Intraurethral Instillation of Ketamine for Male Rigid Cystoscopy

Abstract

Purpose:

This study was conducted to examine the efficacy of ketamine along with lidocaine gel for instillation in the male urethra for easiness of outpatient rigid cystoscopy, as compared with only using lidocaine gel.

Patients and Methods:

A total of 60 consecutive men who were scheduled to undergo rigid cystoscopy were randomly assigned to receive either 10 mL of 2% lidocaine gel combined with 2 mL normal saline, or 10 mL of 2% lidocaine gel combined with 2 mL ketamine (100 mg). Hemodynamic changes and the level of pain perception of patients at the beginning, during, and after every procedure in both groups were recorded by using the visual analogue scale.

Results:

There were no significant differences in hemodynamic changes between the two groups; however, the perception of pain was significantly decreased when lidocaine was used in conjunction with ketamine, most notably during the first 5 minutes of cystoscopy.

Conclusions:

Instillation of lidocaine gel in conjunction with ketamine in the urethra could decrease pain perception and make men undergoing outpatient rigid cystoscopy more comfortable during the procedure.

Introduction

C ystoscopy is one of the most common procedures in urology outpatient clinics. Various anesthetic agents have been used to make cystoscopy more tolerable for patients.

Traditionally, 2% lidocaine gel is widely used as a local anesthetic lubricant in males to reduce patient discomfort before various forms of transurethral instrumentation.^1,2 Nevertheless, a controversial question has been raised over the past few years about reported urethral discomfort when lidocaine gel is the sole lubricant.^3,4

Ketamine is an intravenous hypnotic and analgesic drug that can be administrated in many ways. It crosses from most tissue membranes, which leads to easy absorption. It also has early onset and a short duration of action. Because of peripheral action at both opioid and voltage dependent ion channels, such as sodium and L-type calcium channels, it has been recently used as a topical gel in several medical conditions.⁵ Because of effects on N-methyl-D-aspartic acid (NMDA). and non-NMDA glutamine, monoaminogenic, opioid, nicotinic, and muscarinic cholinergic receptors, intravenous ketamine has been used effectively for treatment of catheter-related bladder discomfort.^6,7 There is no evidence concerning local ketamine use in male urethral procedures.

Thus, we performed a study to evaluate the efficacy of lidocaine gel compared with lidocaine gel with ketamine in outpatient rigid cystoscopy.

Patients and Methods

This double-blind randomized clinical study was performed on male patients, all of whom were candidates for rigid cystoscopy with topical anesthesia in the urology operating room of Sina Hospital, which is affiliated with Tehran University of Medical Sciences. These patients entered the hospital for diagnostic evaluation of lower urinary tract symptoms, microhematuria, or for surveillance of superficial bladder tumors.

After approval of the institutional ethics committee, 60 consenting men (American Society of Anesthesiologists physical status I–II) between the ages of 19 and 50 years were enrolled in this study. The procedure and the objectives of the study were outlined for all the patients, and all patients signed an informed consent form to be part of the study.

Exclusion criteria for this study include: Patient refusal, sensitivity to local anesthetics, urethral stricture, age greater than 50 years, a history of urinary tract infections, repeated cystoscopy or urethral catheterization, and the history of ischemic heart disease.

Before any procedure, all patients had intravenous access secured. All patients had routine monitoring (noninvasive arterial blood pressure, electrocardiography, and oxygen saturation). The patients were randomly assigned to two groups using a computer random number generator. Group 1 patients received urethral lubrication with 10 mL of 2% lidocaine hydrochloride (Xylocaine jelly, Astra Zeneca) in conjunction with 2 mL normal saline. Group 2 patients received urethral lubrication with 10 mL of 2% lidocaine hydrochloride (Xylocaine jelly) in conjunction with 2 mL (100 mg) of ketamine (Rotex Medica, Germany).

The patients and attending urologist were blinded to the study drug used. All patients were examined in the lithotomy position; the urethral meatus was sterilized with povidone–iodine dermal solution. The assigned lubricant (20 mL for both groups) was instilled 15 minutes before cystoscopy. A clamp was used for 15 minutes to prevent ejection and to facilitate the dwell time for lubricant penetration and absorption into the tissue. Cystoscopy was performed using a 17.5F Olympus rigid cystoscope under video-camera guidance, and sterile saline irrigation was used at a pressure of 40 cm H₂O during cystoscopy. Vital signs, mean arterial blood pressure, heart rate, oxygen saturation before cystoscopy, during cystoscopy, and after removal of the cystoscope were recorded.

The intensity of pain was measured by a 10 cm Visual Analogue Scale (VAS) three times: During the entrance of the cystoscope, during cystoscopy (5 minutes after beginning), and 15 minutes after removal of the cystoscope. In both groups, no sedation was expected and drowsiness was considered as a complication in those patients with an Ramsey Sedation Score level of 3 or higher (responds to commands only) after the end of the cystoscopy. All patients were examined for nausea, vomiting, and hallucination.

Statistical analysis

The standard deviation of VAS was 2.2 in our pilot study. Thus, we calculated a sample size of 30 for each study group for α = 0.05 and β = 0.2 (power = 80%) to detect a difference of 2 in mean VAS scores of two groups. We used an independent sample t test and repeated measure analysis of variance to compare outcome measures between the study groups by using SPSS software version 15.

Results

There are no significant differences in the demographic data of the participants (60 men divided into two groups) (Table 1). The mean age of the patients was 40.63 ± 8.66 years, while the range was 19 to 50 years. Hemodynamic changes (mean arterial pressure and heart rate) at the beginning of the procedure, during it, and after removal of cystoscope are listed in Table 2.

Table 1.

Characteristics of Patients

	Lidocaine gel	Lidocaine gel plus ketamine	P value
Age	41.67 ± 8.68	39.6 ± 8.7	0.361^a
MAP	93.28 ± 7.69	92.39 ± 6.98	0.641^a
HR	72.08 ± 3.17	69.67 ± 2.8	0.431^a
Cystoscopy time (min)^b	16 ± 6	15 ± 7	0.284^a

Independent samples t test.

From the insertion of cystoscope sheet to removal.

MAP = mean arterial pressure; HR = heart rate.

Table 2.

Mean Arterial Pressure and Heart Rate During Study

	Lidocaine gel (mean ± SD)	Lidocaine gel + ketamine (mean ± SD)	P value^a	Mean difference ± SD	95% Cl of mean difference	P value (repeated measures ANOVA)
During cystoscopy
MAP 5 min	90.59 ± 6.94	89.68 ± 5.86	0.58	0.91 ± 1.66	−2.41–4.23
MAP 10 min	90.25 ± 6.87	89.53 ± 5.50	0.65	0.72 ± 3.94	−2.49–3.94
MAP 15 min	89.72 ± 8.03	89.53 ± 5.50	0.91	0.18 ± 1.7	−3.36–3.74
MAP 20 min	90.30 ± 7.10	88.25 ± 10.8	0.39	2.04 ± 2.36	−2.69–6.78
After cystoscopy
MAP 5 min	89.83 ± 7.03	90.95 ± 6.96	0.53	−1.12 ± 1.80	−4.74–2.49
MAP 60 min	63.93 ± 5.19	64.95 ± 4.70	0.42	−1.01 ± 1.27	−3.58–1.53	0.81
During cystoscopy
HR 5 min	72.97 ± 8.93	71.53 ± 8.96	0.24	2.6 ± 2.25	−1.85–7.18
HR 10 min	71.57 ± 8.39	70.47 ± 8.68	0.62	1.1 ± 2.20	−3.31–5.51
HR 15 min	70.60 ± 9.81	69.40 ± 11.20	0.66	1.2 ± 2.71	−4.24–6.64
HR 20 min	71.27 ± 8.90	69.20 ± 10.04	0.40	2.1 ± 2.45	−2.83–6.97
After cystoscopy
HR 5 min	70.45 ± 8.20	68.56 ± 9.37	0.44	2.3 ± 2.43	−2.46–7.11
HR 60 min	69.23 ± 8.24	70.30 ± 8.39	0.50	2.2 ± 2.12	−2.74–6.34	0.67

Independent samples t test.

SD = standard deviation; CI = confidence interval; ANOVA = analysis of variance; MAP = mean arterial pressure; HR = heart rate.

The VAS score at the commencement of the procedure, middle of the procedure, and 15 minutes after removal of the cystoscope in both groups were measured (Table 3). Mean pain scores in all stages were found to be significantly lower in the patients of group 2, who were treated with lidocaine and ketamine. None of the patients had nausea, vomiting, and hallucinations. There was no impairment in the level of consciousness in both groups, and all patients were discharged from the operating room 1 hour after the procedure.

Table 3.

Mean Visual Analogue Scale Score

VAS score	Group 1 (mean ± SD)	Group 2 (mean ± SD)	P value	Mean difference ± SD	95% Cl of mean difference	P value (repeated measures ANOVA)
Entrance of cystoscope	6.5 ± 2.17	4.8 ± 1.96	0.003	1.67 ± 0.53	0.5–2.7
During cystoscopy	6.7 ± 2.27	4.7 ± 2.1	0.001	1.9 ± 0.56	0.8–3.1
15 min after end of cystoscopy	5.7 ± 2.26	3.9 ± 1.93	0.002	1.8 ± 0.54	0.7–2.8	0.001

VAS = Visual Analogue Scale; SD = standard deviation; CI = confidence interval; ANOVA = analysis of variance.

Discussion

Our study demonstrates that adding 100 mg ketamine to 2% lidocaine gel significantly lowers delivery discomfort of the cystoscope in the male urethra during rigid cystoscopy. The mean assessed pain score during the procedure and 15 minutes after removal of the cystoscope in group 2 was better than in group 1. Our hypothesis was that using lidocaine in conjunction with ketamine (which has both peripheral and central nervous system effects) could control the pain better than using lidocaine alone during cystoscopy procedures. Because this study was the first one of its kind regarding the use of intraurethral ketamine, we were not allowed morally to use it alone and therefore lidocaine was added for both groups for its analgesic effects. Ketamine at 25 minutes after oral and nasal administration usually provides sedation in pediatric patients.⁸ For that reason, the procedure was performed 15 minutes after urethral instillation to facilitate local and postulated central effects. According to the information collected in Table 2, the ketamine used in group 2 did not cause significant cardiovascular changes compared with the medication used in group 1; this may be from the ketamine (∼2 mg/kg) that was administered.

The scope of this study did not include measuring the plasma concentration of ketamine. There have not been any studies about the pharmacokinetics of intraurethral administration of ketamine. Measuring the plasma concentration of ketamine during and after the cystoscopy procedure is a topic that must be evaluated in a future study.

With regard to the reduction of the mean VAS score when using ketamine in this study, the peripheral and central analgesic effects of ketamine might be suggested. Low plasma levels of ketamine can inhibit nociceptive central sensitization and have a preventive analgesic effect; also, the local analgesic effect of ketamine has been explained by neuronal sodium channel block^8,9 and inhibition of development of secondary hyperalgesia by peripheral action on the NMDA receptor.¹⁰ In a study conducted by Erhan and associates,¹¹ the infiltration of ketamine into the tonsillar region immediately after a tonsillectomy can effectively reduce the first and the total amount of required analgesics during the procedure. Nejati and colleagues¹² reported that intranasal ketamine is an effective agent in reducing the pain of nasogastric tube insertion. In addition, topically applied ketamine reduces capsaicin-evoked mechanical hyperalgesia and was used as an adjuvant for postoperative analgesia prolongation after minor gynecologic procedures.^13,14 Therefore, ketamine, with its peripheral and central nervous system effects, can control pain and thus lower the VAS score. In our study, both groups received lidocaine. Compared with lidocaine alone, lidocaine and ketamine decreased VAS two points. It is possible that in the future studies, ketamine may have a noticeable analgesic effect in comparison with placebo.

Conclusion

This study found that ketamine used in conjunction with lidocaine gel made a tolerable condition for rigid cystoscopy. Additional study is needed to evaluate the efficacy of a higher dosage of ketamine with plain lubricant in this procedure.

Footnotes

Acknowledgment

We acknowledge Mohammad Reza Samadani, anesthesiologist, for his review and helpful comments on this article. We also thank Tahere Sanaei Shoar, M.D., for her support and comments regarding the statistics of the study.

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Dryhurst

, Fowler

. Flexible cystodiathermy can be rendered painless by using 2% lignocaine solution to provide intravesical anaesthesia. BJU Int, 2001; 88:437–438.

Greenland

, Lynch

, Wallace

. Optical urethrotomy under local urethral anaesthesia. Br J Urol, 1991; 67:385–388.

Thompson

, Thompson

, O'Brien

et al. To determine whether the temperature of 2% lignocaine gel affects the initial discomfort which may be associated with its instillation into the male urethra. BJU Int, 1999; 84:1035–1037.

, Thompson

, O'Brien

et al.

Lignocaine gel: Does it cause urethral pain rather than prevent it?

Eur Urol, 2003; 43:194–196.

Tverskoy

, Oren

, Vaskovich

et al. Ketamine enhances local anesthetic and analgesic effects of bupivacaine by peripheral mechanism: A study in postoperative patients. Neurosci Lett, 1996; 215:5–8.

Kohrs

, Durieux

. Ketamine: Teaching an old drug new trick. Anesth Analg, 1998; 87:1186–1193.

Agarwal

, Gupta

, Kumar

et al. Ketamine for treatment of catheter related bladder discomfort: A prospective, randomized, placebo controlled and double blind study. Br J Anaesth, 2006; 96:587–589.

Reves

, Glass

, Lubarsky

. Intravenous nonopioid anesthetics. Miller

. Miller's Anesthesia. Philadelphia: Churchill Livingstone, 2005; 345–350.

Reckziegle

, Feriederich

, Urban

. Ketamine effects on human neural Na⁺ channels. Eur J Anaesthesiol, 2002; 19:634–640.

10.

Warncke

, Jørum

, Stubhaug

. Local treatment with the N-methyl-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action. Neurosci Lett, 1977; 227:1–4.

11.

Erhan

, Göksu

, Alpay

, Bestas

. Ketamine in post-tonsillectomy pain. Int J Pediatr Otorhinolaryngol, 2007; 71:735–739.

12.

Nejati

, Golshani

, Moradi Lakeh

et al. Ketamine improves nasogastric tube insertion. Emerg Med J, 2010Epub ahead of print.

13.

Pöyhiä

, Vainio

. Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia. Clin J Pain, 2006; 22:32–36.

14.

Azevedo

, Lauretti

, Pereira

, Reis

. Transdermal ketamine as an adjuvant for postoperative analgesia after abdominal gynecological surgery using lidocaine epidural blockade. Anesth Analg, 2000; 91:1479–1482.