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ANESTHETIC PHARMACOLOGY

Supplementing Desflurane-Remifentanil Anesthesia with Small-Dose Ketamine Reduces Perioperative Opioid Analgesic Requirements

Bruno Guignard, MD^*, Carole Coste, MD^*, Hélène Costes, MD^*, Daniel I. Sessler, MD, Claude Lebrault, MD^*, William Morris, MD^*, Guy Simonnet, MD, and Marcel Chauvin, MD^*

*Department of Anesthesiology, Hôpital Ambroise Pare, Assistance Publique Hôpitaux de Paris, France; Outcomes Research^TM Institute and Department of Anesthesiology, University of Louisville, Kentucky and Ludwig Boltzmann Anesthesia Institute, University of Vienna, Austria; and Institut National de la Santé et de la Recherche Médicale (INSERM) U 259, Bordeaux, France

Address correspondence and reprint requests to Marcel Chauvin, MD, Department of Anesthesiology, Hôpital Ambroise Pare, 9 Ave. Charles de Gaulle, Boulogne-Billancourt, 92100, France. Address e-mail to marcel.chauvin{at}apr.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Relative large-dose intraoperative remifentanil could lead to the need for more postoperative analgesics. Intraoperative N-methyl-D-aspartate receptor antagonists, such as ketamine, decrease postoperative opioid use. We therefore tested the hypothesis that intraoperative small-dose ketamine improves postoperative analgesia after major abdominal surgery with remifentanil-based anesthesia. Fifty patients undergoing abdominal surgery under remifentanil-based anesthesia were randomly assigned to intraoperative ketamine or saline (control) supplementation. The initial ketamine dose of 0.15 mg/kg was followed by 2 µg · kg^-1 · min^-1. In both groups, desflurane was kept constant at 0.5 minimum alveolar anesthetic concentration without N₂O, and a remifentanil infusion was titrated to autonomic responses. All patients were given 0.15 mg/kg of morphine 30 min before the end of surgery. Pain scores and morphine consumption were recorded for 24 postoperative h. Less of the remifentanil was required in the Ketamine than in the Control group (P < 0.01). Pain scores were significantly larger in the Control group during the first 15 postoperative min but were subsequently similar in the two groups. The Ketamine patients required postoperative morphine later (P < 0.01) and received less morphine during the first 24 postoperative h: 46 mg (interquartile range, 34–58 mg) versus 69 mg (interquartile range, 41–87 mg, P < 0.01). No psychotomimetic symptoms were noted in either group. In conclusion, supplementing remifentanil-based anesthesia with small-dose ketamine decreases intraoperative remifentanil use and postoperative morphine consumption without increasing the incidence of side effects. Thus, intraoperative small-dose ketamine may be a useful adjuvant to intraoperative remifentanil.

IMPLICATIONS: Supplementing remifentanil-based anesthesia with small-dose ketamine decreased intraoperative remifentanil use and postoperative morphine consumption. These data demonstrate that N-methyl-D-aspartate antagonists, such as ketamine, can be a useful adjuvant to intraoperative remifentanil.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Major surgeries with remifentanil-based anesthesia are associated with a frequent incidence of severe postoperative pain (1). Moreover, in a previous study, we found that patients given a relatively large intraoperative dose of remifentanil had more postoperative pain and consumed more morphine than those given intraoperative desflurane, suggesting that exposure to large doses of remifentanil causes acute opioid tolerance and hyperalgesia (2).

Positive interactions have been reported between opioids and N-methyl-D-aspartate (NMDA) receptor antagonists (3–6), such as ketamine (7). Animal studies, using C fiber-evoked responses of spinal dorsal horn neurons (3) or a C fiber reflex (4), demonstrated a potentiation between the effects of opioids and NMDA antagonists administered either intrathecally (3) or IV (4). Ketamine co-administered with epidural morphine potentiated morphine’s analgesic effect in patients undergoing major joint replacement (5), whereas the effects of ketamine and alfentanil are additive after a capsaicin administration in volunteers (6). Furthermore, NMDA antagonists attenuate the development of acute analgesic tolerance to opioids (8) and suppress the rebound hyperalgesia observed after opioid exposure (8,9).

Although ketamine in combination with opioids reduces opioid consumption and prolongs analgesia (10–17), the extent to which adding small-dose ketamine to a general anesthetic regimen based on ultra–short-acting opioids improves postoperative pain management has yet to be evaluated. We therefore tested the hypothesis that intraoperative small-dose ketamine improves postoperative analgesia after major abdominal surgery with remifentanil-based anesthesia.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
With approval of the Ethics Committee of the Hôpital Ambroise Paré, Boulogne-Billancourt, France, and informed consent, we studied adult patients who were scheduled for open colorectal surgery lasting at least 2 h. All were ASA physical status I–III.

Patients were excluded from the study when: (a) immediate extubation was not planned after surgery, (b) they had chronic inflammatory disease including inflammatory bowel disease, (c) they regularly took analgesics or had used opioids within 12 h of surgery, (d) they had a history of drug or alcohol abuse, psychiatric disorder, or obesity (>130% of ideal body weight), or (e) there were contraindications to the self-administration of opioids (i.e., unable to understand the patient controlled analgesia [PCA] device).

Postoperative morphine consumption was used to calculate the statistical power. In a previous study, we observed that the median morphine use for the initial 24 postoperative h after major abdominal surgery in patients given a remifentanil-based anesthesia was 59 mg, with an interquartile range of 43–71 mg (2). A sample size estimate indicated that 24 patients per group would give a power of 80% at a level of 0.05 for detecting a difference in morphine consumption of at least 30%. The study size was thus prospectively set to 50 patients.

The evening before surgery, patients were instructed on the use of a 10-cm-long visual analog scale (VAS) with 0 cm identifying no pain and 10 cm the worst imaginable pain. They were also instructed on the use of a four-point verbal rating scale (VRS) (0 = no pain, 1 = slight pain, 2 = moderate pain, and 3 = intense or severe pain). Finally, we explained the use of the PCA system. Patients were premedicated with lorazepam (1 mg orally) the night before surgery.

Anesthesia was induced with thiopental (6 mg/kg) followed by atracurium (0.5 mg/kg) to facilitate orotracheal intubation. Two minutes after the thiopental injection, a 1-µg/kg initial dose of remifentanil was given for 60 s. After tracheal intubation, the patients were ventilated to normocapnia in 50% oxygen without nitrous oxide. Anesthesia was maintained with desflurane at an end-tidal concentration of 0.5 minimum alveolar anesthetic concentration adjusted for age (18).

Remifentanil was infused throughout surgery in all patients; the infusion was started at 0.25 µg · kg^-1 · min^-1 and subsequently increased stepwise by 0.05-µg · kg^-1 · min^-1 increments if insufficient anesthesia was suspected. Insufficient anesthesia was defined as a heart rate that exceeded preinduction values by 15% or a systolic arterial blood pressure that exceeded baseline values by 20% for at least 1 min.

Hypotension, defined by a systolic arterial blood pressure <80 mm Hg or a mean arterial blood pressure <60 mm Hg, was treated by stepwise reductions in the remifentanil infusion. Additional IV fluids were also given as deemed appropriate by the responsible anesthesiologist. Similarly, atropine or intermittent boluses of ephedrine were given as required to treat bradycardia or persistent hypotension. The atracurium infusion was titrated to maintain one twitch in response to a supramaximal train-of-four stimulus at the orbicularis oculi; atracurium was discontinued 15 min before the end of surgery.

Patients were randomly assigned, in a double-blinded fashion via a computer-generated random-number table, to a Control group or a Ketamine group (n = 25 per group). The hospital pharmacist supplied a 50-mL syringe containing the study drug, which was either isotonic sodium chloride or ketamine diluted to 2.5 mg/mL in isotonic sodium chloride. A continuous IV infusion of the study drug was started 1 min after the thiopental injection. Patients and personnel involved in patient management and data collection were unaware of the group assignment.

The dosing scheme for the ketamine infusion was calculated using published pharmacokinetic variables (19) to achieve a theoretical plasma concentration of 60 ng/mL, which is in the small range of concentrations known to counteract hyperalgesia while producing minimal side effects (20). The initial loading bolus was 0.15 mg/kg and was followed by a maintenance infusion of 2 µg · kg^-1 · min^-1 until skin closure. Patients in the Control group were given equal volumes of saline.

Thirty minutes before the anticipated end of surgery, a 0.15-mg/kg bolus of morphine was given IV. At skin closure, desflurane, remifentanil, and ketamine were discontinued, and residual neuromuscular blockade was antagonized with 40–60 µg/kg IV of neostigmine and 15–20 µg/kg IV of atropine.

After tracheal extubation, patients were transferred to the postanesthetic care unit (PACU). They remained in the unit for at least 4 h and were given oxygen via a face mask at a rate of 3 L/min throughout this period. Postoperative pain was initially treated with morphine chlorohydrate, which was titrated as required by nurses.

During the initial postoperative period, 3 mg of morphine was given IV at 5-min intervals until the behavioral pain score (defined later) was <1 or the VRS was <2. However, morphine administration was discontinued in patients having a sedation score (defined later) of 3 or a respiratory rate of <12 breaths/min. Subsequently, within 4 h after tracheal extubation, patients were connected to a PCA device set to deliver 1 mg of morphine as an IV bolus with a 5-min lockout interval and no background infusion or limits. This PCA regimen was continued for 24 h after tracheal extubation.

The total dose of remifentanil given in the operating room was recorded. Three anesthetic periods were defined: (a) from the induction to the beginning of surgery (Early Period), (b) from incision to the end of colectomy (Middle Period), and (c) from the beginning of closure to the end of surgery (Late Period). Pain was evaluated for the first 15 min after extubation with a behavioral score (0 = calm patient with no verbal or behavioral manifestation of pain, 1 = behavioral or verbal expression of pain, and 2 = intense behavioral or verbal manifestation [crying or extreme agitation]). This behavioral pain scale was performed 5, 10, and 15 min after tracheal extubation.

Pain intensity was assessed by patients giving both VAS and VRS scores at 15-min intervals during the first hour and then hourly for 3 h. Subsequently, pain was evaluated only with the VAS at 4-hour intervals for an additional 20 h. The time from discontinuation of intraoperative remifentanil until the first request for morphine was recorded, as was the amount of morphine consumed for 24 h after tracheal extubation.

Anesthetic-related complications were recorded, including nausea, vomiting, pruritus, dysphoria, hallucinations, or diplopia. Nausea and vomiting were treated by IV boluses of 0.5 mg of droperidol. Sedation was monitored using the following four-point rating scale: 0 = patient fully awake, 1 = patient somnolent and responsive to verbal commands, 2 = patient somnolent and responsive to tactile stimulation, and 3 = patient asleep and responsive to painful stimulation. Postoperative respiratory depression was defined by the combination of a sedation score >1 and a respiratory rate <10 breaths/min.

Postoperative morphine consumption was considered the primary end point. The secondary end-point variables were postoperative pain and remifentanil dose given in the operating room.

Statistical analyses were performed with Statview (version 5.0, SAS Institute Inc, Cary, NC). Age, weight, height, time intervals, temperature at end of study, and cumulative postoperative morphine consumption at 24 h were compared with unpaired Student’s t-tests. The relative frequencies of sex, ASA status, and nausea and vomiting were compared with Fisher’s exact test. Hemodynamic variables and VAS scores for 24 h were analyzed with two-way analysis of variance for repeated measures. The remifentanil infusion rates were analyzed by repeated-measures analysis of variance. Sedation, behavioral and verbal response scores for pain, as well as ephedrine, droperidol, and IV morphine doses were compared with the Mann-Whitney U-test. Fisher’s protected least significant difference tests were used for between-group, post hoc comparisons. Results are presented as mean ± SD or medians and interquartile ranges; P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Fifty patients, 25 per group, were enrolled in this study. None were excluded, and all patients were tracheally extubated immediately after surgery. Morphometric and demographic characteristics, duration of surgery and anesthesia, duration of the three defined anesthetic periods, and types of surgical procedures were comparable in the two groups (Table 1). The Ketamine group received a total ketamine dose of 0.6 ± 0.2 mg/kg.

View larger version (18K): [in this window] [in a new window]   Figure 1. Intraoperative remifentanil infusion rate (mean ± 95% confidence interval) from the induction to the beginning of surgery (Early Period), from incision to the end of colectomy (Middle Period), and from the beginning of closure to the end of surgery (Late Period). Filled squares = Control group and open circles = Ketamine group. *P < 0.01 versus the Ketamine group; #P < 0.01 versus Early Period; P < 0.01 versus Middle Period.

More patients in the Ketamine group were calm with no verbal or behavioral manifestation of pain at 5, 10, and 15 min after extubation (P < 0.05, Fig. 2). Subsequently, VAS and VRS (data not shown) pain scores did not differ significantly between the two groups.

View larger version (21K): [in this window] [in a new window]   Figure 2. Time course of the distribution of the behavioral pain scores during the first 15 min after tracheal extubation in the Ketamine (upper) and Control (lower) groups. Solid bars = calm, gray bars = behavioral or verbal expression of pain, and open bars = intense behavioral or verbal manifestation of pain. Asterisks (*) indicate statistically significant differences between the groups (P < 0.05).

View larger version (16K): [in this window] [in a new window]   Figure 3. Cumulative postoperative morphine consumption in the two groups for 24 h after tracheal intubation. Values are mean ± 95% confidence interval. Filled squares = Control group and open circles = Ketamine group. Area under the curve differed significantly in the two groups (P < 0.05).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The pharmacokinetic and pharmacodynamic profile of remifentanil favors the control of intraoperative stress responses with the benefits of predictable and rapid offset. However, it is associated with severe postoperative pain despite the prophylactic use of morphine (2,21). In a previous study, we compared two doses of morphine administered during surgery for analgesia after remifentanil-based anesthesia (21). The larger dose did not preclude immediate postoperative pain and additional morphine administration in the PACU. Additionally, it exposed the patients to the risk of severe respiratory depression, suggesting that morphine, as the sole drug to control severe postoperative pain after remifentanil-based anesthesia, is not adequate. By contrast, a balanced analgesia using a synergic analgesic combination seems more appropriate. We found that patients who received small-dose ketamine during abdominal surgery had significant reductions in both intraoperative remifentanil and postoperative morphine requirements. The clinical implication of our results is that adding intraoperative small-dose ketamine to a remifentanil-based anesthetic regimen allows implementation of analgesia-based anesthesia without compromising recovery.

The administration of small-dose ketamine during surgery reduces the need for postoperative opioids in various surgical procedures (10–17,22). In most of these, the opioid-sparing effect persisted far longer than the pharmacological actions of ketamine. Further support for this assertion in the present study was provided by the decrease in morphine consumption from four to 24 postoperative hours in the Ketamine group and the progressive and divergent increase in the cumulative morphine dose between the two groups. It seems likely that this long-lasting effect is explained by the preventive action of ketamine on the development of central sensitization induced by tissue injury, such as surgical lesions (12,23).

An alternative explanation is based on the ability of ketamine to decrease intraoperative remifentanil use and, subsequently, to prevent acute tolerance to the analgesic effect of opioids because animal experiments suggest that opioid-induced tolerance and injury-induced central sensitization share the same underlying mechanisms (24). Consistent with this theory, a dose-related induction of acute opioid tolerance (25) and opioid-induced hyperalgesia (9) was demonstrated in animals. We demonstrated that intraoperative large-dose remifentanil increases postoperative pain and morphine consumption (2), and similar doses of remifentanil were used in the Control group in the present study. These doses may cause the development of acute tolerance to remifentanil. Moreover, although the nociceptive input could not be measured, the similar amounts of remifentanil in the Control group during the Middle and Late Periods, despite a presumed substantial reduction in nociceptive stimulation, indirectly support this hypothesis. In marked contrast, remifentanil requirements during the Late Period (skin closure) were significantly less than during the Middle Period in the Ketamine group. One possible explanation for these findings is that ketamine inhibited the development of acute opioid tolerance, as was shown in animal studies (8,9). Moreover, animal studies suggest that the potentiation of opioid analgesia by NMDA receptor antagonists is caused by prevention of opioid tolerance (8,9).

The small dose of ketamine used in our study did not delay awakening or tracheal extubation. However, patients in the Ketamine group did have a prolonged time to the first morphine administration and had lower pain scores after tracheal extubation. Sedation scores were slightly greater in the Ketamine-treated group for the first 15 postoperative minutes; this may have contributed to the delay in first requesting morphine in this group. However, side effects were minimal in both groups; no dysphoric, psychotomimetic symptoms, or nightmares were noted in either group.

In summary, small-dose ketamine seems to be a useful adjunct to remifentanil-based general anesthesia. It decreases both the remifentanil infusion rate during surgery and postoperative morphine consumption without increasing the incidence of side effects. One possible explanation of this observation is that acute opioid tolerance was induced by remifentanil in the Control group but was prevented by ketamine in the Treatment group.

	Acknowledgments

 
Supported, in part, by NIH Grant GM 58273 (Bethesda, MD), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999