fourth, in clinical practice, various agents with antimuscarinic effects are routinely used to decrease CRBD. In this study, however, a direct comparison between the effect of dexmedetomidine and an antimuscarinic agent on the incidence of CRBD was not performed. A further study comparing the preventive efficacy of dexmedetomidine on CRBD with that of an antimuscarinic agent is needed. Finally, in this study, surgical time was short and the positive effect of dexmedetomidine was limited to the first six postoperative hours. In patients undergoing longer endoscopic resections for presumably larger tumours, long-acting treatments might be indicated, as the beneficial effect of a long-term infusion of intraoperative dexmedetomidine on the prevention of CRBD has not yet been investigated.
In conclusion, the intraoperative administration of dexmedetomidine decreases the postoperative incidence and severity of early CRBD without serious side effects and reduces intraoperative desflurane and postoperative opioid requirements in patients undergoing TURB under general anaesthesia.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
1. Agarwal A, Raza M, Singhal V, et al. The efficacy of tolterodine for prevention of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Anesth Analg
2. Tauzin-Fin P, Sesay M, Svartz L, et al. Sublingual oxybutynin reduces postoperative pain related to indwelling bladder catheter after radical retropubic prostatectomy. Br J Anaesth
3. Guenther U, Radtke FM. Delirium in the postanaesthesia period. Curr Opin Anaesthesiol
4. Lepouse C, Lautner CA, Liu L, et al. Emergence delirium in adults in the postanaesthesia care unit. Br J Anaesth
5. Agarwal A, Gupta D, Kumar M, et al. Ketamine for treatment of catheter related bladder discomfort: a prospective, randomized, placebo controlled and double blind study. Br J Anaesth
6. Agarwal A, Yadav G, Gupta D, et al. Evaluation of intra-operative tramadol for prevention of catheter-related bladder discomfort: a prospective, randomized, double-blind study. Br J Anaesth
7. Ryu JH, Hwang JW, Lee JW, et al. Efficacy of butylscopolamine for the treatment of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Br J Anaesth
8. Farag E, Argalious M, Abd-Elsayed A, et al. The use of dexmedetomidine in anesthesia and intensive care: a review. Curr Pharm Des
9. Keniya VM, Ladi S, Naphade R. Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement. Indian J Anaesth
10. Kunisawa T, Ueno M, Kurosawa A, et al. Dexmedetomidine can stabilize hemodynamics and spare anesthetics before cardiopulmonary bypass. J Anesth
11. Lee JH, Kim H, Kim HT, et al. Comparison of dexmedetomidine and remifentanil for attenuation of hemodynamic responses to laryngoscopy and tracheal intubation. Korean J Anesthesiol
12. Yildiz M, Tavlan A, Tuncer S, et al. Effect of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation: perioperative haemodynamics and anaesthetic requirements. Drugs R D
13. Takizuka A, Minami K, Uezono Y, et al. Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells. Naunyn Schmiedebergs Arch Pharmacol
14. Binhas M, Motamed C, Hawajri N, et al. Predictors of catheter-related bladder discomfort in the postanaesthesia care unit. Ann Fr Anesth Reanim
15. Nargund VH, Tanabalan CK, Kabir MN. Management of nonmuscle-invasive (superficial) bladder cancer. Semin Oncol
16. Rodriguez Faba O, Gaya JM, Lopez JM, et al. Current management of nonmuscle-invasive bladder cancer. Minerva Med
17. Bala I, Bharti N, Chaubey VK, Mandal AK. Efficacy of gabapentin for prevention of postoperative catheter-related bladder discomfort in patients undergoing transurethral resection of bladder tumor. Urology
18. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J
19. Yu D, Chai W, Sun X, Yao L. Emergence agitation in adults: risk factors in 2,000 patients. Can J Anaesth
20. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology
21. Agarwal A, Dhiraaj S, Pawar S, Kapoor R, Gupta D, Singh PK. An evaluation of the efficacy of gabapentin for prevention of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Anesth Analg
22. Agarwal A, Dhiraaj S, Singhal V, Kapoor R, Tandon M. Comparison of efficacy of oxybutynin and tolterodine for prevention of catheter related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Br J Anaesth
23. Iirola T, Ihmsen H, Laitio R, et al. Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients. Br J Anaesth
24. Gerlach AT, Dasta JF. Dexmedetomidine: an updated review. Ann Pharmacother
25. Mariappan R, Narayana Prabhu AH, Kuppuswamy B. Comparing the Effects of Oral Clonidine Premedication With Intraoperative Dexmedetomidine Infusion on Anesthetic Requirement and Recovery From Anesthesia in Patients Undergoing Major Spine Surgery. J Neurosurg Anesthesiol
26. Shin HW, Yoo HN, Kim DH, Lee H, Shin HJ, Lee HW. Preanesthetic dexmedetomidine 1 microg/kg single infusion is a simple, easy, and economic adjuvant for general anesthesia. Korean J Anesthesiol
27. Unlugenc H, Gunduz M, Guler T, Yagmur O, Isik G. The effect of pre-anaesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anaesthesiol
28. Gurbet A, Basagan-Mogol E, Turker G, Ugun F, Kaya FN, Ozcan B. Intraoperative infusion of dexmedetomidine reduces perioperative analgesic requirements. Can J Anaesth
29. Ohtani N, Yasui Y, Watanabe D, Kitamura M, Shoji K, Masaki E. Perioperative infusion of dexmedetomidine at a high dose reduces postoperative analgesic requirements: a randomized control trial. J Anesth
30. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology