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