Efficacy of IM dexmedetomidine in alleviating catheter related bladder discomfort and postoperative inflammatory response following percutaneous nephrolithotomy. A prospective randomized controlled study

Abstract

Background and Aims:

Catheter-related bladder discomfort (CRBD) causes significant distress to the patient and requires great attention to analgesia and increases morbidity in the postoperative period. This study evaluated the efficacy of intramuscular dexmedetomidine in alleviating CRBD following percutaneous nephrolithotomy (PCNL) and postoperative inflammatory response.

Material and Methods:

A prospective randomized double-blind study was conducted in a tertiary care hospital from December 2019- March 2020. Sixty seven of ASA I and II patients scheduled for elective PCNL were randomized and group I received 1 μg/kg dexmedetomidine intramuscularly and group II normal saline as control 30 minutes before induction of anesthesia. Standard anesthesia protocol was followed and patients were catheterized with 16 Fr Foleys after induction of anesthesia. Rescue analgesia was paracetamol if the score was moderate. Postoperatively CRBD score and inflammatory markers; total white cell count, erythrocyte sedimentation rate and temperature were noted for 3 days.

Results:

There was a significant low CRBD score in group I. Ramsay sedation score was 2 in group I with p 0.00 and rescue analgesia required was very low with p 0.00. Statistical Package for social Sciences software version 20 was used for analysis. Student ttest, analysis of variance, and Chisquare test were applied for quantitative and qualitative analysis respectively.

Conclusion:

Single dose intramuscular dexmedetomidine is effective, simple and safe in preventing the CRBD and the inflammatory response remained uninfluenced except ESR, the reason remains largely unknown.

Introduction

Catheter-related bladder discomfort (CRBD) is a recognized problem in the early postoperative period causing notable distress to the patient. The incidence of CRBD is around 60% and it ranges from 47% to 90%.^[1] The patient frequently complaints of lower abdominal pain with an intense urge to micturate. Symptoms of CRBD are akin to those of an overactive bladder and is usually accompanied by behavioral responses, such as flailing limbs, strong vocal response and attempting to pull out the urinary catheter. This in turn can lead to an increase in postoperative pain requiring attention to postoperative analgesia and also prolonged hospital stay. Therefore, targeting this discomfort at the earliest is mandatory.

CRBD manifests itself by involuntary contractions in the detrusor muscle due to physical stimulation of the catheter.^[2] The site of origin of the discomfort and dysuria is not clear and could be from any of the following - the renal pelvis, ureter, urinary bladder or the urethra. Various medications like narcotics, antiepileptics, analgesics have been used to treat CRBD with varied results and their adverse effects.^[2-4] So, search for the ideal agent continues. Dexmedetomidine, an α-2 receptor agonist, which has a good sedative, analgesic, and anxiolytic properties have also shown to have antimuscarinic activity (M3 receptor) in animal studies.^[5] It is this potential of dexmedetomidine to reduce the spontaneous bladder contraction via M3 muscarinic receptor antagonism and also by its α-2 receptor agonism, enabled us to further explore its potential benefit in alleviating the incidence and severity of CRBD. So we investigated the efficacy of dexmedetomidine in reducing the incidence and severity of CRBD.

But the dexmedetomidine induced bradycardia or hypotension has recently attracted considerable attention because of its potentially grave consequences, including sinus arrest and refractory cardiogenic shock. A route other than intravenous injection or a low dose may help minimize cardiovascular risks associated with dexmedetomidine. Intramuscular (IM) dexmedetomidine could be a promising alternative by minimizing its cardiovascular risks and preserving respiratory function.^[6]

We hypothesized that the antimuscarinic effect of dexmedetomidine may reduce the CRBD and conducted this prospective randomized study to investigate the clinical effects of low-dose IM dexmedetomidine (1 μg kg–1) on CRBD following percutaneous nephrolithotomy (PCNL) where the patient frequently suffers CRBD rather the surgical site pain.

The primary aim of the present study was to evaluate the role of IM dexmedetomidine in alleviating the catheter related bladder dysfunction based on severity of symptoms.

Material and Methods

The present study has the institutional ethics committee EC/NIMS/2422/2019 dated 15^th Sep 2019 approval and registered in clinical trial registry of India CTRI/2020/01/022597 2^nd Jan 2020. This prospective randomized double-blind study commenced from December 2019 and completed by March 2020 in a tertiary care hospital. Patients aged 18 to 60 years belonging to either sex, who were American Society of Anesthesiologists (ASA) physical status I and II, scheduled to undergo elective PCNL were recruited. [Figure 1] Exclusion criteria were pregnancy, renal failure, patients on analgesics, rate control drugs, heart failure, arrhythmia seizure disorders, antidepressants/antipsychotics, morbid obesity, use of chronic analgesic medication and hepatic or psychiatric disease unwillingness to give consent. Post inclusion exclusion criteria was if excess bleeding occurred during the procedure, surgical procedure extending more than 3 hours, delayed recovery requiring postoperative ventilation, data acquisition was incomplete, and patient withdrawal from the study. All the study participants were informed about the study protocol and the drug its uses and complications. A written informed consent was then obtained and recruited for the study.

Figure 1.

Flow chart

After a thorough preanesthetic evaluation the patients were premedicated with tab pantoprazole 40 mg on the morning of surgery. Sedative/anxiolytic premedication was avoided in view of the study drug. They were randomized in to two groups by computer generated random numbers and sealed envelope method was used for concealment. The study drugs were prepared, labelled and covered with opaque paper in a drug preparation room by a resident doctor who was not part of the study insulin syringe (40 units-1 ml) to get the exact quantity of dexmedetomidine which is available as 100 μg/ml and brought to operating theater before anesthesia induction. The anesthesiologist who conducted the anesthesia induction and maintenance was also blinded to the group allocation throughout the entire study period, including the first 24 hours postoperatively. Group I received 1 μg/kg of IM dexmedetomidine and group II normal saline as control group.

Once the patient was wheeled in to the theatre complex the baseline readings of heart rate (HR), blood pressure (systolic, diastolic and mean), hemoglobin saturation, entropy and sedation score were noted and then the study drug was administered based on randomization either dexmedetomidine or normal saline 30 min before the induction of anesthesia. Patients were anaesthetized as per standard protocol. IV thiopentone 4-5 mg/kg, IV fentanyl 2 μg/kg and the trachea were intubated with appropriate size cuffed endotracheal tube facilitated with IV atracurium. The following readings HR, blood pressure, Spo2, entropy (state and response) and Ramsay sedation score were noted 30 min after study drug and again after endotracheal intubation at 1, 5 and 10 minutes except sedation score by a person not involved in the study. Inj ondansetron 4 mg was given at the time of induction. Anesthesia was maintained with 50% oxygen in air and isoflurane and atracurium tailored to the needs of the patient. In all patients urinary catheterization was done with a 16 Fr Foley’s catheter and its balloon was inflated with 10 ml distilled water after induction of anesthesia by a specialty surgical resident. Local anesthetic gel was used to lubricate the catheter, which was later fixed with an adhesive tape on the medial aspect of thigh without any traction and was left to free drainage. After completion of the surgical procedure, the duration of the procedure and the placement of double J stent (DJ stent) were noted and peritubal infiltration of 10 ml of 0.25% bupivacaine was given at 6 and 12o clock position with 25 G spinal needle under fluoroscopic guidance. All the patients were given IV paracetamol 1 gram intraoperatively and the residual neuromuscular blockade was reversed with inj glycopyrrolate and neostigmine and the trachea were extubated once the extubation criteria was met. Immediately after extubation the severity of CRBD^[7] 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 behavioral response) and as ‘severe’ when reported by patients on their own along with behavioral responses (flailing limbs, strong vocal response and attempt to pull out the catheter) by a person not involved in the study and if the score was moderate IV fentanyl 1 μg/kg was given only for immediate postoperative pain relief. CRBD was assessed for 3 days postoperatively by a resident doctor not involved in the study and rescue analgesia was 1 gm IV paracetamol if the CRBD score was moderate or more. The following investigations were carried and noted in postoperative period for 3 days; total white blood cell count and erythrocyte sedimentation rate and temperature. All the postoperative assessments and data recording were performed by an anesthesiologist blinded to patient allocation and study drugs. Intubation response, Ramsay sedation score, rescue analgesia required, and the inflammatory response as evidenced by fever, total WBC count, ESR and adverse or untoward effect like bradycardia and hypotension were noted as secondary outcome.

A pilot study was done with 10 cases in each group. The difference in proportion of patients having no pain (CRBD score) in the immediate postoperative period was 8%. With an alpha error of 0.5 and power of 80% a total of 54 patients were required. Adding for the dropout rates of 10% a total of 70 patients were recruited for the study. Statistical analysis was performed using International business Machine Statistical Package for social Sciences (IBM SPSS) software version 20. For descriptive statistics: continuous variables; hemodynamic response, entropy were expressed as mean and standard deviation frequency with percentage for CRBD, Ramsay sedation score VAS score which are categorical variables. For analytical statistics - categorical data was compared between the groups using chi square test and continuous data was compared using independent sample test. A two-sided p value of <0.05 was considered significant

Results

Seventy patients [Figure 1 Flow chart] were recruited and 67 were randomized in to two groups. Group I (n-33) dexmedetomidine and group II control group (n-34). The demographic data was comparable except for more number of patients in group II were hypertensive and gained statistical significance [Table 1]. The study results showed a significant difference in CRBD [Figure 2]. Table 2 illustrates the CRBD on day 0, 1, 2 and 3 as number and percentages in both the groups which are significant. The surrogate inflammatory markers were shown in Table 3 which has not gained any significance except for the erythrocyte sedimentation rate. The hemodynamic stress response to intubation was significant at all-time points [Table 4]. There was obtunded hemodynamic response at the time of extubation (p < 0.001)

Table 1.

Patient characteristics

Parameter	G I (n=32) M±SD	G II (n=34) M±SD	P
Age (Years)	37.4±12.3	43.6±12.2	0.852
Gender M/F	25/7	20/14	0.78
Height (Cm)	157.2±10.7	155.7±10.4	0.293
Weight (Kg)	61.8±10.3	59.7±11.2	0.686
DJ Stent
Yes	27 (49.1%)	28 (50.9%)	0.305
No	3 (33.3%)	6 (66.7%)
Diabetes
Yes	4	5	0.540
No	28	29
Hypertension
Yes	1	7	0.033
No	31	27
Thyroid disorder
Yes	0	2	0.262
No	32	32
Duration of surgery (min)	65.9±10.4	68.3±20.2	0.097

Figure 2.

Showing hemodynamic response at various time points during intubation and after extubation

Table 2.

Catheter related bladder discomfort among the two groups

Day	CRBD	Group I (n=32)	Group II (n=34)	P
0	Nil	8 (25%)	1 (2.9%)
	Mild	19 (59.4%)	2 (5.9%)	0.001
	Moderate	5 (15.6%)	19 (55.9%)
	Severe	0	12 (36.3%)
1	Nil	20 (62.5%)	1 (2.9%)	0.001
	Mild	11 (34.4%)	11 (32.4%)
	Moderate	1 (3.1%)	20 (58.8%)
	Severe	0	2 (5.9%)
2	Nil	27 (84.4%)	7 (20.6%)	0.001
	Mild	5 (15.6%)	15 (44.1%)
	Moderate	0	12 (35.3%)
	Severe
3	Nil	31 (96.9%)	29 (85.3%)	0.001
	Mild	1 (3.1%)	4 (11.8%)
	Moderate	0	1 (2.9%)
	Severe

Table 3.

Inflammatory markers

	Day	G I (n=32)	G II (n=34)	P
Temperature	0	98.6±0.0	98.6±0.0	1.0 0.32
	1	98.7±0.35	98.8±0.59	0.60
	2	98.7±0.50	98.6±0.26	1.0
	3	98.6±0.00	98.6±0.00
TLC	0	8.8×103±2.5×103	9.3×103±3.0×103	0.48
	1	10.0×103±3.0×103	11.4×103±2.9×103	0.07
	2	8.8×103±1.8×103	10.2×103±1.8×103	0.00
	3	8.5×103±1.1×103	10.6×103±0.000	0.26
ESR	0	16±14.7	27±30.2	0.04
	1	18.0±26.8	40.2±40.7	0.01
	2	12.0±1.32	25.5±18.0	0.00
	3	9.9±11.5	24.2±18.0	0.00

Table 4.

Hemodynamic response at various time points during intubation and after extubation

Variable	Timing	G 1 (n=32) (Mean±SD)	G 2 (n=34) (Mean±SD)	P
Heart rate	Baseline	77.3±13.4	82.9±11	0.070
	30 min after study drug	71.8±12.4	85.0±10.8	0.001
	1 min After intubation	83.9±15.6	96.2±11.5	0.001
	5 min after intubation	73.9±13.4	86.2±11.8	0.001
	10 min after intubation	69.9±13.2	81.3±13.4	0.001
	After extubation	76.5±18.4	94.4±15.9	0.001
Systolic blood pressure	Baseline	126±16.0	133±20.2	0.089
	30 min after study drug	120±16.3	131±28.9	0.063
	1 min After intubation	135±23.6	152±26.4	0.011
	5 min after intubation	114±17.1	123±16.5	0.043
	10 min after intubation	136±15.8	158±16.9	0.490
	After extubation	131±19.5	144±18.8	0.010
Diastolic blood pressure	Baseline	78±9.2	82±11.3	0.192
	30 min after study drug	72±15.8	83±10.0	0.002
	1 min After intubation	84±18.8	96±16.6	0.010
	5 min after intubation	70±13.7	79±14.4	0.011
	10 min after intubation	66±14.8	78±12.2	0.001
	After extubation	80±14.0	92±13.1	0.001
Mean arterial pressure	Baseline	98±11.1	103±13.5	0.123
	30 min after study drug	93±11.9	102±12.3	0.002
	1 min After intubation	104±17.8	119±18.9	0.002
	5 min after intubation	89±13.6	90.4±14.22	0.319
	10 min after intubation	85±15.3	95±11.2	0.003
	After extubation	100±14.3	113±12.1	0.000

The entropy response was comparable between the groups and was not statistically significant. The mean state entropy in group I and group II at base line was 91 ± 4.3-94 ± 5.6 (p 0.737), 30 min after study drug was 87 ± 4.5 vs 95 ± 9.2 (p 0.252), 1 min after intubation 52 ± 15.8 vs 50 ± 10.9 (0.610), 5 min after intubation 46 ± 12.5 vs 47 ± 10.4 (0.656) 10 min after intubation 46 ± 11.7 vs 52 ± 13.5 (0.100), After extubation 86 ± 4.6 vs 88 ± 1.9 (0.030*) Similarly response entropy in both the groups was not significant. The values being at base line 95 ± 4.3 vs. 94 ± 5.6 (p 0.737), 30 min after the study drug 87 ± 4.5 vs. 95 ± 9.2 (p 0.252), 1 min after intubation 52 ± 15.8 vs. 50 ± 10.9 (p 0.610), 5 min after intubation 50 ± 11.2 vs. 52 ± 10.1 (p0.346), 10 min after intubation 50 ± 12.0 vs. 55 ± 14.3 (p 0.106), After extubation 93 ± 5.8 vs. 93 ± 5.8 (p 0.019*).

Ramsay sedation score gained statistical significance at 30 min after drug administration, group I 2.0 [1.0-2.0] and group II 1.0 [1.0-1.0] with p 0.004. The study drug caused a sedation score of 2.0 where the patient was cooperative oriented and in a state of tranquil even after extubation compared to a sedation score of 1.00 [1.0-1.0] in group II with p 0.00 1.

Ten percent of patients in group I required 1 gram IV paracetamol one dose on day 0 and no requirement of analgesia on day 2 and 3 which was statistically significant (p 0.001). On the other hand, 90% of patients in group II required paracetamol on day 0 and 100% on day 1 and 2 and no request was made on day 3.

There was no incidence of bradycardia or hypotension noted during this study period.

Discussion

The results of this study shows that preoperative intramuscular administration of dexmedetomidine significantly reduced the incidence of postoperative CRBD in patients who underwent PCNL. We selected the patients who underwent PCNL because the possibility of misperception or misinterpretation of CRBD and surgical site symptoms such as pain and abdominal discomfort are reduced due to minimal instrumentation per urethra.

Catheterizing urinary bladder in a patient undergoing a surgical procedure, particularly in urinary interventions and instrumentations may lead to CRBD with varying degrees of severity in the postoperative period. It is very important to monitor and address the issue by an anesthesiologist to alleviate the stressful CRBD. This study is one such; an attempt to ameliorate the CRBD. CRBD may be unaffected by conventional analgesic therapy such as opioids, because of a different underlying mechanism involved unlike postoperative pain. Symptoms of CRBD are akin to overactive bladder, originate from involuntary contractions of the bladder muscle triggered by muscarinic receptors. Dexmedetomidine’s unique action of reducing bladder contractility via M3 muscarinic receptor antagonism and α-2 receptor agonism, helped in alleviation of CRBD in the postoperative period.^[8,9] Along with antimuscarinic effect, dexmedetomidine appears to have a sedative effect on locus ceruleus, pontine nuclei and lateral septal nucleus. Moreover, dexmedetomidine by lowering the level of consciousness and reducing the cerebral cortex sensitivity to the signals from lower urinary tract may help in improving the symptoms of CRBD. Dexmedetomidine reduces the generation of excitatory signals from bladder preventing pontine micturation center and cerebral hemisphere from initiating the impulse to urinate. Thus, dexmedetomidine might reduce bladder contractility via an alpha 2 receptor and antimuscarinic effect.^[10] CRBD troubles more in the initial few hours of early postoperative period, where dexmedetomidine may help in overcoming it. Various studies with different pharmacological agents having antimuscaranic actions which may be responsible for the effective management of CRBD like tolterodine and oxybutynin, tramadol, gabapentin, ketamine have been investigated in the prevention and management of CRBD with varied results.^[1-3,11]

In this study interestingly the patient characteristics has not influenced the incidence of CRBD. The presence of DJ stent, duration of surgery has not influenced the study results. In a study by Maghsoudi R et al.^[1] also found that insertion of DJ stent has no statistically significant influence on postoperative CRBD. However, the history of DJ insertion ameliorated CRBD in all study groups probably due to their previous experience of the symptoms. In a study by Kim et al.^[12] the authors studied the effect of IV dexmedetomidine of postoperative CRBD and found a significant higher score in control group than the study group at 0 (4.6 3.2 vs. 2.7 3.0; P ¼ 0.002), and 1 h (3.8 2.4 vs. 2.7 2.8; P ¼ 0.041 and after 6 hrs the scores were comparable between the groups. Here the authors explained that the case duration was less and the half- life of IV dexmedetomidine is 2-3.7 hours and hence the analgesia lasted for less than 6 hrs. In our study the prolonged effect on CRBD could be first, the IM administration of the drug and second the effect of paracetamol shown to selectively suppress peripheral PGE₂ release in patients with acute inflammation after a brief surgical intervention.^[4] Also the authors in their study has shown that the number of patients who needed rescue analgesia with fentanyl or meperidine (demerol) for postoperative pain was 21 (38%) and 8 (15%) in the control and dexmedetomidine groups, respectively (P ¼ 0.011). In the present study the number of patients who needed analgesia with 1 gm paracetamol was 10% in study group one dose on day 0 and no requirement of analgesia on day 2 and 3 which was highly significant (p 0.00) On the other hand 90% of patients in group II required paracetamol on day 0 and 100% on day 1 and 2 and no request was made on day 3 in both the groups.

The surrogate inflammatory markers temperature, total leucocyte count did not differ and not attained any statistical significance in both the groups but the erythrocyte sedimentation rate has gained statistical significance but not the clinical significance and the reason remains largely unknown.

We also found that IM dexmedetomidine has blunted the hemodynamic stress response to intubation at all point of times. There was a statistically significant decrease in blood pressure (systolic, diastolic and mean arterial pressure) at 1, 5 and 10 minutes after intubation in group I and also after extubation with p 0.000. Such a decrease in pressures can be attributed to dexmedetomidine’s highly selective α₂ agonistic action which causes a decrease in serum norepinephrine concentration thus leading to dose-dependent decrease in arterial blood pressure.^[13-15] In agreement with our study results Sebastian B and coauthors^[16] also showed a significant attenuation of hemodynamic stress response to laryngoscopy and intubation (0.001) with 0.75 μg/kg IV dexmedetomidine.

Dexmedetomidine has a sedative property. Ramsay Sedation Scores in the dexmedetomidine group at 30 min was 2.0[1.0 -2.0] p 0.004 and also at the time of extubation with p 0.000. Dexmedetomidine when given as a pre-medication acts on locus ceruleus to induce sedation and modulates nociceptive neurotransmission. However, there was no difference in either state or response entropy during the induction and intraoperative period but gained statistical significance at the time of extubation 0.030 and 0.019 respectively.

This study is not without any limitation. The patients with prior instrumentation of the urethra were recruited in the study but not the redo PCNL; this might have influenced the postoperative pain scores.

However larger randomized clinical trials are needed for more accuracy.

Conclusion

Single dose intramuscular dexmedetomidine is effective, simple and safe in preventing the CRBD and reduced need for analgesia in the postoperative period following PCNL without any adverse effects. However, it has not influenced the inflammatory response except ESR, the reason remains largely unknown.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.