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PEDIATRIC ANESTHESIOLOGY

Intraoperative Low-Dose Ketamine Does Not Prevent a Remifentanil-Induced Increase in Morphine Requirement After Pediatric Scoliosis Surgery

From the *Department of Anesthesia, and the Division of Orthopedic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Address correspondence and reprint requests to Dr. Crawford, Department of Anesthesia, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8. Address e-mail to mark.crawford{at}sickkids.ca.

Abstract

BACKGROUND: Remifentanil-based anesthesia is commonly used to facilitate neurophysiologic monitoring during pediatric scoliosis surgery. Acute opioid tolerance and/or hyperalgesia resulting from remifentanil-based anesthesia may involve activation of N-methyl-d-aspartate systems. We hypothesized that low-dose intraoperative infusion of the N-methyl-d-aspartate antagonist ketamine would suppress the development of tolerance and thereby decrease postoperative morphine consumption in children receiving remifentanil-based anesthesia for scoliosis surgery.

METHODS: Thirty-four adolescents aged 12–18 yr scheduled for scoliosis surgery were randomly assigned to receive intraoperative low-dose ketamine (bolus dose of 0.5 mg/kg followed by continuous infusion of 4 µg · kg^–1 · min^–1) or an equal volume of saline during propofol/remifentanil anesthesia. Cumulative morphine consumption was assessed using a patient-controlled analgesia device for 72 h after surgery. Postoperative morphine consumption, pain scores at rest and during cough, and sedation scores were recorded by a blinded investigator every hour for the first 4 h, every 4 hours for 20 h, and then every 12 hours for 72 h.

RESULTS: Cumulative morphine consumption at 24, 48, and 72 h after surgery did not differ significantly between groups (ketamine group: 1.57 ± 0.56, 3.05 ± 1.14, and 4.46 ± 1.53 mg/kg; saline group: 1.60 ± 0.53, 2.87 ± 1.05, and 4.11 ± 1.71 mg/kg, respectively). No differences in pain or sedation scores were found. The duration of anesthesia was similar in the two groups.

CONCLUSIONS: These data do not support the use of intraoperative low-dose ketamine to prevent the development of remifentanil-induced acute opioid tolerance and/or hyperalgesia during pediatric scoliosis surgery.

Anesthetic challenges presented by scoliosis surgery include the need to provide profound intraoperative analgesia and to facilitate intraoperative neurophysiologic monitoring of the spinal cord and/or wake-up testing.1 Inhaled anesthetics have profound dose-related effects on the monitored neurophysiologic evoked potentials, causing a reduction in amplitude and an increase in latency.2,3 Remifentanil-based anesthesia is commonly used to avoid these effects during pediatric scoliosis surgery. We described the development of acute opioid tolerance and/or hyperalgesia manifesting as an increase in postoperative morphine requirement after remifentanil-based anesthesia in adolescents undergoing surgical correction of idiopathic scoliosis.4 The underlying mechanisms remain unclear but may involve activation of N-methyl-d-aspartate (NMDA) systems.5 We hypothesized that low-dose intraoperative infusion of the NMDA receptor antagonist ketamine would prevent the development of acute opioid tolerance and thereby decrease postoperative morphine consumption and improve pain scores after surgical correction of idiopathic scoliosis. We tested this hypothesis in a prospective, randomized, placebo-controlled, double-blind trial.

METHODS

With Research Ethics Board and Health Canada approval, 34 unpremedicated ASA physical status I or II adolescents, aged 12–18 yrs, scheduled to undergo posterior instrumentation for correction of idiopathic scoliosis were studied. Written consent was obtained from parents or guardians and assent from each patient. Exclusion criteria included opioid use within 3 months before surgery, inability to self-administer morphine using a patient-controlled analgesia (PCA) device, elective postoperative ventilation, and obesity (>130% of ideal body weight).

Patients were assigned randomly, using a table of random numbers, to receive ketamine as a bolus dose of 0.5 mg/kg followed by a continuous infusion of 4 µg · kg^–1 · min^–1 or a bolus and infusion of an equal volume of placebo (saline). Group assignments were kept in sealed, opaque, sequentially numbered envelopes. Anesthesia was induced with propofol 4 mg/kg and glycopyrrolate 10 µg/kg followed by rocuronium 0.6 mg/kg to facilitate tracheal intubation. Maintenance of anesthesia was with a mixture of 30% oxygen in air, continuous infusion of propofol at a rate of 100–150 µg · kg^–1 · min^–1, and continuous infusion of remifentanil starting at 0.3 µg · kg^–1 · min^–1 and subsequently adjusted according to hemodynamic response. Morphine 150 µg/kg was administered approximately 30 min before the end of surgery. Infusions were discontinued after surgery at the time of tracheal extubation in the operating room. After tracheal extubation, patients were transferred to the postanesthetic care unit where an anesthesiologist or nurse who was blinded to treatment group assessed pain control and administered 50 µg/kg morphine at 5-min intervals until the patient appeared to be comfortable, defined as the absence of any verbal or behavioral expression of pain. Thereafter, PCA was initiated using an IV syringe pump (Graseby 3300, Herts, UK) containing 1 mg/mL morphine. The pump settings were a bolus dose of 20 µg/kg, 6 min lockout interval, and a background infusion of 10 µg · kg^–1 · h^–1.

An anesthesiologist or nurse who was blinded to group assignment collected all postoperative outcome data. Cumulative postoperative morphine consumption, pain scores at rest and on coughing, and sedation scores were recorded every hour for the first 4 h, every 4 hours for 20 h, and then every 12 hours until completion of the study at 72 h. The initial 24-h morphine consumption was calculated as the sum of the morphine administered in the postanesthesia care unit and the PCA morphine self-administered in the first 24 h after surgery divided by the body weight (kg). A numeric rating scale (NRS) was used to assess postoperative pain intensity (0 = no pain; 10 = worst possible pain). Sedation was rated on a numeric scale of 1–5, defined as follows: (1) completely awake; (2) awake but drowsy; (3) asleep but responsive to verbal commands; (4) asleep but responsive to tactile stimuli; (5) asleep but not responsive to any stimulus. Postoperative nausea, vomiting, pruritus, pyrexia, and expressions of unpleasant dreams were recorded. Ondansetron 0.1 mg/kg was given IV for nausea, diphenhydramine 0.5 mg/kg IV for pruritus as needed, and acetaminophen 20 mg/kg orally 6 hourly for 72 h.

Data are expressed as mean ± sd or median and range, as appropriate. The primary outcome was postoperative morphine consumption. The sample size estimation was based on our previous study,4 in which the initial 24-h postoperative morphine consumption after remifentanil-based anesthesia was 1.65 ± 0.41 mg/kg. To demonstrate a 25% difference in initial 24-h morphine requirement, we estimated that 34 patients would be required for a two-tailed = 0.05 and β = 0.1 (power = 90%). Two-way repeated measures analysis of variance was used for comparison of postoperative morphine consumption. The Friedman and Mann-Whitney rank-sum statistics were used for comparison of NRS pain scores and sedation scores. Fisher’s exact test was used to compare nominal data. All comparison tests were two-tailed and P < 0.05 was considered statistically significant.

RESULTS

The study groups were similar with respect to patient characteristics, surgical factors, duration of anesthesia, and doses of propofol and remifentanil (Table 1). Cumulative morphine consumption in the initial 36 h after surgery was almost identical in the two groups (Fig. 1). Mean cumulative PCA morphine consumption at 24, 48, and 72 h after surgery did not differ significantly between groups (ketamine group: 1.57 ± 0.56, 3.05 ± 1.14, 4.46 ± 1.53 mg/kg; saline group: 1.60 ± 0.53, 2.87 ± 1.05, 4.11 ± 1.71 mg/kg, respectively) (Fig. 1). No significant differences between groups were found in NRS pain scores, either at rest or during cough (Figs. 2 and 3). Differences in sedation scores (Fig. 4) and the incidences of nausea and vomiting (37% vs 44% in the ketamine and saline group, respectively) and pruritus (75% vs 55% in the ketamine and saline group, respectively) were not statistically significant. There were no cardiovascular, cognitive, or other neurological complications associated with ketamine administration.

View larger version (15K): [in this window] [in a new window]   Figure 1. Cumulative morphine consumption in the initial 72 h after surgery. Morphine consumption in the initial 36 h after surgery was almost identical in the two groups. No statistically significant difference was found between groups at any time point. Values are mean ± sd.

View larger version (30K): [in this window] [in a new window]   Figure 2. Box and whisker plot showing numeric rating scale (NRS) pain scores at rest. No statistically significant difference was found between groups. Values are median, interquartile range, and range.

View larger version (24K): [in this window] [in a new window]   Figure 4. Box and whisker plot showing sedation scores in the initial 72 h after surgery. No statistically significant difference was found between groups. Values are median, interquartile range, and range.

View larger version (31K): [in this window] [in a new window]   Figure 3. Box and whisker plot showing numeric rating scale (NRS) pain scores during cough. No statistically significant difference was found between groups. Values are median, interquartile range, and range.

DISCUSSION

Remifentanil-based anesthesia is associated with the development of clinically relevant acute opioid tolerance and/or hyperalgesia in humans, as evidenced by a reduced therapeutic benefit from a given dose of opioid.4,6,7 Experimental studies indicate that acute opioid tolerance develops more rapidly with IV infusion of potent opioids, such as remifentanil and alfentanil, than with intermittent boluses of morphine.8,9 The exact mechanism underlying the development of acute opioid tolerance is unknown, but may involve activation of dorsal horn NMDA systems,5,10 inactivation of µ-opioid receptors,11 spinal dynorphin release,12 and upregulation of the cyclic adenosine monophosphate pathway.13,14 The present study tested the hypothesis that low-dose intraoperative infusion of the NMDA receptor antagonist ketamine would prevent the development of remifentanil-induced opioid tolerance15,16 in children undergoing surgical repair of idiopathic scoliosis. Inasmuch as ketamine, at the dose administered intraoperatively, did not reduce postoperative morphine requirement or <NRS pain scores, the results of the present study do not support this hypothesis.

The NMDA receptor is involved in the modulation of windup, allodynia, and acute opioid tolerance.15–19 In animal studies, blockade of the NMDA receptor by ketamine administration suppressed the development of opioid-induced acute tolerance and injury-induced central sensitization even at subanalgesic doses.15–17 It has been suggested that part of ketamine’s effect may be due to opioid receptor angonism20,21; however, opioid receptor blockade did not inhibit ketamine-induced reductions in experimental secondary hyperalgesia in humans.22 In clinical studies, ketamine has been shown to be beneficial in the management of acute postoperative pain after a variety of surgical procedures.23–25 The results showed that pain scores and analgesic consumption were reduced beyond the clinical duration of action of ketamine. Two studies investigated the use of low-dose ketamine infusion in adults receiving remifentanil-based anesthesia for abdominal surgery.26,27 In the first, intraoperative infusion of ketamine 2 µg · kg^–1 · min^–1 decreased initial 24-h morphine consumption and pain scores and delayed time to first analgesic request without producing cognitive or other side effects when compared with placebo.26 A follow-up study by this group investigated the effect of ketamine (intraoperative infusion of 5 µg · kg^–1 · min^–1 followed by 2 µg · kg^–1 · min^–1 for 48 h after surgery) on hyperalgesia and allodynia produced by large-dose remifentanil infusion. The investigators found that ketamine reduced morphine requirement to control values observed with low-dose remifentanil.27

Ketamine and other NMDA antagonists have been studied in a variety of clinical scenarios using a variety of routes and dosage regimens.28,29 The dose of ketamine used in the present study is supported by studies showing that ketamine produces effective analgesia when administered as a single bolus of >0.3 mg/kg, but has no effect on analgesia or morphine consumption when administered at infusion rates <4 µg · kg^–1 · min^–1.30 Generally, ketamine-related side effects occur with the larger doses required for general anesthesia and include cognitive reactions such as hallucinations, unpleasant dreams, and alterations in mood, perception, and body awareness. These occur with an incidence of 5%–30% after general anesthesia with ketamine.30,31 We observed no such side effects at the dose used in our study population. With respect to morphine-related side effects, such as nausea, vomiting, and pruritus, we observed no significant differences between groups; however, the study was not powered to show differences in these secondary outcomes.

Initial 24-h postoperative morphine consumption for each group in the present study is virtually identical to our previously published data for remifentanil-based anesthesia.4 Despite administration of prophylactic morphine before discontinuation of remifentanil infusion in these studies, initial 24-h morphine consumption after remifentanil-based anesthesia was 30% more than control, with or without concomitant low-dose ketamine. Pharmacokinetic differences in children32 may explain, in part, why our results with ketamine differ from those in adults26,27 and it remains open to speculation whether a larger dose of ketamine or an extension of the infusion into the postoperative period would have suppressed the development of remifentanil-induced hyperalgesia. It could be speculated that plasma markers of successful NMDA receptor blockade such as plasma cyclic guanosine monophosphate concentration may indicate sufficient suppression of the NMDA receptor system during remifentanil infusion33 and subsequently guide the dose of intra- and postoperative ketamine infusion required in future studies. Also, the potential role of propofol as a suppressant of NMDA receptor activity will need to be considered as a limiting factor for the use of intraoperative ketamine to prevent the development of remifentanil-induced hyperalgesia.34,35

In conclusion, this study does not support the use of low-dose intraoperative infusion of ketamine to prevent the development of acute opioid tolerance and/or hyperalgesia resulting from remifentanil-based anesthesia.

Footnotes

Accepted for publication May 23, 2008.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Engelhardt, T. Articles by Crawford, M. W. Search for Related Content PubMed PubMed Citation Articles by Engelhardt, T. Articles by Crawford, M. W. Related Collections Anesthetic Techniques Inflammation Clinical Pharmacology Pediatrics Pharmacology