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Departments of Anesthesia and INSERM E 332, Hôpital Ambroise Pare, Assistance Publique-Hôpitaux de Paris, 92100 Boulogne, France; Hôpital Raymond Poincaré, Assistance Publique Hôpitaux de Paris, 92428 Garches, France; and the Outcomes ResearchTM Institute and Departments of Anesthesiology and Pharmacology, University of Louisville, Louisville, Kentucky
Address correspondence and reprint requests to Marcel Chauvin, MD, Publique-Hôpitaux de Paris, 92100 Boulogne, France. Address e-mail to marcel.chauvin{at}apr.ap-hop-paris.fr.
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Abstract |
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Introduction |
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There is a growing body of evidence that ketamine, a noncompetitive antagonist at NMDA receptors (3), can facilitate postoperative pain management (4). Ketamine also alleviates provoked pain by preventing postoperative hyperalgesia (5). Furthermore, a single intraoperative injection of 0.15 mg/kg ketamine improves passive knee mobilization 24 hours after arthroscopic anterior ligament repair (6) and improves postoperative functional outcome after outpatient knee arthroscopy (7).
Total knee arthroplasty generates substantial postoperative pain. Peripheral nerve blocks produce better analgesia than patient-controlled IV opioids, thereby accelerating rehabilitation (8,9). However, continuous isolated femoral nerve blocks provide insufficient analgesia; patients given continuous femoral nerve blocks alone thus usually require rescue treatment with opioids (10,11). Combining a continuous femoral nerve block with small-dose ketamine may be an alternative to concomitant opioid administration. The benefit of adjunctive small-dose ketamine in patients with peripheral nerve blocks has yet to be determined. We therefore tested the hypothesis that small-dose ketamine reduces postoperative pain and speeds rehabilitation after total knee arthroplasty in patients with a continuous femoral nerve block.
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Methods |
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Previous studies (8,9) and our own experience indicate that PCA morphine use over 48 h to be 67 ± 30 mg (mean ± sd) in patients having total knee arthroplasty and regional analgesia. Twenty patients per group thus provided an 80% power for detecting a 40% difference in morphine consumption at an 
level of 0.05. We thus made an a priori decision to evaluate 20 patients per group.
Patients were assigned randomly, in a double-blind fashion, to one of two groups (n = 20 per group): a control group and a ketamine group. Before the study began, a random-number table was generated, specifying the group to which each patient would be assigned on entry into the trial. For each patient, an opaque envelope containing the group assignment was prepared, sealed, and sequentially numbered. On the morning of surgery, a nurse not involved in the evaluation of the patient opened the envelope and prepared two syringes: one 5 mL syringe for the bolus dose and a 50 mL syringe for the continuous infusion containing either saline or 10 mg/mL of ketamine. Moreover, at the end of the study, the nurse confirmed that the treatment matched the randomization. None of the other investigators involved in patient management and data collection was aware of the group assignment. In case of emergency, the anesthesiologist in charge of the patient had ready access to the information about the drugs given.
All patients were premedicated with hydroxyzine 1–2 mg/kg orally 1–2 h before surgery. The patients were taken to a preoperative block room and vital signs were monitored. Midazolam (0.025 mg/kg IV) was given for sedation. A continuous femoral nerve block was performed using the landmarks suggested by Winnie et al. (12), and a catheter was advanced 10–15 cm into the nerve sheaf. Patients were given 0.3 mL/kg ropivacaine 0.75% through the catheter. Absence of sensory response to cold in the area of the femoral nerve confirmed that the catheter was properly positioned.
Anesthesia was subsequently induced with 3–5 mg/kg thiopental, 0.3 µg/kg sufentanil, and 0.5 mg/kg atracurium. The trachea was intubated and controlled ventilation began. Anesthesia was maintained with sufentanil infused at a rate of 0.15 µg · kg–1 · h–1, which was stopped when the surgeon cemented the knee prosthesis (i.e., approximately 30 min before skin closure) and sevoflurane (0.6%–1.5%) in a mixture of nitrous oxide (50%) with oxygen.
In patients assigned to the ketamine group, 0.05 mL/kg of the blinded test solution (i.e., ketamine 0.5 mg/kg) was given IV over 2 min just after the orotracheal intubation and before the skin incision. The initial bolus was followed by a maintenance IV infusion of 3 µg · kg–1 · min–1 of ketamine that was continued until the patient emerged from anesthesia. Subsequently, the infusion rate was reduced to 1.5 µg · kg–1 · min–1 and maintained for 48 h. Patients allocated to the control group were given identical volumes of saline.
After tracheal extubation, patients were transferred to the postanesthesia care unit (PACU). The continuous femoral nerve block was maintained by a continuous infusion of 0.1 mL · kg–1 · h–1 of 0.2% ropivacaine. Adequacy of the femoral nerve block was assessed daily by evaluating the sensory response to cold in the distribution of femoral nerve.
Pain was initially controlled in the PACU by titrating boluses of 3 mg morphine every 5 min until the visual analog rating scale (VAS) score was 
30 mm. Titration was stopped if the sedation score was >2 or the respiratory rate was <12 breaths per min. Additionally, patients were given access to a PCA device set to deliver 1-mg boluses of IV morphine with a lockout period of 5 min and no background infusion or limits. This PCA regimen was continued for 48 h; no other analgesics were given.
Immediately after surgery, all patients started identical physical therapy regimens. During the initial 48–72 h postoperatively, a continuous passive motion machine was used (Kinetec, Tournes, France), with a range of motion set at levels tolerated by the patient. From the day after surgery until hospital discharge, patients also performed assisted and active knee flexion and extension exercises against gravity.
After 48 h, PCA and continuous infusion of ketamine or saline solution were discontinued and the femoral catheter was removed. At this time, the analgesic regimen was standardized to 2 tablets of Di-antalvic (400 mg acetaminophen and 30 mg dextropropoxyphene; Aventis, Inc., Montrouge, France) every 6 h and naproxen sodium 550 mg twice daily. If the patient requested additional analgesia, subcutaneous morphine was given at 6-h intervals. Patients stayed at least 1 wk in the surgical ward and subsequently were admitted to a rehabilitation center.
On the evening before surgery, patients were instructed about the use of VAS (0–100 mm; 0 = no pain, 100 = worst imaginable pain) and the PCA system (Graseby 3300, Watford, UK). Pain was measured with VAS before and after mobilization. The maximal degree of active knee flexion tolerated by each patient was recorded every day until hospital discharge.
The time that elapsed between the end of surgery and the patient’s first request for analgesic medication was recorded. PCA morphine requirements, pain intensity, heart rate, arterial blood pressure, respiratory rate, and sedation score were recorded hourly for 4 h and then every 4 h for 48 h.
Potential side effects of ketamine and opioids were recorded, including nausea, vomiting, pruritus, dysphoria (including hallucinations and dreams), and diplopia. Nausea and vomiting were treated by IV bolus of droperidol 0.5 mg. Sedation was monitored using the following 4-point rating scale: 0 = patient fully awake, 1 = patient somnolent and responsive to verbal commands, 2 = patient somnolent and responsive to tactile stimulation, 3 = patient asleep and responsive to painful stimulation.
After 48 h, patients rated their global satisfaction on a 5-point verbal rating scale (0 = very dissatisfied, 1 = dissatisfied, 2 = neutral, 3 = satisfied, 4 = very satisfied). The number of postoperative days required to obtain 90° of active knee flexion, and the duration of hospital stay were recorded. Surgical follow-up occurred at 6 wk and 3 mo after the procedure, at which time the maximal amplitude of knee flexion was determined.
Morphometric and demographic characteristics of the patients, clinical variables, cumulative and hourly doses of morphine over 48 h, and amplitude of knee flexion in the ketamine and controls groups were compared with unpaired, two-tailed Student’s t-test. VAS pain intensity scores were analyzed by two-way repeated-measures analysis of variance and post hoc comparisons at various points in time by using Bonferroni type I error correction for multiple tests of significance. Because maximal amplitude of knee flexion and morphine consumption did not follow a normal distribution, the Mann-Whitney U-test were used to compare these two outcomes. The number of days required to obtain 90° of active knee flexion in each group was compared with a log-rank test. 
2 tests were used to compare the incidence of side effects and global satisfaction. Results are expressed as mean ± sd or median and 25th–75th percentile ranges; P < 0.05 was considered statistically significant.
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Results |
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There were no statistically significant differences between the two groups in the VAS score at rest and after mobilization either during the first 48 h or at any time thereafter until discharge. Pain was most intense at the first evaluation in the PACU and after mobilization (Fig. 1).
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The delay before the first request for analgesics in the PACU was similar in the groups (control group: 9 ± 7 min; ketamine group: 10 ± 7 min). Morphine requirements in the PACU were also similar in each group: 13 ± 7 mg in the control patients and 10 ± 7 mg in the ketamine patients (P = 0.26). However, cumulative morphine consumption over 48 postoperative hours was significantly more in the control patients than in those given ketamine (69 ± 30 mg versus 45 ± 20 mg; P < 0.02). Incremental morphine consumption during the first postoperative 48 h was also less in the ketamine than in the control patients (Fig. 2) (P < 0.01) with significant differences at 12–20 h and 28–36 h (P < 0.03). From 48 h until hospital discharge, supplemental morphine consumption was similar in the two groups (10.0 ± 10.3 mg and 10.5 ± 9.6 mg in the control and ketamine groups, respectively).
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Preoperative knee flexion was comparable in the two groups; active knee flexion was also similar after 6 weeks (control group: 102° ± 14°; ketamine group: 104° ± 14°) and 3 mo (control group: 106° ± 16°; ketamine group: 112° ± 11°). However, maximal active knee flexion was significantly greater in the ketamine than in the control group during the first 7 postoperative days (Fig. 3) (P < 0.02), with significant differences on days 6 and 7 (P < 0.02). The time required to reach 90° of active knee flexion was significantly shorter in the ketamine than in the control group (7 [5–11] versus 12 [8–45] days, median [25%–75% interquartile range]; P < 0.03) (Fig. 4).
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Nausea and vomiting requiring treatment occurred at similar rates in each group (3 and 2 patients in the control and ketamine groups, respectively). No patient in either group reported sedation, hallucinations, nightmares, or diplopia. Seventy percent of the patients in the control group and 75% in the ketamine group were satisfied or very satisfied with their surgeries. The duration of hospital stay was similar in each group, with the average for all patients being 11 ± 3 days.
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Discussion |
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There are three possible explanations for this beneficial effect of ketamine. The first is that there is an interaction between ketamine and the femoral block, peripherally. Peripheral ionotropic glutamate receptors, such as NMDA receptors, have been identified on peripheral nerve fibers (13), and their number may increase during inflammation (14). However, although a peripheral analgesic effect of ketamine has been suggested (15), evidence for such an effect remains controversial despite local administration (16). The importance of peripheral NMDA receptors could be evaluated with peripherally restricted antagonists, but none is currently available for human use.
A second possibility is an interaction between ketamine and morphine. In animals, the concomitant administration of ketamine and morphine results in a synergistic analgesic effect (17). These two classes of analgesics act at different targets (18). Furthermore, animal studies indicate that activation of NMDA receptors by opiates mediates tolerance to opioids (19) and that tolerance is thus attenuated by NMDA receptor antagonists, including ketamine (20). In our study, the reduction of morphine requirements in the ketamine group may thus have resulted from attenuation of acute tolerance to opioids.
A third explanation for the morphine-sparing effect of ketamine is that ketamine has a central antihyperalgesic effect. It is widely accepted that tissue injury often results in a prolonged sensitization of the central nociceptive system, which is at least in part mediated by activation of NMDA receptors (2). In rats, NMDA receptors are recruited by inflammation and NMDA receptor antagonists are more effective when the inflammatory reaction is intense (21). Total knee arthroplasty elicits a substantial inflammatory response during the first two or three postoperative days (22), possibly recruiting NMDA receptors. It is therefore likely that the beneficial effect of ketamine we observed results at least in part because the drug prevents development of neuronal hyperexcitability. These preventive effects of ketamine on central sensitization may explain the long-lasting postoperative analgesia, extending well beyond the administration period. These current data are consistent with previous reports (5–7,23). However, complementary investigations are necessary to clarify the underlying mechanisms of this prolonged analgesic effect of ketamine.
Nitrous oxide, used in the present anesthetic regimen, might have enhanced NMDA receptor inhibition by ketamine because nitrous oxide was also reported to exert NMDA antagonist properties (24). However, it is unlikely that nitrous oxide confounded our results, as it was also present in the control group.
The most important information obtained from our study is that continuous IV ketamine allowed an improvement in active knee flexion during the first week after surgery and a shorter recovery to 90° knee flexion. Our results are consistent with previous studies that indicate a beneficial effect of ketamine during mobilization after orthopedic surgery (6,7). Ketamine did not improve VAS scores; this is unsurprising and simply indicates that patients in both groups used PCA correctly to obtain adequate comparable analgesia. Similarly, the ketamine group did not have less pain on movement during physical therapy sessions. However, the maximal degree of active knee flexion tolerated by the patient was greater in the ketamine group, indicating that the drug was an effective adjunct.
Despite the shorter delay to obtain 90° of active knee flexion in the ketamine patients, the duration of hospital stay was comparable in the two groups The primary reason is that, in our system, discharge timing depends largely on rehabilitation center availability rather than surgical recovery per se. Similarly, no differences were observed between the two groups in active knee flexion at 6 weeks and 3 months. This simply indicates that, as expected, most patients had reached functional recuperation at 6 weeks (9). Moreover, as previously reported, benefits on early postoperative functional rehabilitation do not affect long-term outcome (8).
In summary, adding an IV infusion of small-dose ketamine to a continuous femoral block for 48 hours after surgery decreased morphine consumption by 35% and improved early rehabilitation with a similar incidence of adverse effects. However, there were no long-term improvements in the recovery of functional outcome.
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Footnotes |
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None of the authors has a personal financial interest in this research.
Accepted for publication July 27, 2004.
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  S. S. Reuben and A. Buvanendran Preventing the Development of Chronic Pain After Orthopaedic Surgery with Preventive Multimodal Analgesic Techniques J. Bone Joint Surg. Am., June 1, 2007; 89(6): 1343 - 1358. [Abstract] [Full Text] [PDF]
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 F. Adam, C. Menigaux, D. I. Sessler, and M. Chauvin A Single Preoperative Dose of Gabapentin (800 Milligrams) Does Not Augment Postoperative Analgesia in Patients Given Interscalene Brachial Plexus Blocks for Arthroscopic Shoulder Surgery Anesth. Analg., November 1, 2006; 103(5): 1278 - 1282. [Abstract] [Full Text] [PDF]
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 T. T. Horlocker, S. L. Kopp, M. W. Pagnano, and J. R. Hebl Analgesia for total hip and knee arthroplasty: a multimodal pathway featuring peripheral nerve block. J. Am. Acad. Ortho. Surg., March 1, 2006; 14(3): 126 - 135. [Abstract] [Full Text] [PDF]
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