Intraoperative Small-Dose Ketamine Enhances Analgesia After Outpatient Knee Arthroscopy

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1 Intraoperative Small-Dose Ketamine Enhances Analgesia After Outpatient Knee Arthroscopy Christophe Menigaux, MD*, Bruno Guignard, MD*, Dominique Fletcher, MD*, Daniel I. Sessler, MD, Xavier Dupont, MD*, and Marcel Chauvin, MD* *Department of Anesthesiology, Hôpital Ambroise Pare, Boulogne-Billancourt, France; and Outcomes Research Institute and Department of Anesthesiology, University of Louisville, Louisville, KY, and Ludwig Boltzmann Anesthesia Institute, University of Vienna, Vienna, Austria Ketamine may prevent postoperative hyperalgesia. In patients undergoing arthroscopic meniscectomy using general anesthesia, we tested whether a single intraoperative dose of ketamine enhanced postoperative analgesia and improved functional outcome compared with a typical multimodal analgesic regimen. After the induction of anesthesia, 50 patients were randomly assigned to ketamine (0.15 mg/kg IV just after the induction of anesthesia) or a vehicle placebo. Standardized general anesthesia included propofol, alfentanil, and nitrous oxide. Bupivacaine (0.5%) and morphine (5 mg) were given intraarticularly at the end of surgery. Postoperative analgesia was initially provided with morphine and subsequently with naproxen sodium (550 mg orally twice daily) and Di-Antalvic (400 mg acetaminophen and 30 mg dextropropoxyphene) as needed. Pain scores, analgesic requirements, side effects, and ability to walk were assessed in the ambulatory unit and at home for three postoperative days. Times to awakening and to discharge were similar in the two groups. However, the Ketamine group had significantly less postoperative pain at rest and during mobilization on Days 0, 1, and 2. Furthermore, they consumed significantly fewer Di-Antalvic tablets than the control group (13 [7 17] vs 27 [16 32], median [25% 75% interquartile range]). Patients given ketamine were also able to walk for longer periods of time on the first postoperative day. In conclusion, adding smalldose ketamine to a multimodal analgesic regimen improved postoperative analgesia and functional outcome after outpatient knee arthroscopy. (Anesth Analg 2001;93:606 12) Arthroscopic meniscal surgery is a common procedure that is well suited for outpatient surgery. Adequate pain control facilitates early ambulation, which in turn improves patients functional outcomes (1,2). Nonsteroidal antiinflammatory drugs (NSAIDs), alone or in combination with intraarticular bupivacaine and morphine, are often given for postoperative analgesia in these patients (1,2). However, recent studies suggest that ketamine may be a useful analgesic adjunct. Ketamine, which is an N-methyl-d-aspartate (NMDA) channel blocker (3), greatly alleviates provoked pain by preventing postoperative hyperalgesia (4,5). For example, we have shown previously that a Supported by NIH Grant GM 58273, the Joseph Drown Foundation, and the Commonwealth of Kentucky Research Challenge Trust Fund. None of the authors has a financial relation with any company related to this research. Accepted for publication May 11, Address correspondence and reprint requests to Marcel Chauvin, MD, Department of Anesthesiology, Hôpital Ambroise Pare, 9 Avenue Charles de Gaulle, Boulogne-Billancourt, 92100, France. Address to marcel.chauvin@apr.ap-hop-paris.fr. single intraoperative injection of 0.15 mg/kg ketamine decreases morphine use after arthroscopic anterior ligament repair and facilitates passive knee mobilization at 24 h (6). Better pain relief during movement accelerates functional recovery after orthopedic surgery, thus enabling patients to return to their normal activities more quickly. However, the potential benefit of intraoperative small-dose ketamine for analgesia and active mobilization remains unknown in the outpatient orthopedic setting. Furthermore, the postoperative duration of analgesia induced by intraoperative ketamine has yet to be evaluated. We therefore tested the hypothesis that a small intraoperative dose of ketamine improves postoperative analgesia and facilitates ambulation after arthroscopic meniscectomy and that the benefits last for several days. Methods With approval of the IRB at Hôpital Ambroise Pare and informed consent, we studied ASA physical status I or II outpatients. All were scheduled to undergo 2001 by the International Anesthesia Research Society 606 Anesth Analg 2001;93: /01

2 ANESTH ANALG AMBULATORY ANESTHESIA MENIGAUX ET AL ;93: KETAMINE AND POSTOPERATIVE ANALGESIA elective arthroscopic meniscal surgery and were between 18 and 60 yr old. Exclusion criteria included ASA physical status II, surgery performed under regional anesthesia, history of chronic pain, chronic use of analgesic medications, drug or alcohol abuse, psychiatric disorders, or contraindications to NSAIDs. Pain intensity on the first postoperative day was used to calculate the statistical power. Previous studies (2,7) indicated that the mean intensity of pain the day after arthroscopic meniscectomy on a visual analog scale (VAS) during walking is approximately 30 mm, with sds ranging from 5 to 15 mm. A sample size estimate indicated that 25 patients per group would give a power of 80% at an level of 0.05 for detecting a difference of at least 40% pain intensity during walking on Day 1. The study size was thus prospectively set to 50 patients, with 25 assigned to each treatment group. At the preanesthetic visit, patients were instructed about the use of a 100-mm VAS (0 no pain to 100 worst pain) and a five-point verbal rating scale (VRS) (0 no pain, 1 light pain, 2 moderate pain, 3 intense pain, 4 severe pain). They were also instructed in the use of the study questionnaires and were asked to record relevant information for 3 days. Patients were premedicated with 100 mg hydroxyzine orally, 1 2 h before surgery. Anesthesia was induced with propofol at an initial target concentration of 5 g/ml (i.e., 2 mg/kg), followed by 20 g/kg alfentanil. A laryngeal mask airway was then inserted. General anesthesia was maintained with a continuous infusion of propofol (target concentration 2 6 g/ml; i.e., g kg 1 min 1 ), titrated to maintain heart rate and mean arterial pressure within 20% of preoperative baseline, and 60% N 2 O in oxygen. All patients were mechanically ventilated. The arthroscopic meniscal surgery was performed with standard technique by the same surgeon. Twenty milliliters of 0.5% bupivacaine and 5 mg morphine were injected into the knee joint through the arthroscope at the completion of the procedure, shortly before tourniquet deflation. The propofol infusion was discontinued when the trocars were removed from the knee. Patients were assigned randomly, in a doubleblinded fashion, to one of two groups (25 per group): a Control group and a Ketamine group. Allocations were based on a computer-generated random-number table. Before starting the study, a 10-mL syringe containing either isotonic sodium chloride or 0.15 mg/kg ketamine diluted in isotonic sodium chloride solution was prepared by the hospital pharmacist. One of the solutions was injected IV just after anesthetic induction. Patients and personnel involved in patient management and data collection were unaware of the group assignment. After emerging from anesthesia, patients were transferred to the postanesthesia care unit (PACU) until they achieved a modified Aldrete score of 9 on two sequential measurements (8). They were then transferred to the ambulatory unit. They were discharged 6 h later if they met home-readiness criteria that included orientation to time and place, stable vital signs, absence of nausea, control of pain, and ability to void and ambulate. Analgesia in the PACU was provided by titrating morphine in increments of 3 mg every 5 min until the VAS pain score was 30 mm or the VRS score was 2. In the ambulatory unit, naproxen sodium, 550 mg orally, was given to all patients. Before discharge from the hospital, patients were instructed to take 550 mg naproxen sodium twice daily and two tablets Di- Antalvic (400 mg acetaminophen and 30 mg dextropropoxyphene; Aventis, Inc., Montrouge, France) every 6 h as needed for pain. Patients were told to resume their normal activities without restrictions as soon as possible. The total doses of propofol and alfentanil, durations of surgery and anesthesia, temperature at the end of surgery, and any intraoperative anesthetic or surgical complications were recorded. Recovery times were defined from the end of surgery. Emergence time to awakening (i.e., opening eyes on verbal command) was determined at 1-min intervals. The time to laryngeal mask airway removal, time from discontinuation of anesthesia until the transfer to the PACU, time from admission until discharge from the PACU, and time until patients met criteria for home readiness were noted. The home-readiness criteria were evaluated after PACU discharge at the same intervals as analgesia (specified below). Pain intensity was assessed by the patients with use of a VAS and a VRS. Pain scores were recorded at rest and with mobilization every 15 min for 1 h, then at 2, 4, and 6 h after the completion of surgery. Sedation scores and side effects were similarly recorded. Sedation was measured on a numeric scale of 0 3 (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). We also specifically evaluated potential side effects, including respiratory depression (defined as a sedation score 1 and a respiratory rate 10 breaths/min), nausea, vomiting, pruritus, dysphoria (including hallucinations and dreams), and diplopia. The ability of the patients to sit, stand, and ambulate was tested as well. The mobilization assessment was stopped if the patient had a VAS score 30 mm, a VRS score 2, or a sedation score 2, or whenever hypotension (mean arterial pressure 60 mm Hg), bradycardia (heart rate 50 bpm), or any other side effect occurred.

3 608 AMBULATORY ANESTHESIA MENIGAUX ET AL. ANESTH ANALG KETAMINE AND POSTOPERATIVE ANALGESIA 2001;93: After discharge, patients were asked to complete postal questionnaires daily for the first three postoperative days; the operative day was considered Day 0. These questionnaires asked patients to record 1) pain during the night, at the first step, and overall in the day by using a VAS that consisted of a 100- mm-long horizontal line with the two end points labeled no pain and the worst imaginable pain (patients were required to mark the line at a point that corresponded to the level of pain intensity); 2) the number of painful events that occurred in the day: between 0 and 5, between 6 and 10, or more than 10; 3) the duration of walking during that day (whether they were unable to walk, walked for 1 h, walked between 1 and 3 h, or walked entirely normally); 4) the number of doses of Di-Antalvic and any concomitant medication used during the day; 5) side effects; 6) whether they had bad dreams; and 7) the global score of patient satisfaction with pain control. To do this, patients were asked to mark a line at the point on a VAS that corresponded to the overall level of satisfaction with the pain control they experienced that day. Pain management satisfaction was scored by the patients before hospital discharge and at the end of each day throughout the study. One of the investigators, also blinded to the group assignment, called each patient on the first and third postoperative days to remind them to complete the questionnaires and return them. Postoperative pain was considered the primary end point. The secondary end point variables were analgesic consumption and return of normal walking. Statistical analyses were performed with NCSS 6.0 (Statistical Solution, Cork, Ireland). Age, weight, length of surgery, total amount of intraoperative propofol and alfentanil, time interval from end of surgery to spontaneous ventilation and to laryngeal mask removal, time from arrival in the PACU, time in PACU, and time to home discharge were compared by using unpaired Student s t-tests. The VAS scores at rest and during movement were analyzed with two-way repeated-measures analysis of variance and post hoc comparisons at various points in time by using Bonferroni s type I error rate correction for multiple tests of significance. Cumulative doses of morphine in the PACU, total consumption of Di-Antalvic during the three postoperative days, sedation scores, and pain episodes at home were analyzed with the Mann- Whitney U-test. 2 tests were used to compare frequency of side effects, sex distribution, and walking ability. Results are presented as mean sd or median and 25th 75th percentile ranges; P 0.05 was considered statistically significant. Results Fifty patients, 25 per group, were enrolled in the study. None was excluded, and all patients returned the follow-up postal questionnaires. All patients were compliant with the naproxen sodium regimen treatment. The two groups were comparable with respect to demographic and morphometric characteristics, duration of surgery and anesthesia, and intraoperative doses of propofol and alfentanil. The times from the end of surgery until spontaneous ventilation, awakening, and laryngeal mask removal were also comparable in the two groups (Table 1). After laryngeal mask removal, all patients were transferred to the PACU within 5 min. The distribution of sedation scores during the first 30 min in the PACU did not differ significantly between the two groups. All patients obtained a modified Aldrete score of 9 in the PACU within 30 min and met homereadiness criteria within 120 min (Table 2). In the PACU, patients in both groups were able to stand and walk at similar rates. However, significantly more patients required morphine titration in the Control group (Table 2, P 0.05). The titration dose never exceeded one bolus of 3 mg of morphine. In the PACU, patient pain was localized at the tourniquet regions. The Ketamine group had lower VAS pain scores in the PACU and in the ambulatory unit, with statistically significant differences at each elapsed time (Fig. 1). Pain scores were significantly lower in the Ketamine than Control groups during the night, at the first step, and throughout the first 2 days (Fig. 2). Additionally, patients in the Ketamine group had significantly fewer pain episodes on the first postoperative day (Fig. 3) and were able to walk significantly longer (Fig. 4). The fraction of patients who returned to normal walking activity on the second postoperative day was larger in the Ketamine group compared with the Control group (Fig. 4, P 0.10). The cumulative number of selfadministered Di-Antalvic tablets was significantly less in the Ketamine patients than in the Control group throughout the study (Fig. 5, Table 2). Postoperative pain scores at home and total Di-Antalvic consumption were similar in the Control patients who did and did not require morphine in the PACU. Although VAS pain scores were lower in the Ketamine group, the scores for pain management satisfaction did not differ significantly in the two groups. Values were near 9 in both groups on each of the first three postoperative days. There were no reports of nausea, vomiting, dysphoria, hallucinations, diplopia, cognitive or memory impairments, or respiratory depression. Two patients in the Ketamine group and one in the Control group noted sleep difficulties on Days 1 and 2, but they denied bad dreams or any

4 ANESTH ANALG AMBULATORY ANESTHESIA MENIGAUX ET AL ;93: KETAMINE AND POSTOPERATIVE ANALGESIA Table 1. Patient Characteristics and Intraoperative Data Variable Ketamine Control Age (yr) Sex (M/F) 17/8 16/9 Weight (kg) Length of surgery (min) Length of anesthesia (min) Total propofol dose (mg) Time to spontaneous ventilation (min) Time to awakening (min) Time to laryngeal mask airway removal (min) Data are presented as mean sd, or number of patients. There were no statistically significant differences between the groups. Table 2. Postoperative Results Variable Ketamine Control Sedation scores (0/1/2) Time 0 1/24/0 0/24/1 Time 15 25/0/0 24/1/0 Time 30 25/0/0 25/0/0 Aldrete score of 9 Time Time Home-readiness Time Ambulation Time Time Morphine titration (n) 3 9* Total dose of Di-Antalvic (No. tablets) 13 (7 17) 27 (16 32)** Times are expressed in minutes and defined from the arrival in the postanesthetic care unit (Time 0). All rows report the number of patients in each category except for the last row (total cumulative dose of Di-Antalvic ), in which the median and 25% 75% interquartile range are given for the number of tablets consumed per patient. * P 0.05; ** P Figure 2. Visual analog scale (VAS) pain scores (0 100 mm) in the two groups during the night, at first step, and overall for the day during postoperative Days 1, 2, and 3. Control group, Ketamine group. Values are mean sd. Asterisks indicate statistically significant differences between the groups (*P 0.05, **P 0.01). other psychological sequelae that might be attributed to ketamine. Figure 1. Visual analog scale (VAS) pain scores (0 100 mm) in the two groups during the first 6-h period after arrival in the postanesthesia care unit. Control group; Ketamine group. Values are mean sd. Asterisks indicate statistically significant differences between the groups (*P 0.05, **P 0.01). Discussion Standard analgesia for outpatient arthroscopic meniscectomy is the administration of NSAIDs alone or in combination with local or narcotic analgesics. However, the addition of small-dose ketamine to the analgesic regimen has been effective in reducing the need for narcotic analgesics in other surgical procedures.

5 610 AMBULATORY ANESTHESIA MENIGAUX ET AL. ANESTH ANALG KETAMINE AND POSTOPERATIVE ANALGESIA 2001;93: Figure 3. Distribution of pain episodes per day during postoperative Days 1, 2, and 3 in the Control group (P) and in the Ketamine group (K). Open bars, 0 5 episodes; hatched bars, 6 10 episodes; solid bars, 10 episodes. Asterisk indicates statistically significant differences between the groups (*P 0.05). Figure 4. Distribution of walking activity per day during postoperative Days 1, 2, and 3 in the Control group (P) and in the Ketamine group (K). Open bars, normal walking; hatched bars, between 1 and 3 h; solid bars, 1 h. Asterisks indicate statistically significant differences between the groups (*P 0.05). For example, we reported previously that patients receiving intraoperative ketamine at a dose of 0.15 mg/kg required 50% less morphine during the initial two days after arthroscopic anterior cruciate ligament repair (6). Additionally, small-dose ketamine (75 or 100 g/kg, IV) given intraoperatively reduced postoperative morphine requirements by 35% 40% during phase 1 recovery in various elective outpatient surgeries, including hardware removal, inguinal hernia repair, and superficial surgery (9). However, these observations were limited to the duration of hospitalization. The late effects of ketamine were thus not evaluated in this previous outpatient study (9). This study extends previous results by showing that patients given a single small dose of intraoperative ketamine had less postoperative pain and that the benefit persisted over a full two-day postoperative period. Consequently, fewer patients in the Ketamine group required IV morphine in the PACU, and they required less Di-Antalvic. It is important to note that Figure 5. Cumulative Di-Antalvic consumption during the day of surgery (Day 0) and postoperative Days 1, 2, and 3 in the two groups. Open boxes Ketamine group; hatched boxes Control group. The box represents the 25th 75th percentiles; the dark line is the median; the extended bars represent the 10th 90th percentiles, and the circles represent values outside this range. Asterisks indicate statistically significant differences between the groups (P 0.01). enhanced postoperative analgesia improved walking activity on the first postoperative day. However, further studies will be required to determine whether improved analgesia provides economic benefits by allowing patients to return to work earlier. An analgesic effect of ketamine extending beyond the pharmacologic actions of the drug has also been noted in other studies (4,5,10). In all these, the analgesic benefit of ketamine was prolonged several days after its administration. In fact, an analgesic effect of ketamine was reported four days after its administration, with a reduction in the area of punctuate mechanical hyperalgesia surrounding the nephrectomy incision (4). In each of these studies (4,5,10), though, the main postoperative analgesic regimen was morphine by patient-controlled analgesia. In this study, we demonstrated that intraoperative small-dose ketamine is also an important adjunct to NSAIDs, paracetamol, and a weak opioid. Ketamine also reduces secondary hyperalgesia in humans after peripheral burns (11). The ability of ketamine to alleviate allodynia for mechanical stimuli in an area surrounding the injury is consistent with its ability to prevent the development of central sensitization in response to peripheral noxious stimulation (3). It seems likely that this action explains the longlasting analgesic effect after a single dose or a shortterm infusion of ketamine. Together, these findings suggest that ketamine prevents development of hyperalgesia, thereby significantly reducing postoperative pain and the need for analgesics (12). Ketamine is a noncompetitive antagonist of NMDA ion-channel receptors that does not interact with opioid receptors (3). As do other NMDA antagonists, ketamine reduces the temporal summation of pain that underlies the induction of central sensitization (13). Nonetheless, some clinical studies failed to demonstrate any improvement of postoperative analgesia with ketamine (14 16), whereas we demonstrated substantial benefit. The critical distinction is that the

6 ANESTH ANALG AMBULATORY ANESTHESIA MENIGAUX ET AL ;93: KETAMINE AND POSTOPERATIVE ANALGESIA negative studies were preformed mainly in visceral surgery via large incisions. Recently, an NMDA receptor antagonist was found not to affect hyperalgesia to von Frey hair stimulation around the surgical wound (17). These findings are supported by animal studies showing that NMDA receptor antagonists produce minimal effects on mechanical hyperalgesia in the rat model of incisional pain (18). In contrast, animal studies demonstrate a significant contribution of NMDA receptors to the inflammation-induced hyperexcitability in an acute model of arthritis (19,20); this suggests that NMDA processes are more involved in dynamic than in static mechanical hyperalgesia. Our study is among the few that have evaluated the analgesic effect of ketamine in orthopedic surgery (6,21). The long-term effect of the single intraoperative dose of ketamine in this study may be explained by prevention of the development of neuronal hyperexcitability (19,20). An alternative hypothesis is potentiation among NSAIDs and NMDA antagonists. Support for this theory is provided by rat models of adjuvant-induced arthritis (22); synergy apparently results because the two classes of drugs act predominantly at different sites. The primary pharmacologic action of NSAIDs on inflammation is peripheral, whereas NMDA antagonists prevent or reverse central sensitization that results from release of excitatory amino acids and activation of NMDA receptors. The third possible mechanism is a central interaction between the effects of naproxen and ketamine (23). NMDA receptor activation by excitatory amino acids results in increased intracellular Ca 2, which triggers a cascade of events that includes stimulation of cyclooxygenase (3,24) and subsequent central prostaglandin production. It is established that this mechanism contributes to hyperalgesia (23). Few clinical studies have evaluated the benefit of adding NMDA antagonists to NSAIDs (12). For example, no additive or synergistic analgesic effects were found between dextromethorphan and ibuprofen in patients scheduled for surgical termination of pregnancy (25). Finally, instead of or in addition to its interaction with NSAIDs, ketamine may increase the effectiveness of dextropropoxyphene (a component of Di-Antalvic ) via a synergistic interaction between opioids and NMDA antagonists (12). Emergence from anesthesia was not prolonged after intraoperative ketamine. Recovery times and sedation scores in the PACU were also comparable in the two groups. Only one previous study with intraoperative small-dose ketamine has been performed in outpatient surgery (9). Three doses of ketamine (50, 75, and 100 g/kg) were compared with a placebo. There were no differences between the groups in the Observer s Assessment of Alertness/ Sedation scores or drowsiness VAS scores at any postoperative time. As in this study, the treated group and the Control group had similar times to eligibility for PACU and hospital discharges. Ketamine in sufficient doses impairs cognitive function and alters mood states and sensory perception (12). Our results were nonetheless similar to others showing that intraoperative small-dose ketamine does not cause dysphoric, psychotomimetic symptoms or nightmares (5,6,9,10,12,14). In summary, our study demonstrated that adding intraoperative small-dose ketamine (0.15 mg/kg, IV) to a multimodal regimen combining intraarticular bupivacaine and morphine, NSAIDs, and Di-Antalvic improves postoperative analgesia and functional outcome after outpatient meniscectomy without increasing the incidence of adverse effects. 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