Clonidine acts on pre- and postsynaptic α2-adrenergic receptors and although it cannot produce anaesthesia for surgery alone , it increases the duration of local analgesic blocks when infused intradurally and prolongs the pain-free interval after operation [2-6]. Although the side-effects of clonidine include hypotension, bradycardia and sedation , such effects seem to have no clinical relevance when clonidine is used in low doses in spinal anaesthesia [7-9].
The adjuvant effects of clonidine have been described in studies with bupivacaine [9-11], tetracaine , lidocaine [4,12] and mepivacaine . However, no studies are available for prilocaine, which we commonly use in transurethral resections of bladder tumours. Recent studies have suggested that clonidine can decrease the incidence of severe postoperative pain associated with the use of urethral catheters [5,6], thus making the use of clonidine as an adjuvant to prilocaine desirable in transurethral surgery. The current study was therefore designed to examine the effects of clonidine on prilocaine spinal block and on postoperative analgesia in patients undergoing removal of bladder tumours.
After obtaining approval by the local Ethics Committees of the participating hospitals and the Pharmacy Section of the Spanish Health Ministry (EC-98/235), we enrolled 40 consecutive patients who were to undergo elective transurethral resection of bladder tumours under spinal anaesthesia. Written informed consent was obtained from all patients; they were then randomized into two groups. Exclusion criteria were any contraindication for spinal anaesthesia, coagulation abnormalities, local anaesthetic or clonidine allergies, and treatment with drugs that might interact with clonidine (antihypertensive drugs, monoamine oxidase inhibitors or antidepressants). Patients, nurses and physicians in charge of perioperative care, and the staff involved with communicating with patients, those administering the anaesthetics and collecting the postoperative data were all blinded to the group allocations. Inclusion criteria were males aged 60-85 yr, body weight 50-100 kg, ASA I-III, and sufficient cognitive ability to understand the protocol and give informed consent.
All patients were premedicated with ranitidine 300 mg and diazepam 5 mg, orally. Both groups received an infusion of lactated Ringer's solution, 1000 mL, during the placement of the block. Lumbar puncture was performed using a 25-G pencil-point spinal needle (Braun, Inc., Melsungen, Germany) at the L3-L4 intervertebral space with the patients the sitting position. The spinal solution was prepared, under sterile conditions, by the Pharmacy Department of our hospital in numbered syringes (case numbers) to assure blinding. The clonidine group received 5% prilocaine 1.5 mL (75 mg) in a solution with 0.015% clonidine 0.5 mL (75 μg). The control group received 5% prilocaine 1.5 mL (75 mg) in a solution with 0.9% NaCl 0.5 mL. Monitoring included non-invasive arterial pressure (systolic, diastolic and mean), electrocardiography and pulse oximetry (SPO2). After surgery, the patients remained in the recovery room until they met the discharge criteria of no pain, no motor block, no sensory level above L2 and haemodynamic stability (no hypertension or hypotension). At the end of the surgical procedure, the urologist inserted a flexible transurethral catheter to flush the bladder continuously during the postoperative period.
Spinal block assessment
We assessed the sensory block by complete loss of sensation to pinprick every 5 min until completion of surgery. Motor block was assessed using a modified Bromage scale, which was defined as: levels 0: no block (the ability to flex the knees and feet); 1: partial block (the ability to flex the knees and stand with full movement of the feet); 2: nearly complete block (the inability to flex the knees but retaining the ability to flex the feet); and 3: complete block (the inability to move the legs or feet). The duration of motor block was the time from when the highest grade of motor block had been reached to the return to level 0 on the Bromage scale. The times from the lumbar puncture to the times when the highest motor and cephalad extension of the sensory block, the duration of sensory block at L2, and the two segments regression were also recorded.
The 'pain-free interval' was defined as the elapsed time from lumbar puncture to the onset of pain after operation. Pain was considered present when the patient indicated a score on the visual analogue scale (VAS) ≥ 3 (on a scale of 0-10: 0: no pain; 10: greatest imaginable pain). Pain was scored every 15 min in the recovery room and every 6 h in the surgical ward. Whenever VAS ≥3 and there was no evidence of blood clots in the bladder, patients received metamizol (dipyrone) 2 g intravenously (i.v.). Pain was re-evaluated 15 min later by the VAS. If ≥3, a bolus of morphine 2 mg i.v. was administered.
Haemodynamic variables (systolic, diastolic and mean arterial pressures) and SPO2 were measured immediately before lumbar puncture, every 5 min during the operation, every 15 min in the recovery room and every 6 h thereafter in the surgical ward.
We defined adverse effects to be: hypotension (systolic arterial pressure < 90 mmHg), heart rate < 50 beats min−1, SPO2 < 92%, vasopressors or blood transfusion given or occlusion of the urinary catheter by blood clots. We assessed sedation (evaluated by the Ramsey Scale) in the recovery room (0: awake; 1: light sleep; 2: deeper sleep; 3: coma). Asymptomatic hypotension was treated by infusion of hydroxyethyl starch 6%. Symptomatic hypotension was treated by administering a vasopressor.
Quantitative results were presented as mean ± SD and qualitative results appear as percentages. According to the method applied by Dobrydnjov and Samarütel , we used a sample size of at least 17 patients per group to provide 80% power at α = 0.05; the number was increased to 20 patients to cover withdrawn patients (5%). To randomize patient assignment, we used the GRANMO® statistical package (Institut Municipal d'Investigació Mèdica, Barcelona, Spain).
Statistical analysis was performed with the SPSS® package (SPSS Inc., Chicago, IL, USA). Analysis of variance and a t-test compared of means. Fisher's exact test compared the results, expressed as percentages, and a U-test compared ordinal variables. P < 0.05 was considered as significant.
One patient in each group changed his mind and withdrew from the study despite having signed the informed consent form the previous night. Another patient in the control group was excluded because of failure of the spinal blockade. Demographic data and duration of surgery were similar in both groups (Table 1).
Table 2 summarizes the times relating to onset of analgesia, sensory and motor blockade, showing that the pain-free interval lasted much longer in the clonidine group (mean duration of analgesia > 8 h). The duration of the motor block and regression of the sensory block to L2 were also significantly longer in the clonidine group. We observed no significant difference in the highest sensory block or in the motor block during the first 160 min after puncture. VAS was < 3 for 72.4% of patients in the clonidine group and 56% in the control group during the first 12 h after operation. When re-evaluated at 24 h, the rates were 82 and 66%, respectively.
Table 3 summarizes postoperative events, vasopressor and analgesic consumption and blood transfusion requirements, showing that metamizol consumption was significantly higher in the control group. An episode of oral paraesthesia was observed during recovery in one patient in the clonidine group. No patients developed excessive sedation (Ramsay score > 1).
The addition of clonidine to prilocaine prolonged the motor and sensory blockade produced by the local anaesthetic. This finding is in accord with previous studies using other local anaesthetics [6,7,10-13]. Moreover, clonidine provided safe [14-17], effective postoperative analgesia without adverse effects to an extent that some patients required no postoperative analgesia at all during their stay in hospital.
Although we observed less urinary obstruction from blood clots in the clonidine group, our study did not have sufficient statistical power to allow us to conclude that this was an effect of spinal clonidine. Our observation is consistent with reports that clonidine is a potent inhibitor of bladder outlet sphincter reflexes caused by bladder catheters and that bladder irrigation is improved [18-19]. Herman and colleagues  used clonidine to treat bladder hypertonicity in patients with chronic spinal injuries. Decreased urinary retention after spinal clonidine anaesthesia has also been demonstrated .
We found clonidine to be clinically useful at a dose of 75 μg. This finding differs from the observations of Larsen and colleagues  who found that clonidine 75 and 150 μg, added to mepivacaine, had no effect on the duration of sensory and motor blockade, and failed to reduce the demand for analgesics after operation. However, in a dose of 150 μg, both the sensory and motor blockade lasted longer (about 50 and 40 min, respectively), although the difference was not significant. Niemi  added clonidine 3 μg kg−1 to bupivacaine 15 mg and obtained a longer duration of action - about 57 and 54 min for sensory and motor blockade, respectively. The analgesic interval we observed at the lower dose was similar to that reported by Niemi at the higher dose of 150 μg. Our findings suggest that a lower dose of clonidine may be used to minimize the incidence of side-effects.
In conclusion, the addition of clonidine 75 μg to prilocaine during spinal anaesthesia for transurethral resection of bladder tumours prolonged the analgesic interval and reduced the requirements for additional analgesia in the postoperative period.
The authors are grateful for a grant from the Acadèmia de Ciències Mèdiques de Girona. They thank Susanna Vargas Vila for the translation of the original manuscript, Lee Randol Barker for helpful comments on the manuscript, and Mary Ellen Kerans for correction of style.
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