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Dexmedetomidine reduces catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study.

Catheter-related bladder discomfort (CRBD) secondary to the use of an indwelling urinary catheter is one of the most distressing symptoms patients experience during recovery from anesthesia in the immediate postoperative period. Such patients characterize it as an urge to void or discomfort in the suprapubic region. The symptoms of CRBD, which are due to catheter-related bladder irritation, mimic those of an overactive bladder (OAB): urinary frequency and urgency with or without urge incontinence (1,2). It has been reported that 27% to 55% of the patients in the postanesthesia care unit (PACU) who have undergone intraoperative bladder catheterization suffer from moderate or severe CRBD (3,4), whereas mild CRBD is experienced by more than 80% of such patients. Because this condition is as a major cause of postoperative agitation (5), recent studies have evaluated various drugs in the prevention and treatment of CRBD, including ketamine (6), gabapentin (7), butylscopolamine (8), tramadol (9), oxybutynin, and tolterodine (4). However, these work involves 2 major concerns and limitations. First, bladder irritation and discomfort experienced by patients after urinary surgery, as in the studies mentioned, can be due to the surgical procedure directly. In other words, the effects of those drugs in nonurinary surgeries are not clear. Second, none of the studied drugs have been shown enhance the effects of general anesthesia, whereas dexmedetomidine, as an ancillary drug for general anesthesia, can maximize the efficacy of the anesthetic, thereby reducing the need for additional sedatives and/or analgesics. In clinical practice we noticed that patients given dexmedetomidine were less agitated after surgery. However, the mechanism underlying this observation is not clear, although it has been reported that dexmedetomidine has a sedative effect. Our hypothesis is that by blocking the sensory input from the lower urinary tract and suppressing the sympathetic nervous system, dexmedetomidine reduces bladder tone and thus relieves CRBD. In the present study we sought to evaluate the efficacy of dexmedetomidine in preventing or reducing the incidence and severity of CRBD in the PACU.

Materials and Methods

This was a randomized controlled trial conducted at the Second Xiangya Hospital of Central South University, a tertiary university-affiliated hospital that had 3500 beds with more than 40 clinical departments in Changsha, Hunan Province, PRC. For this prospective randomized double-blind placebo-controlled study, approval was obtained from the Medical Ethics Committee of the hospital as well as written informed consent from the patients. A total of 138 ASA class I and II male patients were recruited, all of whom were scheduled for elective open upper-middle abdominal surgery requiring catheterization of the urinary bladder.

Exclusion criteria included age >60 years, chronic opioid use, bladder outflow obstruction, OAB (frequency >3 times in the night or >8 times in 24 hours), neurogenic bladder, diabetes mellitus, Parkinson's disease, or end-stage renal disease (urine output <400 mL in 24 hours), and abnormal liver function (Child-Pugh score [greater than or equal to]7).

All the patients received phenobarbital (100 mg IM) and atropine (0.5 mg IM) 30 minutes before the induction of anesthesia. With the help of a computer-generated table of random numbers, they were randomized into 2 groups, C and D, of 69 patients each. Group D received dexmedetomidine (0.5 [micro]g/kg IV) (Jiang Su Heng Rui Medicine Co., Ltd., China) at the rate of 5 [micro]g/kg per hour as the abdominal cavity was being closed; group C (control) received saline solution administered in the same way. Anesthesia was induced with midazolam (0.04 [micro]g/kg), sufentanil (0.3 [micro]g/kg), and propofol (1.5 mg/kg). Orotracheal intubation was facilitated with cis-atracurium (0.2 mg/kg). Urinary bladder catheterization was implemented with a 16F Foley catheter lubricated with paraffin oil and its balloon was inflated with 10 mL of distilled water. Thereafter, to prevent traction, the catheter was fixed with adhesive tape in the suprapubic region. Anesthesia was maintained with propofol infused at the rate of 50 to 200 [micro]g/kg per minute as well as intermittent sufentanil and cisatracurium as required, with standard ASA monitoring. At the conclusion of surgery, postoperative nausea and vomiting were prevented with tropisetron (5 mg), while neuromuscular blockade was reversed with neostigmine (0.04 mg/kg) and atropine (0.02 mg/kg). After satisfactory recovery, the patients were extubated and offered intravenous sufentanil via a patient-controlled analgesia system set to deliver a bolus dose of 1 [micro]g (1 mL) with a 10-min lockout interval and background infusion of 1.5 [micro]g/h. Patient bladder discomfort was evaluated at the time of extubation and again at 1, 2, and 6 hours postoperatively by an anesthesiologist who was unaware of the type of medication received by the patient. The severity of CRBD was graded according to the method described by Agarwal (5), with the degree of bladder discomfort set as severe (subjective complaint with behavioral abnormalities such as flailing limbs, pulling out of catheter, or loud vocalization) or moderate (complaint without questioning and no behavioral abnormalities).When interviewed in the PACU, in order to exclude pain caused by previous procedures, patients reporting discomfort were required to point to the affected region. Confirmed complaints of bladder discomfort (urge to urinate or discomfort in the suprapubic area) were classified as mild bladder discomfort.

Postoperative pain was assessed at 0, 1, 2, and 6 hours after extubation using a verbal numeric rating scale (NRS-11). Patients were asked to rate their pain on a scale from 0 to 10, where 0 represents "no pain" and 10 represents "the worst pain possible," using whole numbers (11 integers including 0). The same registrar observed patients postoperatively for sedation using the Ramsay score (from 1 to 6) (10).

To assess possible adverse reactions caused by dexmedetomidine, multiple clinical indexes were quantified and compared between the 2 groups, including the incidence of nausea, vomiting, hypotension (systolic blood pressure <90 mmHg, or 30% lower than preinfusion values, or diastolic blood pressure <50 mmHg), hypertension (systolic blood pressure >180 mmHg, or 30% higher than preinfusion values, or diastolic blood pressure >100 mmHg), bradycardia (heart rate <60 beats per minute, or 30% lower than preinfusion values), respiratory depression after extubation (respiratory rate <8 breaths per minute, or SpO2 <90), and excessive sedation (Ramsay score of 5 or more).

Statistical analysis

The incidence of CRBD (58%) at 1 hour after extubation was ascertained from Agarwal's study (4) and applied in the sample size calculation. At least a 25% difference in incidence rate between groups C and D was considered to be clinically significant. Given [alpha] = 0.05 (statistically significant level), [beta] = 0.2 (power of a test), a sample size of 69 subjects in each group was calculated by STATA 12.0 (Stata Corp, College Station, Texas). A flowchart of the study's progress is presented in Figure 1.

Quantitative variables were compared by student's t-test. The incidence of bladder discomfort and related adverse clinical events was analyzed by Fisher's exact test, while the severity of discomfort (mild, moderate, or severe), postoperative pain (NRS-11), and sedation level (Ramsay score) were analyzed with the Mann-Whitney test. SPSS 15.0 (SPSS Inc., Chicago, Illinois) was used for statistical analysis. A p-value of less than 0.05 was considered significant.

Results

There were no significant differences between groups C and D in general characteristics as reviewed based on age, weight, duration of surgery, or sufentanil use (p>0.05; Table 1).

At 0 hours after extubation, the incidence of CRBD in group D was reduced to 23%, compared with 74% in group C (p<0.05; Table 2). The absolute risk reduction in group D was 51% at this time point. At 1, 2, 6 hours after extubation, the incidence of CRBD in group D remained at a level significantly lower than that in group C (p<0.05). The severity of CRBD was also reduced in group D at all the time points evaluated in this study (p<0.05).

Postoperative pain was assessed with NRS-11 (Table 3); the postoperative sedation level was quantified with the Ramsay score in the same cohorts of patients (Table 4). Compared with patients in group C, patients in group D showed better pain control and deeper sedation.

We also assessed the incidence of potential adverse reactions to dexmedetomidine, as shown in Table 5. Bradycardia, hypotension, hypertension, nausea/vomiting, respiratory depression, and oversedation were reviewed; among these indexes, only bradycardia and hypotension were significantly different in group D as compared with group C (p<0.05).

Discussion

On the basis of percentages given in Agarwal's study, in our study patients in group C experienced a higher incidence of CRBD (68% at 1 hour after extubation) compared with the expected incidence (58% at 1 hour after extubation) (4). A plausible explanation could be that all of the patients in the present study were male, since Binhas (3) has pointed out that male gender is an independent risk factor for CRBD. Our study demonstrated that the administration of dexmedetomidine (0.5 [micro]g/kg IV) at the conclusion of the surgery could reduce the incidence and severity of CRBD in the PACU without causing severe drug-related adverse events. Dexmedetomidine hydrochloride is an alpha2 adrenergic receptor agonist with high efficacy and selectivity (11). Alpha2 adrenergic receptors are distributed widely throughout the central and peripheral nervous systems, including autonomic ganglia; therefore dexmedetomidine can enhance sedation, analgesia, and inhibition of sympathetic nerve activity by activating alpha2 adrenergic receptors.

Based on these facts we hypothesized that dexmedetomidine would reduce the incidence and severity of CRBD through its suppressing effect on the central and peripheral nervous systems.

Bladder sensation is generated by cerebral cortex as it perceives afferent nervous signals originating from the lower urinary tract. The mechanisms underlying the pathogenesis of micturition and its related disorders are still unclear. Micturition is fundamentally a spino-bulbo-spinal reflex facilitated and inhibited by more advanced brain centers, such as the pontine micturition center (12). The completion of the physiological reflex pathway is dependent on both brain function and the firing rate of sensory fibers from the bladder and urethra (12). The neural signals generated by the bladder and urethra are transmitted to midbrain periaqueductal gray substance through the spinal cord, then projected to the pontine micturition center and the cerebrum (13). When the activity of this pathway passes a threshold, the urge to void becomes difficult to ignore. Meanwhile the flow of urine through the urethra plays an overall excitatory role itself, promoting voiding in a positive feedback loop until the bladder has been emptied (14). An indwelling urinary catheter may stimulate the mucous membrane of the urethra and thus initiate the micturition reflex, leading to an urgent need to urinate; this may be one of the key mechanisms in the pathogenesis of CRBD. Dexmedetomidine appears to have a sedative effect on the locus ceruleus, lateral parabrachial nucleus, pontine nuclei, pontine tegmental reticular nucleus, and lateral septal nucleus (15). At the same time it lowers the level of consciousness and reduces the cerebral cortex's sensitivity to signals from lower urinary tract, thereby ameliorating the symptoms of CRBD.

Dexmedetomidine inhibits the activity of the sympathetic nervous system and decreases bladder tension, thereby reducing the transmission of afferent impulses. In 1992, Harada proved that dexmedetomidine inhibits the micturition reflex activated by high bladder volume in rats (16). In 1993, Harada further demonstrated that dexmedetomidine reduces detrusor muscle tone and pressure in the bladder (17). Inhibition of the sympathetic nervous system by dexmedetomidine decreases sympathetic tone, mainly by selectively activating the postsynaptic [alpha]2 adrenergic receptors in the central nucleus tractus solitarius, thereby preventing sympathetic neurons in the anterior lateral horn of the spinal cord from transmitting impulses (17). The bladder's detrusor muscle is controlled by sacral parasympathetic preganglionic neurons and lumbar sympathetic preganglionic neurons (18). During the storage phase, these afferent neurons fire at low frequencies because the bladder wall is insufficiently stretched. High-frequency afferent signals generated by a stretched urinary bladder wall initiate contraction of the bladder by simultaneously exciting sacral parasympathetic preganglionic neurons and inhibiting lumbar sympathetic preganglionic neurons. Afferent inputs induce contraction of the sphincter by the excitation of Onuf's nucleus; contraction of the bladder neck and urethra is initiated by the excitation of sympathetic preganglionic neurons. Dexmedetomidine may reduce the generation of excitatory signals from the bladder, thereby preventing pontine micturition center and cerebrum from initiating the impulse to urinate.

In this study, extubation was performed at about 40 minutes after the administration of dexmedetomidine. The NRS-11 values at 0 and 1 hour after extubation in group D were lower than those in group C; at the same time points the Ramsay scores were higher in group D, and there was no significant difference between the 2 groups at 2 and 6 hours after extubation. However, the incidence and severity of CRBD were significantly reduced in group D at each time point (0, 1, 2, and 6 hours) compared with group C. We also noticed that the incidence and severity of CRBD decreased in the control group with the passage of time after extubation.

Although Ramsay scores were higher in group D, no instance of oversedation was observed in either group. In the present study, no patients had orientation problems after waking up and all were able to clearly report any discomfort they might be having. Thus our results suggest that

dexmedetomidine does not reduce CRBD simply by compromising the patients' ability to perceive discomfort. Besides the sedative effect of dexmedetomidine, other mechanisms may also be involved in reducing the incidence of CRBD, since sedatives such as midazolam or propofol had no significant effect in the prevention of CRBD.

Although the incidence of bradycardia was higher in group D, bradycardia that affects hemodynamic stability (heart rate <45 beats per minute or bradycardia accompanied by hypotension) was not observed. Several patients suffered from episodes of transient hypotension or hypertension and were stabilized quickly by treatment with ephedrine or nitroglycerin. We therefore concluded that the effect of dexmedetomidine on hemodynamic stability was acceptable and easily managed, which supports the practicability of our proposal to use dexmedetomidine in preventing CRBD.

Conclusions

We evaluated the effect of dexmedetomidine in preventing or ameliorating CRBD in patients after open upper-middle abdominal surgeries. However, detailed data demonstrating the dose-effect relationship were not collected in this study. We suggest that a comparative study be conducted between dexmedetomidine and other anticholinergic drugs, such as oxybutynin chloride and tolterodine. In conclusion, the single use of dexmedetomidine (0.5 [micro]g/kg IV) can safely reduce the severity and incidence of CRBD.

References

(1.) Tauzin-Fin P, Stecken L, Sztark F. [Catheter-related bladder discomfort in post-anaesthesia care unit]. Ann Fr Anesth Reanim 2012; 31:605-608.

(2.) Banakhar MA, Al-Shaiji TF, Hassouna MM. Pathophysiology of overactive bladder. Int Urogynecol J 2012;23:975-982.

(3.) Binhas M, Motamed C, Hawajri N, Yiou R, Marty J. Predictors of catheter-related bladder discomfort in the post-anaesthesia care unit. Ann Fr Anesth Reanim 2011;30:122-125.

(4.) 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 2006;96:377-380.

(5.) 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 2007;105:1454-1457.

(6.) Safavi M, Honarmand A, Atari M, Chehrodi S, Amoushahi M. An evaluation of the efficacy of different doses of ketamine for treatment of catheter-related bladder discomfort in patients underwent urologic surgery: A prospective, randomized, placebo-controlled, double-blind study. Urol Ann 2014;6:51-56.

(7.) 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 2012;79:853-857.

(8.) Ryu JH, Hwang JW, Lee JW, Seo JH, Park HP, Oh AY, et al. Efficacy of butylscopolamine for the treatment of catheter-related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. Br J Anaesth 2013;111:932-937.

(9.) Agarwal A, Yadav G, Gupta D, Singh PK, Singh U. Evaluation of intraoperative tramadol for prevention of catheter-related bladder discomfort: a prospective, randomized, double-blind study. Br J Anaesth 2008;101:506-510.

(10.) Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2:656-659.

(11.) Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. Anesthesiology 1992;77:1125-1133.

(12.) Blok BF, Holstege G. Direct projections from the periaqueductal gray to the pontine micturition center (M-region). An anterograde and retrograde tracing study in the cat. Neurosci Lett 1994;166:93-96.

(13.) Sie JA, Blok BF, de Weerd H, Holstege G. Ultrastructural evidence for direct projections from the pontine micturition center to glycine-immuno-reactive neurons in the sacral dorsal gray commissure in the cat. J Comp Neurol 2001;429:631-637.

(14.) Jung SY, Fraser MO, Ozawa H, Yokoyama O, Yoshiyama M, De Groat WC, et al. Urethral afferent nerve activity affects the micturition reflex; implication for the relationship between stress incontinence and detrusor instability. J Urol 1999;162:204-212.

(15.) Mantz J, Josserand J, Hamada S. Dexmedetomidine: new insights. Eur J Anaesthesiol 2011;28:3-6.

(16.) Harada T, Kigure T, Yoshida K, Nishizawa O, Noto H, Tsuchida S, et al. The effect of alpha-2 agonists and antagonists on the upper urinary tract of the rat. J Smooth Muscle Res 1992; 28:139-151.

(17.) Harada T, Constantinou CE. The effect of alpha 2 agonists and antagonists on the lower urinary tract of the rat. J Urol 1993;149:159-164.

(18.) Yoshimura N, Chancellor MB. Neurophysiology of lower urinary tract function and dysfunction. Rev Urol. United States; 2003;5 (Suppl 8: S3-S10).

Yang Zhao Yun, MD *; Xu Jun Mei, MD, PhD ([dagger]); Zhu Rong, MD, PhD *; Dai Ru Ping, MD, PhDP ([double dagger]), Liu Lei, MD, PhD *

* Attending Doctor, tChief Physician, ([dagger]) Associate Chief Physician, Department of Anesthesiology, The Second Xiangya Hospital, Central South University, China

The authors have no conflicts of interest to disclose.

Address correspondence to: Liu Lei, MD, Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China. Email: radiumliu@139.com

Caption: Figure 1. Flowchart of study progress
Table 1. Demographic data, Duration of surgery, and Sufentanil
requirement

Groups            Control              Dexmedetomidine

Number of         69                   69
  patients
Age (years)       42.1 [+ or -] 10.5   39.8 [+ or -] 9.7
Weight (kg)       60.7 [+ or -] 10.8   62.5 [+ or -] 11.0
Duration of       160 [+ or -] 28      167 [+ or -] 31
  surgery (min)
Intraoperative    0.72 [+ or -] 0.06   0.68 [+ or -] 0.05
  sufentanil
Requirement
  ([micro]g/kg)

Data are presented as number of patients or mean [+ or -] standard
deviation.

Table 2. Incidence and Severity of CRBD

Time (h)              0                     1
Groups          Control   DEX         Control  DEX

Number of       69        69          69       69
  patients
No discomfort   18 (26)   53 (77) *   22 (32)  55 (80) *
Discomfort      51 (74)   16 (23) *   47 (68)  14 (20) *
Grading of
  discomfort
Mild            19 (28)   10 (14) *   21 (30)  11 (16) *
Moderate        25 (36)   6 (9) *     20 (29)  3 (4) *
Severe          7 (10)    0 (0) *     6 (9)    0 (0) *

Time (h)              2                     6
Groups          Control   DEX         Control   DEX

Number of       69        69          69        69
  patients
No discomfort   28 (41)   55 (80) *   36 (52)   54 (78) *
Discomfort      41 (59)   14 (20) *   33 (48)   15 (22) *
Grading of
  discomfort
Mild            22 (32)   11 (16) *   21 (30)   13 (19) *
Moderate        15 (22)   3 (4) *     11 (16)   2 (3) *
Severe          4 (6)     0 (0)  *    1 (2)     0 (0)

Data are presented as number of patients (percentage), DEX denotes
Dexmedetomidine, * p<0.05 in intergroup comparison.

Table 3. Severity of pain, by verbal numeric rating scale (NRS-11)
(presented as median With interquartile range)

Time (h)         0                       1
Groups     Control     DEX         Control     DEX
(n = 69)
NRS-11     3           1.5 *       2.5         2 *
  (0-10)   (2.0-4.0)   (1.0-2.0)   (2.0-4.0)   (1.75-3.0)

Time (h)         2                       6
Groups     Control     DEX         Control     DEX
(n = 69)
NRS-11     2.5         2.5         2           2
  (0-10)   (2.0-3.0)   (2.0-3.0)   (1.0-2.0)   (1.0-2.0)

DEX denotes Dexmedetomidine, * p<0.05 during intergroup comparison

Table 4. Sedation level, quantified by Ramsay score (presented
as median with interquartile range)

Time (h)         0                        1
Groups     Control      DEX         Control     DEX
(n = 69)

Ramsay     3            3 *         2.0         2.0 *
  score
  (1-6)    (1.75-3.0)   (2.0-4.0)   (2.0-3.0)   (2.0-3.0)

Time (h)         2                       6
Groups     Control     DEX         Control     DEX
(n = 69)

Ramsay     2.0         2.0         2.0         2.0
  score
  (1-6)    (2.0-2.0)   (2.0-2.0)   (2.0-2.0)   (2.0-2.0)

DEX denotes Dexmedetomidine, * p<0.05 during intergroup comparison

Table 5. Incidence of adverse clinical events after injecting
Dexmedatomidine or Placebo

Groups                   Control   DEX

Number of patients       69        69
Bradycardia              0 (0)     32 * (46)
Hypotension              0 (0)     4 * (6)
Hypertension             0 (0)     2 (3)
Nausea and vomiting      4 (6)     3 (4)
Respiratory depression   0 (0)     0 (0)
Oversedation             0 (0)     0 (0)

Data are presented as number of patients (percentage), DEX denotes
Dexmedetomidine, * p<0.05 during intergroup comparison
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Title Annotation:FULL-LENGTH ARTICLES
Author:Yun, Yang Zhao; Mei, Xu Jun; Rong, Zhu; Ping, Dai Ru; Lei, Liu
Publication:Puerto Rico Health Sciences Journal
Article Type:Clinical report
Date:Dec 1, 2016
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