Spinal anaesthesia is widely used for transurethral prostate resection, despite the risk of hypotension, because it allows early recognition of symptoms caused by overhydration and hyponatraemia ('transurethral resection of the prostate' or TURP syndrome). The elderly are at increased risk of developing complications from hypotension because they have a reduced physiological reserve and a higher incidence of systemic disease .
Studies on the intrathecal administration of racemic ketamine in adults have given conflicting results. Bion  used ketamine as the sole anaesthetic agent for lower limb surgery and demonstrated a lack of cardiovascular depression that might be advantageous in an elderly population. However, the frequency of psychomimetic disturbances, inadequate analgesia, and short duration of action preclude its use as the sole anaesthetic agent in spinal anaesthesia . Although the use of racemic ketamine, as an adjunct for spinal anaesthesia, has a local anaesthetic sparing effect, the high incidence of central adverse effects and poor patient satisfaction limit its clinical use . S(+) ketamine, one of the two enantiomers of ketamine has the threefold analgesic potency of R(−) ketamine. Klimscha and colleagues  described the antinociceptive effects of S(+) ketamine after intrathecal administration in rats and observed effective analgesia. As S(+) ketamine is available in a preservative-free formulation it can be given intrathecally. In this study we evaluated the effects of intrathecal S(+) ketamine in combination with bupivacaine in elderly patients undergoing transurethral resection of the prostate.
After obtaining approval from our institutional Ethics Committee and informed patient consent, we enrolled 40 ASA I and II patients with prostate hypertrophy undergoing transurethral prostate resection under spinal anaesthesia. Patients with deformities of the spinal column, mental disturbances or neurological disease were excluded. Patients were randomly allocated to receive either intrathecal bupivacaine 10 mg alone or bupivacaine 7.5 mg with preservative-free S(+) ketamine 0.1 mg kg−1 (Ketanest S®; Parke Davis, Vienna, Austria). Anaesthetic solutions were prepared in the operating room by one of the authors who was not involved in data collection. The solutions were diluted with NaCl 0.9% to give a total volume of 4 mL. The patients and the anaesthesiologist who performed the spinal anaesthesia and recorded the data were blinded to the treatment.
Patients had fasted for 6 h preoperatively and were premedicated with diazepam 0.2 mg kg−1 orally. All received an intravenous (i.v.) preload of lactated Ringers' solution 10 mL kg−1 before the subarachnoid block. Lumbar puncture was performed with the patient in the left lateral decubitus position with a 25-G spinal needle at the L2/3 or L3/4 interspace using a midline technique under aseptic precautions. With the spinal needle orifice oriented cephalad, cerebrospinal fluid was aspirated and the study solution was injected slowly at about 0.2 mL s−1. Immediately after the injection, the patients were placed supine. Patients remained in the supine position for 5 min and were then placed in the lithotomy position for the operative procedure. Heart rate (HR), oxygen saturation (SPO2), respiratory rate, and non-invasive systolic and diastolic arterial pressures were recorded every 5 min for 15 min and then every 15 min until the end of the procedure. Arterial pressure was supported within 20% of baseline by the infusion of crystalloid solutions. Small doses of i.v. ephedrine were given if systolic arterial pressure was <90 mmHg. The patients were assessed for motor and sensory block and side-effects such as sedation, nystagmus, dizziness, nausea, vomiting, and psychomimetic effects. Sensory block was assessed by pinprick. Motor block was assessed by the modified Bromage score (0, no motor loss; 1, inability to flex the hip; 2, inability to flex the knee; 3, inability to flex the ankle). Patients were tested every 3 min up to the maximal spread of blockade, and thereafter every 15 min until recovery. Sedation was assessed every 15 min using a four-point scale (1, awake; 2, drowsy but responsive to verbal stimulus; 3, drowsy but responsive to physical stimulus; 4, unresponsive to verbal and physical stimulus).
Offset of sensory block was defined as return of bilateral sensation to pinprick at the S2 dermatome was recovered. Complete motor recovery was assumed when the modified Bromage score was zero. Duration of spinal analgesia was measured from the time of spinal anaesthetic administration to the first time at which the patient complained of pain in the postoperative period. Oxygen was given via nasal prongs if arterial oxygen saturation was less than 95% with the patient breathing ambient air.
Tramadol (25 mg i.v.) was used to treat postoperative pain. The interval from the injection of spinal anaesthesia to the request for the first dose of tramadol and the total amount of tramadol required in the first 24 h were recorded.
The patients were discharged from the recovery room after 6 h if motor block was completely resolved. Further discharge criteria were stable vital signs, minimal nausea or vomiting and no severe pain or bleeding.
In the period after operation, the patients were asked to rate their satisfaction with the anaesthetic procedure on a five-point score (0, poor; 1, fair; 2, adequate; 3, good; 4, excellent). On the third postoperative day, the patients were interviewed again regarding their opinion of the anaesthetic procedure, occurrence of headache or backache, and whether they would choose the same anaesthetic again for a similar operation.
Patient characteristics and clinical data such as onset time, duration of sensory and motor blockade, and time to first analgesic requirement were analysed using χ2-tests with Yates' correction and Fisher's exact tests wherever appropriate. Haemodynamic variables and respiratory rate were compared between the two groups by unpaired t-tests. Maximum sensory block level, number of tramadol doses given in the first 24 h and patient satisfaction scores were compared between the groups by the U-test. P < 0.05 was considered statistically significant.
All 40 patients recruited for the study were evaluated. The groups were comparable with regard to age, height, weight, ASA Grade and duration of surgery (Table 1).
There was an insignificant trend towards more rapid onset of motor and sensory block in the bupivacaine plus S(+) ketamine group. The time to achieve complete motor block of the legs (Bromage score of 3) was shorter in the bupivacaine plus S(+) ketamine group. However, this level of motor block was only obtained in four of the 20 patients in the bupivacaine plus S(+) ketamine group opposed to all 20 patients in the other group (Table 2). The duration of complete motor block was shorter in the bupivacaine plus S(+) ketamine group (65-133 min) than in the bupivacaine group (100-230 min).
There was no difference in the number of segments blocked in each group. The duration of sensory block was similar in both groups but the duration of spinal analgesia and motor recovery was significantly shorter in patients in the ketamine group (Table 2). The mean upper limit of sensory block was T8 in the bupivacaine plus S(+) ketamine group and T6 in the bupivacaine group.
No patients required additional intraoperative analgesics. Postoperative analgesic requirements were similar in both groups during the first 24 h (Table 2).
There were no significant differences between the groups with respect to satisfaction score (3.2 in the bupivacaine plus S(+) ketamine group and 3.3 in the bupivacaine group).
None of the patients required treatment for hypotension or bradycardia. There was no significant change of arterial pressure during the intraoperative period in either group. HR decreased after spinal anaesthesia in the bupivacaine plus S(+) ketamine group and was significantly lower than in the bupivacaine group until the end of the anaesthesia (Fig. 1) (P < 0.05). Respiratory depression was not observed, and SPO2 values during and after operation did not differ between groups.
Adverse psychological effects were not observed in either group. Side-effects such as sedation, nystagmus, dizziness, nausea or vomiting occurred in 30% of the patients in the bupivacaine plus S(+) ketamine group and 50% of those in the bupivacaine group (Table 3).
In previous studies, it was assumed that ketamine exerts analgesic effects after epidural, caudal, or intrathecal administration [2,6], due to its interaction with spinal antinociceptive receptors. Due to the potential neurotoxicity of preservatives added to commercially available racemic ketamine preparations, the drug was not recommended for epidural or intrathecal administration . Compared with the R(−) isomer, the S(+) enantiomer has a threefold higher analgesic potency, whereas the other pharmacological properties are similar [8,9].
Lauretti and colleagues  demonstrated that low doses of S(+) ketamine (0.1 and 0.2 mg kg−1) administered epidurally had an antinociceptive effect as was reported from another study that used a dose of 0.25 mg kg−1.
In our study, we observed adequate intraoperative effects of S(+) ketamine 0.1 mg kg−1 with a reduced dose of bupivacaine for spinal anaesthesia in elderly patients, although it did not have a beneficial effect on postoperative analgesia. S(+) ketamine did not prolong the duration of spinal analgesia. In addition, we found that S(+) ketamine administered with a lower dose of bupivacaine causes less motor blockade than the higher dose of bupivacaine alone. In our experience, addition of intrathecal S(+) ketamine and reduction of the bupivacaine dose shortened the motor and sensory block onset time and decreased the duration of analgesia. Our results are consistent with the observation that S(+) ketamine has a particular local anaesthetic effect when used with bupivacaine in spinal anaesthesia, as evidenced by onset time and total analgesic consumption and improved patient satisfaction. Furthermore, when used in elderly patients it had no adverse haemodynamic effects.
Chia and colleagues  demonstrated an additive analgesic effect when ketamine was added to a multimodal patient-controlled analgesia regimen. Caudal co-administration of ketamine and bupivacaine gave better postoperative analgesia than did bupivacaine alone in children after inguinal herniorrhaphy . Yanli and Eren  have shown that extradural ketamine reduces onset time and increases the level of bupivacaine block by two segments. Gantenbein and colleagues  reported that the local anaesthetic activity of bupivacaine was significantly enhanced by ketamine. The ketamine-induced increase in the local anaesthetic effect of bupivacaine may thus be explained by kinetic modifications, i.e. a possible inhibiting effect of ketamine on the metabolism of bupivacaine. We can explain the adequate intraoperative effects of intrathecal S(+) ketamine administered with low dose of bupivacaine in our study by this possible inhibiting effect.
In our study, haemodynamic responses after intrathecal administration of S(+) ketamine were comparable with those after intrathecal administration of bupivacaine. We did not observe increases in HR or arterial pressure after administration of S(+) ketamine. This indicates that the analgesic effect of intrathecally administered S(+) ketamine is caused primarily by a direct effect on the spinal cord with little systemic effects. The use of ketamine via the intrathecal route was associated with a significant increase in side-effects affecting the central nervous system [3,4] although we did not observe these in our study. Weir and Fee  observed significant sedation in patients who had received extradural ketamine with bupivacaine. They explained the excessive sedation that was observed in their patients as due to lipid solubility and extensive intravascular absorption of ketamine from the epidural space. All patients in our study were premedicated with diazepam and this might have prevented psychomimetic adverse effects. Since we used only a low dose of intrathecal S(+) ketamine, we did not observe any serious sedative effects. In this study, the addition of S(+) ketamine was not associated with an increase in the incidence of nausea and vomiting which was low. We conclude that intrathecal S(+) ketamine administered with smaller dose of bupivacaine provides shorter motor and sensory block onset time, shorter duration of action and less motor blockade in elderly patients.
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