For effective postoperative analgesia, the timing of treatment should cover the entire duration of high-intensity noxious stimulation initiating the altered sensory processing. Additionally, complete intraoperative blockade of afferent signals to the central nervous system (CNS) is fundamental in decreasing postoperative pain. Therefore, both interception of nociceptive input and blockade of N-methyl-d-aspartate (NMDA) activation may be necessary to provide effective postoperative analgesia. Previous studies demonstrated that NMDA receptor antagonists potentiated the effects of other analgesics, such as morphine and local anesthetics (1,2). Activation of C-fibers by the surgical tissue trauma produces central sensitization. When a massive barrage of afferent nociceptive impulses reaches the spinal cord, a hyperexcitable state of CNS sensitization, known as “wind-up,” results (3). This sensitization is connected with the activation of NMDA receptors (4). Ketamine, a noncompetitive NMDA antagonist, not only modifies peripheral afferent noxious stimulation, but can also reduce the activation of spinal sensory neurons.
Renal nociception is conducted multisegmentally by both the spinal nerves (T10 to L1) and the vagus nerve (5). Nociception mediated by the vagus nerve induces c-fos expression in brainstem neurons (6). Brainstem neurons express c-fos after visceral nociception. The dorsal vagal complex in the brainstem is the main visceral pain center (7). Aida et al. (8) demonstrated that epidural analgesia alone was insufficient to provide effective postoperative analgesia after laparotomy. The combination of spinal and supraspinal analgesia can produce sufficient postoperative analgesia. However, Ilkjaer et al. (9) were unable to demonstrate an (additive) analgesic or opioid-sparing effect of ketamine combined with epidural bupivacaine or morphine after renal surgery.
The purpose of this study was to evaluate the effect of the combination of spinal and supraspinal analgesia with IV small-dose ketamine administered during surgery and epidural segmental analgesia with epidural bupivacaine plus morphine on postoperative pain after renal surgery.
Forty patients of ASA physical status I or II who underwent elective renal surgery were studied with their informed consent; the approval of the Dicle University Ethics Committee was also obtained. Patients were those with the following characteristics: severe hepatic, renal, cardiovascular, or psychological disorders; contraindications to ketamine and insertion of an epidural catheter; and a history of drug or alcohol abuse. Patients who were administered opioid before surgery and who were unable to cooperate were excluded. A day before surgery, patients were instructed about the use of the visual analog scale (VAS; 0 = no pain, 10 = worst pain ever) and the patient-controlled epidural analgesia (PCEA) device (Acute Pain Manager; Abbott, North Chicago, IL).
On the basis of the computer-generated random sequence, the study solutions were prepared before surgery for group C (normal saline) and group K (ketamine). For use in the induction of anesthesia, 10 mL of normal saline was prepared in group C, and 10 mL of ketamine (5 mg/mL) was prepared in group K. For infusion in the maintenance of anesthesia, 50 mL of normal saline was prepared in group C, and 50 mL of ketamine (2 mg/mL) was prepared in group K. These study solutions were transferred to an investigator blinded to solutions.
After 5 mg of diazepam IV was administered for premedication, all patients were taken to an intervention room, and electrocardiogram, noninvasive blood pressure, and peripheral oxygen saturation were monitored. An epidural catheter was inserted into the epidural space at the T8-9 or T9-10 level and tested with 2 mL of lidocaine 2% containing epinephrine (1:200,000). A PCEA device, containing morphine 0.2 mg/mL and bupivacaine 1.25 mg/mL, was started. Ten milliliters of solution was epidurally administered as an initial loading dose. By using the pinprick test, sensory block was determined with a 22-gauge needle in the midline. If this dose was not sufficient to obtain dermatomal anesthesia between the T8 and L1 levels, additional doses (2 mL) were administered. After dermatomal anesthesia between the T8 and L1 levels was obtained, a PCEA device was initially programmed to administer 4 mL/h with a bolus dose of 5 mL and with a 4-h limit of 40 mL. The lockout time was 20 min. The patients were then transferred to the operating room.
General anesthesia was induced with midazolam 0.05 mg/kg, study solution 0.1 mL/kg (ketamine 0.5 mg/kg in group K or normal saline in group C), propofol 1–2 mg/kg, vecuronium 0.1 mg/kg, and remifentanil 1 μg/kg and was maintained with sevoflurane 1%–2% in 100% oxygen. Study solution 0.25 mL/h (ketamine 0.5 mg · kg−1 · h−1 in group K) was continuously given until skin closure. No other analgesics were administered during operation.
After emerging from anesthesia, the patients were transferred to postanesthesia care unit (PACU), where they stayed for 2 h, and they were then discharged to the ward. Another blinded observer assessed VAS pain score in the postoperative period. The PCEA demand button was given to the patients who could open their eyes, grip a finger, and breathe deeply on request. The time to first analgesic request was recorded. If pain relief was satisfactory (VAS <3), basal infusion was stopped at the sixth postoperative hour. VAS, sedation (0 = none, 1 = slight, 2 = moderate/sleeping when not disturbed, 3 = severe/sleeping during visit), nausea and pruritus (0 = none, 1 = slight, 2 = moderate, 3 = severe/request treatment), and dysphoria (including hallucinations and dreams) were noted at 0.5, 1, 2, 4, 6, 12, 24, and 48 h. Pain during coughing was also assessed at 12, 24, and 48 h after surgery. The number of analgesic demands and the number of deliveries were recorded. If a patient experienced pain (VAS >4), an additional loading dose (10 mL) was epidurally administered via the PCEA device. Thirty minutes after this administration, if pain still continued or intensified, 7 mL of 1% lidocaine was administered epidurally to assist in checking for correct placement of the epidural catheter. Patients did not receive any other analgesic medications orally or IV. At the end of the study, patient satisfaction related to analgesic therapy was recorded according to a three-point scale: 0 = unsatisfactory, 1 = satisfactory, 2 = very satisfactory.
Statistical analysis was performed with SPSS 10.0 for Windows (SPSS Inc., Chicago, IL). An a priori power analysis was performed to determine the number of patients per group sufficient to detect a decrease of ≥30% in the PCEA opioid analgesic requirements during the 48 h after surgery, on the basis of the results of Chia et al. (10). With a power of 80% and a Type 1 error of 5%, it was estimated that 19 patients were required per group. VAS, sedation, nausea, pruritus, and satisfaction score were compared by using the Mann-Whitney U-test. Age, weight, length of surgery, time to first analgesic request, number of analgesic demands and deliveries, and amount of analgesic consumption were compared by using Student’s t-test. The χ2 test was used to compare frequency of side effects, type of operation, and sex distribution. The values were expressed as mean ± sd or median and range. P < 0.05 was considered statistically significant.
The two groups were comparable with respect to demographic data, types of surgery, and duration of surgery (Table 1). VAS pain scores at rest were significantly lower in group K during the first 6 h (P < 0.01). VAS pain scores on coughing were also significantly lower in group K (P < 0.01) (Fig. 1). Both the number of demands and the number of deliveries were smaller in group K (P < 0.0001) (Table 2). Cumulative postoperative total analgesic consumption was less in group K on Days 1 and 2 (P < 0.001) (Table 2). The first analgesic demand time was shorter in group C (9.2 ± 11.5 min) than in group K (22.3 ± 17.1 min) (P < 0.0001). There was no respiratory depression, motor block, or dysphoria in either group. The incidences of side effects are summarized in Table 3. The incidence of nausea and pruritus was more frequent in group C. In group C, the severity of nausea (1 [0–3]) and pruritus (2 [0–3]) was also higher than in the ketamine group (0 [0–3] and 1 [0–3], respectively) (P < 0.05). Diplopia was reported by three patients in group K. Patients in group K were more sedated than those in group C during the first 2 h, but no deep sedation occurred in either group (Table 4). All patients recovered completely within 2 h in the PACU. There was no need to check correct placement of the epidural catheter. No patients required another analgesic medication. Patients generally were satisfied with their analgesia (85% in group K and 80% in group C).
Combination of analgesics has been proposed to provide superior postoperative analgesia with fewer side effects (10,11). In abdominal surgery, epidural morphine or IV ketamine alone produced insufficient analgesia (12,13). Thus, combined and preemptive administration of ketamine and morphine has been suggested to provide satisfactory postoperative analgesia (14). We observed that ketamine potentiated the analgesic effects of epidural morphine and bupivacaine. Opioids, apart from very large doses, do not inhibit the process called “wind-up” but do delay the onset of NMDA receptor activation (15). NMDA antagonists modify the induction of central sensitization and can contribute significantly to the prevention of pain (16).
Ketamine, a noncompetitive NMDA antagonist, potentiates the analgesic effect of epidural morphine (17). It interacts with multiple binding sites, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and monoaminergic and opioid receptors (3). NMDA receptor antagonism accounts for most of the analgesic effects of ketamine (3). Several studies reported that small-dose ketamine is capable of reducing postoperative morphine consumption (10,14,18,19). Menigaux et al. (18) suggested that the analgesic effect of small doses of ketamine might be explained with synergistic or additive interaction among opioids. Kissin et al. (20) reported that acute tolerance to opioids developed within hours in rats. Acute tolerance has also been reported in humans after 24 hours of morphine infusion (21). NMDA agonists seem to prevent the development of acute tolerance to opioids (22).
We believe that both the spinal and supraspinal effects of ketamine account for the additive analgesic effect. Curatolo et al. (23) showed that even bupivacaine 0.5% (20 mL) could not block temporal summation of pain. In our study, bupivacaine 0.125% with morphine produced satisfactory analgesia when epidural block was combined with IV ketamine.
It was reported that ketamine did not provide effective analgesia in patients with cortical disease and brain injury (24,25). Thus, one of the analgesic action sites of ketamine is believed to be in the supraspinal structures. Visceroperitoneal nociception is transmitted multiply by spinal nerves and vagus nerves. This nociception induces central sensitization not only segmentally, but also multisegmentally (14). Aida et al. (19) suggested that epidural morphine affected the spinal cord segmentally and that IV ketamine might block brainstem sensitization via the vagus or phrenic nerve during upper abdominal surgery. Hence, we thought that a supraspinal effect of ketamine was an important contributing factor to providing effective analgesia.
Ilkjaer et al. (9) investigated the additive analgesic effects of ketamine on postoperative pain after renal surgery. In this study, a bolus dose of ketamine 10 mg, followed by an infusion of ketamine 10 mg/h for 48 hours after operation, was administered IV. The authors concluded that ketamine did not reduce postoperative pain and that larger doses of ketamine would provide increased analgesia. Ketamine produces dose-related analgesia (26). Fu et al. (27) showed that 0.5 mg/kg of ketamine had a preemptive analgesic effect in patients undergoing abdominal procedures. Thus, we administered a larger bolus dose of ketamine (0.5 mg/kg) than that of Ilkjaer et al. (9). It was also demonstrated that IV ketamine administered continuously at 0.5 mg · kg−1 · h−1 until skin closure did not prolong recovery times and did not cause significant side effects in the postoperative period (19).
There has been a challenge concerning the effect of ketamine on VAS pain scores. Menigaux et al. (18) demonstrated that ketamine had no beneficial effect on pain scores at rest but that it significantly relieved pain on movement. Choe et al. (28) reported similar results after abdominal surgery. Adriaenssens et al. (14) found that ketamine did not affect pain scores but reduced morphine consumption. In our study, although analgesic consumption was significantly larger in group C, ketamine produced more pain relief at rest and during coughing.
We observed that the analgesic effect of ketamine, evaluated with both VAS and morphine consumption, extended to the second postoperative day. This time is beyond the pharmacological actions of ketamine. However, similar results have been reported in different studies. Stubhaug et al. (29) infused ketamine for three days after nephrectomy. They found that ketamine reduced the area of punctuate mechanical hyperalgesia surrounding the surgical incision for the seven postoperative days. With preemptive administration of ketamine, a decrease in postoperative morphine consumption was observed for two postoperative days after abdominal surgery (27). Tverskoy et al. (30) reported a decrease in wound hyperalgesia for 48 hours after ketamine anesthesia. We believe that this long-lasting postoperative analgesia might be explained with a preemptive analgesic effect of ketamine, but further investigation is necessary to clarify the underlying mechanism of this persistent analgesic effect of ketamine.
Because morphine consumption was smaller in group K, the incidence of morphine-associated side effects, such as pruritus and nausea, was also decreased. We did not observe any psychomimetic effects related to ketamine. Large doses and rapid administration predispose to this side effect (26). Furthermore, we used benzodiazepines in premedication and anesthesia induction, because they are useful in reducing reactions to ketamine (31). No serious adverse effects, such as respiratory depression, deep sedation, motor block, dysphoria, or hallucinations, were noted in our study.
In conclusion, effective postoperative analgesia was achieved by the combination of intraoperative ketamine and PCEA with morphine plus bupivacaine. Analgesic consumption and incidences of morphine-related side effects were reduced by IV ketamine.
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