Journal of Clinical Anesthesia (2015) xx, xxx–xxx
Original Contributions
Evaluation of the effect of ketamine on remifentanil-induced hyperalgesia: a double-blind, randomized study☆,☆☆,★ Plínio C. Leal MD ⁎, Reinaldo Salomão MD, PhD, Milena K.C. Brunialti PhD, Rioko K. Sakata MD, PhD Federal University of São Paulo, São Paulo, Brazil Received 29 September 2013; revised 16 November 2014; accepted 3 February 2015
Keywords: Hyperalgesia; Interleukins; Ketamine; Opioid-induced hyperalgesia; Remifentanil
Abstract Abstract study objective: Opioids are associated with hyperalgesia that can reduce their analgesic effect. The aim of this study was to determine whether the addition of ketamine reduces remifentanil-induced hyperalgesia; improves its analgesic effect; and alters interleukin 6 (IL-6), IL-8, and IL-10 levels. Design: This is a prospective, randomized, double-blind study. Setting: The setting is in a operating room and ward in a university hospital. Patients: There are 56 patients, aged ≥ 18 years, American Society of Anesthesiologists I or II, who underwent laparoscopic cholecystectomy. Interventions: Anesthesia was induced with remifentanil, 50% oxygen, and isoflurane. Patients randomized to group 1 received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients randomized to group 2 received remifentanil (0.4 μg/kg per minute) and saline solution. Postoperative analgesia was achieved using morphine via patient-controlled analgesia. Measurements: The measurements were postoperative pain intensity during 24 hours; morphine consumption; time to first morphine supplementation; hyperalgesia (using monofilaments and an algometer) and allodynia (using a soft brush) in the thenar eminence of the nondominant hand and in the periumbilical region 24 hours after surgery; extent of hyperalgesia using a 300-g monofilament near the periumbilical region 24 hours after surgery; and serum levels of IL-6, IL-8, and IL-10. Main results: Groups were similar for baseline characteristics. There were no differences in pain intensity, time to first request of morphine, and total 24 hours dose of morphine between groups. There was a difference in hyperalgesia using monofilaments 24 hours after the surgery in the thenar eminence of the nondominant hand, with a better profile for the experimental group. However, there were no differences in hyperalgesia using an algometer, in allodynia using a soft brush; in extent of hyperalgesia; or in levels of IL-6, IL-8, and IL-10. Conclusions: It was not possible to demonstrate that the addition of ketamine (5 μg/kg per minute) is effective in preventing or reducing remifentanil-induced postoperative hyperalgesia in laparoscopic cholecystectomy. © 2015 Elsevier Inc. All rights reserved.
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Funding received: grant 2009/53335-4, São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. ☆☆ Conflict of interest: none. ★ Authors' contributions: Plínio Cunha Leal: study conception and design, data collection, and article writing.Reinaldo Salomão: data analysis.Milena Karina Coló Brunialti: data analysis.Rioko Kimiko Sakata: article writing, critical revision of the intellectual content, and final version approval. ⁎ Corresponding author at: Alameda Mearim, 07 Olho d'água, São Luís, MA, 65065-280. E-mail address: [email protected] (P.C. Leal). http://dx.doi.org/10.1016/j.jclinane.2015.02.002 0952-8180/© 2015 Elsevier Inc. All rights reserved.
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1. Introduction Opioids are very effective in pain relief, but they might lower pain threshold, making the patient more sensitive to a pain stimulus, a condition known as hyperalgesia [1]. Opioid-induced hyperalgesia (OIH) is usually defined as a reduction in nociceptive thresholds in the peripheral field of the sensitized fibers [2], and it is associated with increased pain and higher demand for postoperative analgesia [3]. This phenomenon adversely impacts pain control and has been suggested to occur in the perioperative context, especially associated with the use of remifentanil, a short-acting opioid [3]. Several mechanisms have been proposed to explain the hyperalgesia phenomenon, but the most important seems to be the activation of N-methyl-D-aspartate (NMDA) receptors [4]. Ketamine is a NMDA receptor antagonist that has been shown to reduce postoperative pain and the need for postoperative anesthetics and analgesics. Therefore, it is proposed that ketamine could prevent hyperalgesia, resulting in more effective and long-lasting postsurgical analgesia [4]. The results of studies of low dose of ketamine in the prevention of remifentanil-induced hyperalgesia are controversial. Joly et al [5] demonstrated a reduction in the consumption of opioids and in hyperalgesia assessed with monofilaments. However, Engelhardt et al [6] showed no differences in pain scores or in postoperative opioid consumption. In addition, some authors observed higher levels of proinflammatory cytokines, associated with increased pain in mice receiving chronic opioid (morphine) infusion [7,8]. Furthermore, administration of proinflammatory cytokine inhibitors reduced phosphorylation of NMDA receptors [9]. However, no study has examined the relationship between the use of remifentanil, the most frequently implicated opioid in OIH [3], ketamine (drug capable of inhibiting NMDA receptors and cytokines) [10], and the inflammatory response. The aim of this study was to determine if the addition of ketamine reduces remifentanil-induced hyperalgesia, improves its analgesic effect, inhibits IL-6 and IL-8 (inflammatory cytokines), and stimulates IL-10 (an antiinflammatory cytokine) in patients submitted to laparoscopic cholecystectomy, a procedure with an usually neglected potential for postoperative pain and that has been poorly investigated in association with OIH.
2. Materials and methods This was a prospective, randomized, double-blind, and monocentric study. The study was registered with ClinicalTrials.gov under study number NCT01301079. This study was approved by the Ethics Committee of the Federal University of São Paulo (no. 1020/10), and signed informed consent was obtained from all study participants. Inclusion criteria were aged ≥ 18 years, any sex, classified as American Society of Anesthesiologists (ASA) physical
P.C. Leal et al. status I or II, and undergoing laparoscopic cholecystectomy at Hospital São Paulo/Federal University of São Paulo, from September 2010 to September 2012. Patients were excluded if they were chronic users of analgesics or had used opioids within 12 hours of surgery; had a history of drug or alcohol abuse or psychiatric disorder; had contraindications to self-administration of opioids (ie, unable to understand the patient-controlled analgesia [PCA] device); or had a contraindication for the use of ketamine, such as a psychiatric disorder, acute cardiovascular disorder, or unstable hypertension. Patients were randomized into 2 groups with the use of the computer program Randomizer. On the morning of the operation and before anesthesia, an anesthesiologist not involved in assessing the patients opened the sealed and opaque envelope related to that patient, which had been done according to the computer randomization. This physician prepared the assigned syringes with remifentanil and ketamine or with remifentanil and saline solution. None of the other researchers involved in the study or in the data collection knew to what group the patient was assigned. A cardioscope, a capnograph, a pulse oximeter, and a noninvasive blood pressure meter were used to monitor the patients. Propofol (2-4 mg/kg), 1 μg/kg remifentanil, and atracurium (0.5 mg/kg) were administered for intubation. Atracurium was titrated to maintain muscle relaxation. Anesthesia was maintained with remifentanil, 0.8% isoflurane, and 50% oxygen without nitrous oxide. Infusion of the solutions was continued until skin closure. The patients in group 1 (G1) received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients in group 2 (G2) received remifentanil (0.4 μg/kg per minute) and saline solution. Remifentanil was administered as necessary until skin closure. Neostigmine was used for antagonizing the neuromuscular block. Insufficient anesthesia was defined as a heart rate that exceeded preinduction values by 15% and/or systolic arterial blood pressure exceeding baseline values by 20% for at least 1 minute. Patient's movements, coughing, tearing, and sweating were also considered signs of inadequate anesthesia. Inspired isoflurane concentration was increased stepwise by 0.4% when insufficient anesthesia was suspected. Hypotension, defined by a systolic arterial pressure of b 80 mm Hg or a mean arterial pressure of b 60 mm Hg, prompted stepwise 0.4% reductions in isoflurane concentration. Additional intravenous fluids were also given as deemed appropriate by the responsible anesthesiologist. Similarly, atropine or intermittent bolus of ephedrine was given as required to treat bradycardia or persistent hypotension. At the end of the operation, 0.1 mg/kg morphine, 20 mg metoclopramide, and 4.0 mg ondansetron were administered. Postoperative analgesia was achieved with morphine via a PCA device set to deliver 2 mg of morphine as an intravenous bolus with a 10-minute lockout interval; continuous infusion was not allowed.
Effect of ketamine associated with remifentanil The primary end point was postoperative pain intensity. Secondary end points were time to first morphine supplementation; morphine consumption within 24 hours; hyperalgesia after 24 hours as measured with monofilaments and an algometer; extension of hyperalgesia; allodynia as detected with a soft brush; and serum level of interleukin 6 (IL-6), IL-8, and IL-10. Pain intensity was assessed using a scale ranging from 0-10 at 30-minute intervals for the first 4 hours and then on hours 6, 12, 18, and 24 after surgery. The pain threshold was assessed using 6 von Frey monofilaments (0.05, 0.2, 2, 4, 10, and 300 g). The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to 2 of the determinations for each monofilament. In addition, the mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/s until the patient complained of pain. The mean of 3 determinations was calculated. Allodynia was assessed using a soft brush. The evaluations using the monofilaments, the algometer, and the soft brush were performed 2-3 cm from the incision in the periumbilical region (where the large trocar was placed) and in the thenar eminence of the nondominant hand before surgery and 24 hours after the operation. The 300-g filament was used 24 hours after the operation to induce a stimulus and delineate the extent of hyperalgesia from the periumbilical region. The stimulus was started outside the periumbilical region, where no pain sensation was reported, and continued every 0.5 cm until the 4 points of the periumbilical scar were reached (top, right side, left side, and bottom). The first point, where the patient complained of pain, was marked. If no pain sensation was reported, the stimulus was terminated 0.5 cm from the incision. The distance of each point from the surgical incision was measured, and the sum of the distances of the points was determined. Blood samples were drawn in EDTA tubes before and 5 hours and 24 hours after surgery. The blood was centrifuged to separate the plasma and was stored at − 70°C. Interleukin 6, IL-8, and IL-10 were analyzed using the enzyme-linked immunosorbent assay methodology. Adverse effects were recorded. Sedation was assessed using a modification of the University of Michigan Sedation Scale [5]: “0,” when the patient was fully awake; “1,” when the patient was drowsy and responding to verbal commands; “2,” when the patient was drowsy and responding to tactile stimuli; and “3,” when the patient was asleep but responding to painful stimuli. Sedation was assessed at the same prespecified time points as for pain intensity evaluations for the first 4 hours.
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2.1. Statistical analysis The sample size calculation was performed using SPSS 17. A difference of 2 points in pain intensity according to a numerical scale was considered clinically significant. Based on a preliminary evaluation, a SD of 2.0 was estimated for the pain intensity score within the group of patients [5]. For a 95% power and a 95% confidence interval, the calculated sample size for each group was 25. Considering a possible patient loss of 20%, a total of 30 patients per group were aimed. The software program SPSS 17 was used for statistical analysis. The level of statistical significance was set at ≤ 0.05. The Kolmogorov-Smirnov and Shapiro were used to evaluate the normality of the data and whether parametric or nonparametric tests should be used. After that, the following tests were used: Fisher exact test (allodynia and use of atropine), Mann-Whitney test (duration of anesthesia and surgery, time to first supplemental analgesia, total dose of remifentanil, and dose of ephedrine), χ2 test (ASA physical status, sex, and adverse effects), likelihood ratio (sedation), and Student t test (age, weight, height, body mass index, dose of remifentanil based on ideal weight, awakening time, isoflurane consumption, morphine consumption, pain intensity, hyperalgesia as detected with monofilaments and algometer, extent of hyperalgesia, and cytokine levels).
3. Results The protocol sequence is outlined in the CONSORT flow chart (Figure). Four patients were lost to follow-up due to withdrawal from the study during the postoperative period for not wanting to use the PCA or to be submitted to the sensitivity tests. The groups had similar demographic characteristics (Table 1). There were no significant differences in surgical characteristics (including duration of surgery, duration of anesthesia, awakening times, isoflurane consumption, doses of remifentanil, use of atropine, and dose of ephedrine), time to first supplementary analgesia, or doses of morphine consumed in 24 hours (Table 2). There were no significant differences in pain intensities between the groups (Table 3). There were no statistically significant differences in the extent of hyperalgesia in the periumbilical region (G1, 10.61 ± 8.63 cm and G2, 11.82 ± 8.36 cm; P = .595). There was a significant difference between the groups in the hyperalgesia evaluation in the thenar eminence of the nondominant hand using monofilaments 24 hours after the operation, with less OIH for the ketamine group (Table 4). However, there were no differences between the groups in the hyperalgesia evaluations in the periumbilical region using monofilaments 24 hours after the operation (Table 4). There were no significant differences between the groups in the occurrence of hyperalgesia in the thenar eminence of
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P.C. Leal et al. Table 1
Patient characteristics b
Age in y (SD) Weight in kg (SD) b Height in cm (SD) b BMI (SD) b Sex (M:F) a ASA I/II a
G1 (n = 28)
G2 (n = 28)
45.8 (13.1) 75.1 (14.5) 166 (9.6) 27.3 (4.4) 4/24 12/16
43.4 (15.9) 74.8 (15.2) 163 (10.6) 28.6 (5.6) 5/23 16/12
Abbreviations: BMI, body mass index; M:F, male:female. P values were not significant. a χ2 test. b Student t test.
Figure
CONSORT flow chart.
the hand or in the periumbilical region using an algometer 24 hours after the operation (Table 4). There were no differences in the soft brush evaluations as well. There were no significant differences between the groups for levels of IL-6, IL-8, and IL-10 at the evaluated times (Table 5). Sedation was more frequent with ketamine after 60 minutes (P = .016), 90 minutes (P = .035), and 180 minutes (P = .041). Diplopia/nystagmus (G1, 5 and G2, 0; P = .019) and vomiting (G1, 16 and G2, 8; P = .031) occurred more frequently with ketamine (Table 6).
4. Discussion In this study, there were no differences in postoperative pain intensity, time to first supplementation with PCA, postoperative opioid consumption, and extent of hyperalgesia, allodynia, or IL levels with the addition of ketamine to remifentanil; however, there was an increase in adverse effects for the intervention group with ketamine.
Although laparoscopic cholecystectomy is a minimally invasive surgical technique associated with a lower degree of postoperative pain compared with open cholecystectomy, it is recognized that multiple methods of analgesia are necessary for postoperative control of pain in the surgical incision, visceral pain, and referred pain [11]. Several studies have demonstrated the association of high-dose intraoperative remifentanil with increased postoperative pain intensity [5,12,13]. In the present study, the dose of remifentanil was titrated as needed similarly to other reports in the literature [3,6]. The use of high-dose remifentanil (0.3 μg/kg per minute) is known to cause increased pain intensity, increased area of hyperalgesia, and decreased mechanical hyperalgesia threshold compared with low-dose remifentanil (0.05 μg/kg per minute) in minimally invasive laparoendoscopic single-site urologic surgery [14], demonstrating the existence of remifentanil-induced postoperative hyperalgesia in minimally invasive procedures after high-dose infusion. Hood et al [15] have studied the effect of remifentanil in volunteers submitted to topical capsaicin plus intermittent heating to create a nociceptive stimulus. During the infusion of remifentanil, the areas of hyperalgesia and allodynia decreased; however, they continuously enlarged up to 4 hours after remifentanil was discontinued. Another study in healthy volunteers using 0.1 μg/kg per minute of remifentanil over 90 minutes expanded the area of electricity-induced skin hypersensitivity within 30 minutes [16]. These findings confirm remifentanil's potential to promote hyperalgesia in settings rather than a major surgical intervention. In addition, a retrospective study by Ma et al [17] concluded that surgical duration was one of the major factors associated with remifentanil-induced postoperative hyperalgesia after procedures with incisions shorter than 4 cm. Although this was a retrospective study, it suggested that other factors rather than the intensity of surgical trauma itself may drive the development of remifentanil-induced postoperative hyperalgesia. The rapid termination of remifentanil's action requires the use of other analgesics before its discontinuation. The administration of a long-acting opioid, such as morphine, can
Effect of ketamine associated with remifentanil Table 2
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Characteristics of the surgical procedure and postoperative analgesic consumption a
Duration of the operation (min) Duration of anesthesia (min) a The wakening time (min) (SD) b Isoflurane consumption (MAC) (SD) b Dose of remifentanil (μg/kg per minute) (SD) b Total dose of remifentanil (mg) a Use of atropine (yes/no) c Dose of ephedrine (mg) a Time to the first supplementary analgesia (min) a Dose of morphine consumed (mg) (SD) b
G1 (n = 28)
G2 (n = 28)
125 (60-240) 170 (100-280) 12.3 (5.05) 0.8 (0.1) 0.4 (0.1) 3.7 (1.2-7.2) 1/27 5 (0-20) 18 (0-600) 27.4 (18.3)
100 (45-255) 150 (78-310) 14.0 (9.92) 0.8 (0.1) 0.4 (0.1) 3.1 (1.5-7.5) 1/27 0 (0-20) 15 (2-130) 27.7 (12.9)
Abbreviation: MAC, minimum alveolar concentration. P values were not significant. a (Minimal value − maximal value) according to Mann-Whitney test. b Student t test. c Fisher exact test.
ensure that patients do not waken in severe pain. In this study, morphine was administered as a bolus at the end of the procedure as previously described by others [18], and it was maintained through PCA. However, the use of a long-term opioid (morphine) after surgery could mask hyperalgesia [3], which may have occurred in this study. An expected effect of combining different analgesic drugs during anesthesia is the improvement in adverse effects profile due to the lower required doses of each medication. In this study, there was no reduction in adverse effects in the experimental group. In fact, some adverse events were introduced with the addition of ketamine. Despite the use of metoclopramide and ondansetron, the most common adverse effect in both groups was vomiting, more prominent for G1 patients. Inhalational anesthesia, laparoscopic procedures, use of remifentanil, and use of morphine are known to contribute to this effect [19,20]; but their use was similar in both groups and should not account for any differences.
Nystagmus, diplopia, and sedation were also more frequent with the addition of ketamine (Table 6). Monofilaments have been used to map and delineate areas of postoperative hyperalgesia [5,21]. In the present study, sensitivity threshold and pain distal or proximal to the surgical incision were measured using monofilaments and an algometer, in the same way done by others [2,5,22]. The upper limbs were used to evaluate hyperalgesia because they are distant from the surgical incision [5,13]. In this study, there were no differences in hyperalgesia measured with an algometer nor allodynia assessed in the periumbilical region and in the thenar eminence of the hand. Furthermore, there was no difference in the extent of hyperalgesia in the periumbilical region. However, there was a difference in hyperalgesia assessed with monofilaments in the thenar eminence of the hand after 24 hours of Table 4
Evaluation of hyperalgesia
Methods of evaluation Table 3 Pain intensity score at prespecified postsurgical evaluations Time in hours
G1 (n = 28)
G2 (n = 28)
½ 1 1½ 2 2½ 3 3½ 4 6 12 18 24
5.5 (3.5) 4.6 (3.0) 3.4 (2.4) 2.2 (2.1) 1.4 (1.7) 1.1 (1.5) 0.9 (1.6) 1.0 (1.7) 0.9 (1.2) 1.6 (1.8) 1.57 (1.8) 1.4 (1.5)
6.2 (2.6) 5.1 (2.5) 3.4 (2.3) 2.0 (1.8) 1.4 (1.6) 1.3 (1.5) 1.2 (1.5) 1.1 (1.5) 0.7 (1.0) 1.4 (2.0) 1.3 (1.6) 0.8 (1.0)
P values were not significant. Student t test: (mean [SD]).
Monofilament Thenar eminence Preoperative a Postoperative b Periumbilical Preoperative Postoperative Algometer Thenar eminence Preoperative Postoperative Periumbilical Preoperative Postoperative
G1 (n = 28)
G2 (n = 28)
300 (0) 290 (54.8)
300 (0) 247 (115)
279 (77.1) 248 (114)
269 (92) 205 (140)
2.51 (1.43) 0.56 (0.44)
2.19 (0.92) 0.51 (0.44)
3.6 (1.5) 3.5 (1.6)
3.9 (1.4) 3.7 (1.7)
Student t test: results shown in mean (SD) a All patients had the same response to filament stimulus before surgery. b P b .05.
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P.C. Leal et al. Table 5 Serum levels of IL-6, IL-8, and IL-10 at prespecified perioperative time evaluation
IL-6 (pg/mL) Preoperative 5 h after incision 24 h after surgery IL-8 (pg/mL) Preoperative 5 h after incision 24 h after surgery IL-10 (pg/mL) Preoperative 5 h after incision 24 h after surgery
G1 (n = 28)
G2 (n = 28)
3.3 (9.5) 29.3 (23.6) 24.1 (21.3)
2.1 (3.4) 34.8 (48.7) 24.8 (31.5)
3.3 (4.1) 8.0 (6.8) 6.0 (7.2)
2.2 (3.2) 11.3 (15.1) 4.5 (6.1)
7.8 (20) 9.1 (19.1) 8.6 (18.5)
1.9 (3.3) 5.5 (7.9) 5.0 (5.5)
Student t test: results shown in mean (SD); P values were not significant
the procedure but not in the periumbilical region. Therefore, the use of ketamine reduced hyperalgesia at a site that was distant from the umbilicus, the primary injury site. This may be associated with increased sensitivity due to a centralized mechanism that involves NMDA receptors and is able to affect distant sites from the surgical incision. Several authors have reported that the activation of NMDA receptors is implicated in the mechanisms of OIH, and NMDA receptor blockers can reduce its incidence [1,4,23]. Different studies demonstrated that the addition of ketamine to remifentanil prevented OIH in major abdominal surgeries, resulting in improved and longer lasting postoperative analgesia [5,23]. This study investigated the benefit of adding ketamine to remifentanil in laparoscopic cholecystectomy, a minimally invasive procedure, to reduce OIH. Low-dose ketamine has the advantage of reducing adverse effects, reason why it was chosen for this study. The same dose of 5 μg/kg per minute without an initial bolus was also used by Koppert et al [2], and they were able to demonstrate reduction in the extent of hyperalgesia surrounding a transcutaneous electrical stimulation in healthy volunteers. However, they also used a lower
Table 6
Ketamine-associated adverse
Unrest Hallucination Diplopia/nystagmus a Dysphoria Nausea Loss of reality Itching Vertigo Vomiting* χ2 test. a P value b .05.
G1 (n = 28)
G2 (n = 28)
5 5 5 1 22 1 3 11 16
3 2 0 0 21 1 3 17 8
dose of remifentanil (0.1 μg/kg per minute), which could explain the difference in their final results. Therefore, the use of low-dose ketamine might have caused the lack of observed OIH prevention [24]. Different infusion rates and the use of an induction bolus and of postoperative maintenance of ketamine may have promoted the positive results of other studies. Joly et al [5] demonstrated a reduction in the consumption of opioids and in the incidence of hyperalgesia assessed with monofilaments with the addition of ketamine to remifentanil; however, they used a ketamine bolus of 0.5 mg/kg and a postoperative maintenance of 2 μg/kg per minute in addition to the same infusion rate of this study. Cytokine levels have been associated with the development of OIH [25,26]. IL-6 is a known relevant marker of the degree of tissue damage during surgery [25,26]. Interleukin 6 can stimulate the production of IL-8, which has been described as a marker of several inflammatory conditions [27]. Interleukin 10 is a primary antiinflammatory cytokine with a similar half-life to IL-6. Previous studies have demonstrated increased production of IL-10 with the use of ketamine [10,28]. There are no publications to current date looking at the association between remifentanil, ketamine, and inflammatory response. In the present study, serum levels of IL-6, IL-8, and IL-10 were measured; and serum concentrations were obtained before the surgery, between hours 4 and 6 (peak) and at 24 hours after surgery. It was expected that the addition of ketamine would reduce IL-6 and IL-8 and increase IL-10 serum concentrations, with a significant difference in IL levels between groups, but no differences between groups were observed for any of the cytokines measured. One reason for this finding could be that the impact of ketamine on cytokine levels is more evident for major surgeries, such as cardiac surgery [10]. One possible explanation for the lack of a preventative effect on OIH in the surgical area could be due to the times when hyperalgesia was assessed. However, the time intervals of hyperalgesia manifestation after surgical trauma are well known, and the assessments performed in this study were done accordingly. In a previous study of remifentanilinduced hyperalgesia, patients were evaluated up to 48 hours after surgery; however, hyperalgesia was always present within the first 24 hours if it were to happen in the 48-hour evaluation period [5]. Others have shown that hyperalgesia can last from 2-10 days [4]. The conflicting results reported in various studies may also reflect different methods of evaluation. Other sensory tests could possibly demonstrate an effect for the studied medication (ie, heat, cold, and vibration), but they have not been reproducible in clinical practice because of the longer testing time required (N 30 minutes) and because they can be confusing to patients [13]. The absence of a placebo group not receiving remifentanil is a limitation of this study, preventing remifentanil to being directly implicated in the induction of hyperalgesia in both
Effect of ketamine associated with remifentanil groups. The lack of difference could simply be due to no OIH in either group. However, the vast majority of studies demonstrates that remifentanil induces postoperative hyperalgesia at high doses, as it was used in this study [5,12,13]. The use of a lower dose of remifentanil and/or the use of a bolus dose of ketamine before maintenance with a continuous infusion might be interesting approaches for the prevention of OIH that require further investigation. Future studies with different doses and protocols should be conducted to identify the most appropriate algorithm to prevent OIH, a phenomenon that negatively affects postoperative pain control.
4.1. Final considerations The addition of ketamine (5 μg/kg per minute) to remifentanil during laparoscopic cholecystectomy reduced remifentanilinduced hyperalgesia at a site distant from the primary injury but not at the incision site. It did not affect postoperative pain intensity, opioid consumption, or cytokine levels. Different outcomes reported in the literature may be due to the intensity of pain stimulus, timing of assessment, doses of ketamine and remifentanil, and study protocol. In conclusion, it was not possible to demonstrate that ketamine (5 μg/kg per minute) in addition to remifentanil has an effect in preventing or reducing remifentanil-induced hyperalgesia after laparoscopic cholecystectomy.
Acknowledgments Fundação de Amparo à Pesquisa do Estado de São Paulo and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
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7 [8] Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD. Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision. Mol Pain 2008;4:7. [9] Zhang RX, Li A, Liu B, Wang L, Ren K, Zhang H, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 2008;135:232-9. [10] Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg 2012;115:934-43. [11] Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 2001; 90:261-9. [12] Jo HR, Chae YK, Kim YH, Chai HS, Lee WK, Choi SS, et al. Remifentanil-induced pronociceptive effect and its prevention with pregabalin. Korean J Anesthesiol 2011;60:198-204. [13] Schmidt S, Bethge C, Förster MHM, Schäfer M. Enhanced postoperative sensitivity to painful pressure stimulation after intraoperative high dose remifentanil in patients without significant surgical site pain. Clin J Pain 2007;23:605-11. [14] Lee C, Lee H, Kim J. Effect of oral pregabalin on opioid-induced hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery. Korean J Anesthesiol 2013;64:19-24. [15] Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 2003;97:810-5. [16] Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003;106:49-57. [17] Ma JF, Huang ZL, Li J, Hu SJ, Lian QQ. Cohort study of remifentanilinduced hyperalgesia in postoperative patients. Zhonghua Yi Xue Za Zhi 2011;91:977-9. [18] Albrecht S, Fechner J, Geisslinger G, Maass AB, Upadhyaya B, Moecke H, et al. Postoperative pain control following remifentanilbased anaesthesia for major abdominal surgery. Anaesthesia 2000;55: 315-22. [19] Dershwitz M, Michałowski P, Chang Y, Rosow CE, Conlay LA. Postoperative nausea and vomiting after total intravenous anesthesia with propofol and remifentanil or alfentanil: how important is the opioid? J Clin Anesth 2002;14:275-8. [20] Fujii Y. Management of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Surg Endosc 2011;25:691-5. [21] Ilkjaer S, Bach LF, Nielsen PA, Wernberg M, Dahl JB. Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain 2000;86:19-24. [22] Carvalho B, Zheng M, Aiono-Le Tagaloa L. Evaluation of experimental pain tests to predict labour pain and epidural analgesic consumption. Br J Anaesth 2013;110:600-6. [23] Reznikov I, Pud D, Eisenberg E. Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain. Br J Clin Pharmacol 2005;60:311-8. [24] Parikh B, Maliwad J, Shah VR. Preventive analgesia: effect of small dose of ketamine on morphine requirement after renal surgery. J Anaesthesiol Clin Pharmacol 2011;27:485-8. [25] Gebhard F, Pfetsch H, Steinbach G, Strecker W, Kinzl L, Brünckner UB. Is interleukin 6 an early marker of injury severity following major trauma in humans? Arch Surg 2000;135:291-5. [26] Hong JY, Lim KT. Effect of preemptive epidural analgesia on cytokine response and postoperative pain in laparoscopic radical hysterectomy for cervical cancer. Reg Anesth Pain Med 2008;33:44-51. [27] Shahzad A, Knapp M, Lang I, Köhler G. Interleukin 8 (IL-8)—a universal biomarker? Intern Arch Med 2010;3:11. [28] Welters ID, Feurer MK, Preiss V, Müller M, Scholz S, Kwapisz M, et al. Continuous S-(+)-ketamine administration during elective coronary artery bypass graft surgery attenuates pro-inflammatory cytokine response during and after cardiopulmonary bypass. Br J Anaesth 2011;106:172-9.
Original Contributions
Evaluation of the effect of ketamine on remifentanil-induced hyperalgesia: a double-blind, randomized study☆,☆☆,★ Plínio C. Leal MD ⁎, Reinaldo Salomão MD, PhD, Milena K.C. Brunialti PhD, Rioko K. Sakata MD, PhD Federal University of São Paulo, São Paulo, Brazil Received 29 September 2013; revised 16 November 2014; accepted 3 February 2015
Keywords: Hyperalgesia; Interleukins; Ketamine; Opioid-induced hyperalgesia; Remifentanil
Abstract Abstract study objective: Opioids are associated with hyperalgesia that can reduce their analgesic effect. The aim of this study was to determine whether the addition of ketamine reduces remifentanil-induced hyperalgesia; improves its analgesic effect; and alters interleukin 6 (IL-6), IL-8, and IL-10 levels. Design: This is a prospective, randomized, double-blind study. Setting: The setting is in a operating room and ward in a university hospital. Patients: There are 56 patients, aged ≥ 18 years, American Society of Anesthesiologists I or II, who underwent laparoscopic cholecystectomy. Interventions: Anesthesia was induced with remifentanil, 50% oxygen, and isoflurane. Patients randomized to group 1 received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients randomized to group 2 received remifentanil (0.4 μg/kg per minute) and saline solution. Postoperative analgesia was achieved using morphine via patient-controlled analgesia. Measurements: The measurements were postoperative pain intensity during 24 hours; morphine consumption; time to first morphine supplementation; hyperalgesia (using monofilaments and an algometer) and allodynia (using a soft brush) in the thenar eminence of the nondominant hand and in the periumbilical region 24 hours after surgery; extent of hyperalgesia using a 300-g monofilament near the periumbilical region 24 hours after surgery; and serum levels of IL-6, IL-8, and IL-10. Main results: Groups were similar for baseline characteristics. There were no differences in pain intensity, time to first request of morphine, and total 24 hours dose of morphine between groups. There was a difference in hyperalgesia using monofilaments 24 hours after the surgery in the thenar eminence of the nondominant hand, with a better profile for the experimental group. However, there were no differences in hyperalgesia using an algometer, in allodynia using a soft brush; in extent of hyperalgesia; or in levels of IL-6, IL-8, and IL-10. Conclusions: It was not possible to demonstrate that the addition of ketamine (5 μg/kg per minute) is effective in preventing or reducing remifentanil-induced postoperative hyperalgesia in laparoscopic cholecystectomy. © 2015 Elsevier Inc. All rights reserved.
☆
Funding received: grant 2009/53335-4, São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. ☆☆ Conflict of interest: none. ★ Authors' contributions: Plínio Cunha Leal: study conception and design, data collection, and article writing.Reinaldo Salomão: data analysis.Milena Karina Coló Brunialti: data analysis.Rioko Kimiko Sakata: article writing, critical revision of the intellectual content, and final version approval. ⁎ Corresponding author at: Alameda Mearim, 07 Olho d'água, São Luís, MA, 65065-280. E-mail address: [email protected] (P.C. Leal). http://dx.doi.org/10.1016/j.jclinane.2015.02.002 0952-8180/© 2015 Elsevier Inc. All rights reserved.
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1. Introduction Opioids are very effective in pain relief, but they might lower pain threshold, making the patient more sensitive to a pain stimulus, a condition known as hyperalgesia [1]. Opioid-induced hyperalgesia (OIH) is usually defined as a reduction in nociceptive thresholds in the peripheral field of the sensitized fibers [2], and it is associated with increased pain and higher demand for postoperative analgesia [3]. This phenomenon adversely impacts pain control and has been suggested to occur in the perioperative context, especially associated with the use of remifentanil, a short-acting opioid [3]. Several mechanisms have been proposed to explain the hyperalgesia phenomenon, but the most important seems to be the activation of N-methyl-D-aspartate (NMDA) receptors [4]. Ketamine is a NMDA receptor antagonist that has been shown to reduce postoperative pain and the need for postoperative anesthetics and analgesics. Therefore, it is proposed that ketamine could prevent hyperalgesia, resulting in more effective and long-lasting postsurgical analgesia [4]. The results of studies of low dose of ketamine in the prevention of remifentanil-induced hyperalgesia are controversial. Joly et al [5] demonstrated a reduction in the consumption of opioids and in hyperalgesia assessed with monofilaments. However, Engelhardt et al [6] showed no differences in pain scores or in postoperative opioid consumption. In addition, some authors observed higher levels of proinflammatory cytokines, associated with increased pain in mice receiving chronic opioid (morphine) infusion [7,8]. Furthermore, administration of proinflammatory cytokine inhibitors reduced phosphorylation of NMDA receptors [9]. However, no study has examined the relationship between the use of remifentanil, the most frequently implicated opioid in OIH [3], ketamine (drug capable of inhibiting NMDA receptors and cytokines) [10], and the inflammatory response. The aim of this study was to determine if the addition of ketamine reduces remifentanil-induced hyperalgesia, improves its analgesic effect, inhibits IL-6 and IL-8 (inflammatory cytokines), and stimulates IL-10 (an antiinflammatory cytokine) in patients submitted to laparoscopic cholecystectomy, a procedure with an usually neglected potential for postoperative pain and that has been poorly investigated in association with OIH.
2. Materials and methods This was a prospective, randomized, double-blind, and monocentric study. The study was registered with ClinicalTrials.gov under study number NCT01301079. This study was approved by the Ethics Committee of the Federal University of São Paulo (no. 1020/10), and signed informed consent was obtained from all study participants. Inclusion criteria were aged ≥ 18 years, any sex, classified as American Society of Anesthesiologists (ASA) physical
P.C. Leal et al. status I or II, and undergoing laparoscopic cholecystectomy at Hospital São Paulo/Federal University of São Paulo, from September 2010 to September 2012. Patients were excluded if they were chronic users of analgesics or had used opioids within 12 hours of surgery; had a history of drug or alcohol abuse or psychiatric disorder; had contraindications to self-administration of opioids (ie, unable to understand the patient-controlled analgesia [PCA] device); or had a contraindication for the use of ketamine, such as a psychiatric disorder, acute cardiovascular disorder, or unstable hypertension. Patients were randomized into 2 groups with the use of the computer program Randomizer. On the morning of the operation and before anesthesia, an anesthesiologist not involved in assessing the patients opened the sealed and opaque envelope related to that patient, which had been done according to the computer randomization. This physician prepared the assigned syringes with remifentanil and ketamine or with remifentanil and saline solution. None of the other researchers involved in the study or in the data collection knew to what group the patient was assigned. A cardioscope, a capnograph, a pulse oximeter, and a noninvasive blood pressure meter were used to monitor the patients. Propofol (2-4 mg/kg), 1 μg/kg remifentanil, and atracurium (0.5 mg/kg) were administered for intubation. Atracurium was titrated to maintain muscle relaxation. Anesthesia was maintained with remifentanil, 0.8% isoflurane, and 50% oxygen without nitrous oxide. Infusion of the solutions was continued until skin closure. The patients in group 1 (G1) received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients in group 2 (G2) received remifentanil (0.4 μg/kg per minute) and saline solution. Remifentanil was administered as necessary until skin closure. Neostigmine was used for antagonizing the neuromuscular block. Insufficient anesthesia was defined as a heart rate that exceeded preinduction values by 15% and/or systolic arterial blood pressure exceeding baseline values by 20% for at least 1 minute. Patient's movements, coughing, tearing, and sweating were also considered signs of inadequate anesthesia. Inspired isoflurane concentration was increased stepwise by 0.4% when insufficient anesthesia was suspected. Hypotension, defined by a systolic arterial pressure of b 80 mm Hg or a mean arterial pressure of b 60 mm Hg, prompted stepwise 0.4% reductions in isoflurane concentration. Additional intravenous fluids were also given as deemed appropriate by the responsible anesthesiologist. Similarly, atropine or intermittent bolus of ephedrine was given as required to treat bradycardia or persistent hypotension. At the end of the operation, 0.1 mg/kg morphine, 20 mg metoclopramide, and 4.0 mg ondansetron were administered. Postoperative analgesia was achieved with morphine via a PCA device set to deliver 2 mg of morphine as an intravenous bolus with a 10-minute lockout interval; continuous infusion was not allowed.
Effect of ketamine associated with remifentanil The primary end point was postoperative pain intensity. Secondary end points were time to first morphine supplementation; morphine consumption within 24 hours; hyperalgesia after 24 hours as measured with monofilaments and an algometer; extension of hyperalgesia; allodynia as detected with a soft brush; and serum level of interleukin 6 (IL-6), IL-8, and IL-10. Pain intensity was assessed using a scale ranging from 0-10 at 30-minute intervals for the first 4 hours and then on hours 6, 12, 18, and 24 after surgery. The pain threshold was assessed using 6 von Frey monofilaments (0.05, 0.2, 2, 4, 10, and 300 g). The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to 2 of the determinations for each monofilament. In addition, the mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/s until the patient complained of pain. The mean of 3 determinations was calculated. Allodynia was assessed using a soft brush. The evaluations using the monofilaments, the algometer, and the soft brush were performed 2-3 cm from the incision in the periumbilical region (where the large trocar was placed) and in the thenar eminence of the nondominant hand before surgery and 24 hours after the operation. The 300-g filament was used 24 hours after the operation to induce a stimulus and delineate the extent of hyperalgesia from the periumbilical region. The stimulus was started outside the periumbilical region, where no pain sensation was reported, and continued every 0.5 cm until the 4 points of the periumbilical scar were reached (top, right side, left side, and bottom). The first point, where the patient complained of pain, was marked. If no pain sensation was reported, the stimulus was terminated 0.5 cm from the incision. The distance of each point from the surgical incision was measured, and the sum of the distances of the points was determined. Blood samples were drawn in EDTA tubes before and 5 hours and 24 hours after surgery. The blood was centrifuged to separate the plasma and was stored at − 70°C. Interleukin 6, IL-8, and IL-10 were analyzed using the enzyme-linked immunosorbent assay methodology. Adverse effects were recorded. Sedation was assessed using a modification of the University of Michigan Sedation Scale [5]: “0,” when the patient was fully awake; “1,” when the patient was drowsy and responding to verbal commands; “2,” when the patient was drowsy and responding to tactile stimuli; and “3,” when the patient was asleep but responding to painful stimuli. Sedation was assessed at the same prespecified time points as for pain intensity evaluations for the first 4 hours.
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2.1. Statistical analysis The sample size calculation was performed using SPSS 17. A difference of 2 points in pain intensity according to a numerical scale was considered clinically significant. Based on a preliminary evaluation, a SD of 2.0 was estimated for the pain intensity score within the group of patients [5]. For a 95% power and a 95% confidence interval, the calculated sample size for each group was 25. Considering a possible patient loss of 20%, a total of 30 patients per group were aimed. The software program SPSS 17 was used for statistical analysis. The level of statistical significance was set at ≤ 0.05. The Kolmogorov-Smirnov and Shapiro were used to evaluate the normality of the data and whether parametric or nonparametric tests should be used. After that, the following tests were used: Fisher exact test (allodynia and use of atropine), Mann-Whitney test (duration of anesthesia and surgery, time to first supplemental analgesia, total dose of remifentanil, and dose of ephedrine), χ2 test (ASA physical status, sex, and adverse effects), likelihood ratio (sedation), and Student t test (age, weight, height, body mass index, dose of remifentanil based on ideal weight, awakening time, isoflurane consumption, morphine consumption, pain intensity, hyperalgesia as detected with monofilaments and algometer, extent of hyperalgesia, and cytokine levels).
3. Results The protocol sequence is outlined in the CONSORT flow chart (Figure). Four patients were lost to follow-up due to withdrawal from the study during the postoperative period for not wanting to use the PCA or to be submitted to the sensitivity tests. The groups had similar demographic characteristics (Table 1). There were no significant differences in surgical characteristics (including duration of surgery, duration of anesthesia, awakening times, isoflurane consumption, doses of remifentanil, use of atropine, and dose of ephedrine), time to first supplementary analgesia, or doses of morphine consumed in 24 hours (Table 2). There were no significant differences in pain intensities between the groups (Table 3). There were no statistically significant differences in the extent of hyperalgesia in the periumbilical region (G1, 10.61 ± 8.63 cm and G2, 11.82 ± 8.36 cm; P = .595). There was a significant difference between the groups in the hyperalgesia evaluation in the thenar eminence of the nondominant hand using monofilaments 24 hours after the operation, with less OIH for the ketamine group (Table 4). However, there were no differences between the groups in the hyperalgesia evaluations in the periumbilical region using monofilaments 24 hours after the operation (Table 4). There were no significant differences between the groups in the occurrence of hyperalgesia in the thenar eminence of
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P.C. Leal et al. Table 1
Patient characteristics b
Age in y (SD) Weight in kg (SD) b Height in cm (SD) b BMI (SD) b Sex (M:F) a ASA I/II a
G1 (n = 28)
G2 (n = 28)
45.8 (13.1) 75.1 (14.5) 166 (9.6) 27.3 (4.4) 4/24 12/16
43.4 (15.9) 74.8 (15.2) 163 (10.6) 28.6 (5.6) 5/23 16/12
Abbreviations: BMI, body mass index; M:F, male:female. P values were not significant. a χ2 test. b Student t test.
Figure
CONSORT flow chart.
the hand or in the periumbilical region using an algometer 24 hours after the operation (Table 4). There were no differences in the soft brush evaluations as well. There were no significant differences between the groups for levels of IL-6, IL-8, and IL-10 at the evaluated times (Table 5). Sedation was more frequent with ketamine after 60 minutes (P = .016), 90 minutes (P = .035), and 180 minutes (P = .041). Diplopia/nystagmus (G1, 5 and G2, 0; P = .019) and vomiting (G1, 16 and G2, 8; P = .031) occurred more frequently with ketamine (Table 6).
4. Discussion In this study, there were no differences in postoperative pain intensity, time to first supplementation with PCA, postoperative opioid consumption, and extent of hyperalgesia, allodynia, or IL levels with the addition of ketamine to remifentanil; however, there was an increase in adverse effects for the intervention group with ketamine.
Although laparoscopic cholecystectomy is a minimally invasive surgical technique associated with a lower degree of postoperative pain compared with open cholecystectomy, it is recognized that multiple methods of analgesia are necessary for postoperative control of pain in the surgical incision, visceral pain, and referred pain [11]. Several studies have demonstrated the association of high-dose intraoperative remifentanil with increased postoperative pain intensity [5,12,13]. In the present study, the dose of remifentanil was titrated as needed similarly to other reports in the literature [3,6]. The use of high-dose remifentanil (0.3 μg/kg per minute) is known to cause increased pain intensity, increased area of hyperalgesia, and decreased mechanical hyperalgesia threshold compared with low-dose remifentanil (0.05 μg/kg per minute) in minimally invasive laparoendoscopic single-site urologic surgery [14], demonstrating the existence of remifentanil-induced postoperative hyperalgesia in minimally invasive procedures after high-dose infusion. Hood et al [15] have studied the effect of remifentanil in volunteers submitted to topical capsaicin plus intermittent heating to create a nociceptive stimulus. During the infusion of remifentanil, the areas of hyperalgesia and allodynia decreased; however, they continuously enlarged up to 4 hours after remifentanil was discontinued. Another study in healthy volunteers using 0.1 μg/kg per minute of remifentanil over 90 minutes expanded the area of electricity-induced skin hypersensitivity within 30 minutes [16]. These findings confirm remifentanil's potential to promote hyperalgesia in settings rather than a major surgical intervention. In addition, a retrospective study by Ma et al [17] concluded that surgical duration was one of the major factors associated with remifentanil-induced postoperative hyperalgesia after procedures with incisions shorter than 4 cm. Although this was a retrospective study, it suggested that other factors rather than the intensity of surgical trauma itself may drive the development of remifentanil-induced postoperative hyperalgesia. The rapid termination of remifentanil's action requires the use of other analgesics before its discontinuation. The administration of a long-acting opioid, such as morphine, can
Effect of ketamine associated with remifentanil Table 2
5
Characteristics of the surgical procedure and postoperative analgesic consumption a
Duration of the operation (min) Duration of anesthesia (min) a The wakening time (min) (SD) b Isoflurane consumption (MAC) (SD) b Dose of remifentanil (μg/kg per minute) (SD) b Total dose of remifentanil (mg) a Use of atropine (yes/no) c Dose of ephedrine (mg) a Time to the first supplementary analgesia (min) a Dose of morphine consumed (mg) (SD) b
G1 (n = 28)
G2 (n = 28)
125 (60-240) 170 (100-280) 12.3 (5.05) 0.8 (0.1) 0.4 (0.1) 3.7 (1.2-7.2) 1/27 5 (0-20) 18 (0-600) 27.4 (18.3)
100 (45-255) 150 (78-310) 14.0 (9.92) 0.8 (0.1) 0.4 (0.1) 3.1 (1.5-7.5) 1/27 0 (0-20) 15 (2-130) 27.7 (12.9)
Abbreviation: MAC, minimum alveolar concentration. P values were not significant. a (Minimal value − maximal value) according to Mann-Whitney test. b Student t test. c Fisher exact test.
ensure that patients do not waken in severe pain. In this study, morphine was administered as a bolus at the end of the procedure as previously described by others [18], and it was maintained through PCA. However, the use of a long-term opioid (morphine) after surgery could mask hyperalgesia [3], which may have occurred in this study. An expected effect of combining different analgesic drugs during anesthesia is the improvement in adverse effects profile due to the lower required doses of each medication. In this study, there was no reduction in adverse effects in the experimental group. In fact, some adverse events were introduced with the addition of ketamine. Despite the use of metoclopramide and ondansetron, the most common adverse effect in both groups was vomiting, more prominent for G1 patients. Inhalational anesthesia, laparoscopic procedures, use of remifentanil, and use of morphine are known to contribute to this effect [19,20]; but their use was similar in both groups and should not account for any differences.
Nystagmus, diplopia, and sedation were also more frequent with the addition of ketamine (Table 6). Monofilaments have been used to map and delineate areas of postoperative hyperalgesia [5,21]. In the present study, sensitivity threshold and pain distal or proximal to the surgical incision were measured using monofilaments and an algometer, in the same way done by others [2,5,22]. The upper limbs were used to evaluate hyperalgesia because they are distant from the surgical incision [5,13]. In this study, there were no differences in hyperalgesia measured with an algometer nor allodynia assessed in the periumbilical region and in the thenar eminence of the hand. Furthermore, there was no difference in the extent of hyperalgesia in the periumbilical region. However, there was a difference in hyperalgesia assessed with monofilaments in the thenar eminence of the hand after 24 hours of Table 4
Evaluation of hyperalgesia
Methods of evaluation Table 3 Pain intensity score at prespecified postsurgical evaluations Time in hours
G1 (n = 28)
G2 (n = 28)
½ 1 1½ 2 2½ 3 3½ 4 6 12 18 24
5.5 (3.5) 4.6 (3.0) 3.4 (2.4) 2.2 (2.1) 1.4 (1.7) 1.1 (1.5) 0.9 (1.6) 1.0 (1.7) 0.9 (1.2) 1.6 (1.8) 1.57 (1.8) 1.4 (1.5)
6.2 (2.6) 5.1 (2.5) 3.4 (2.3) 2.0 (1.8) 1.4 (1.6) 1.3 (1.5) 1.2 (1.5) 1.1 (1.5) 0.7 (1.0) 1.4 (2.0) 1.3 (1.6) 0.8 (1.0)
P values were not significant. Student t test: (mean [SD]).
Monofilament Thenar eminence Preoperative a Postoperative b Periumbilical Preoperative Postoperative Algometer Thenar eminence Preoperative Postoperative Periumbilical Preoperative Postoperative
G1 (n = 28)
G2 (n = 28)
300 (0) 290 (54.8)
300 (0) 247 (115)
279 (77.1) 248 (114)
269 (92) 205 (140)
2.51 (1.43) 0.56 (0.44)
2.19 (0.92) 0.51 (0.44)
3.6 (1.5) 3.5 (1.6)
3.9 (1.4) 3.7 (1.7)
Student t test: results shown in mean (SD) a All patients had the same response to filament stimulus before surgery. b P b .05.
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P.C. Leal et al. Table 5 Serum levels of IL-6, IL-8, and IL-10 at prespecified perioperative time evaluation
IL-6 (pg/mL) Preoperative 5 h after incision 24 h after surgery IL-8 (pg/mL) Preoperative 5 h after incision 24 h after surgery IL-10 (pg/mL) Preoperative 5 h after incision 24 h after surgery
G1 (n = 28)
G2 (n = 28)
3.3 (9.5) 29.3 (23.6) 24.1 (21.3)
2.1 (3.4) 34.8 (48.7) 24.8 (31.5)
3.3 (4.1) 8.0 (6.8) 6.0 (7.2)
2.2 (3.2) 11.3 (15.1) 4.5 (6.1)
7.8 (20) 9.1 (19.1) 8.6 (18.5)
1.9 (3.3) 5.5 (7.9) 5.0 (5.5)
Student t test: results shown in mean (SD); P values were not significant
the procedure but not in the periumbilical region. Therefore, the use of ketamine reduced hyperalgesia at a site that was distant from the umbilicus, the primary injury site. This may be associated with increased sensitivity due to a centralized mechanism that involves NMDA receptors and is able to affect distant sites from the surgical incision. Several authors have reported that the activation of NMDA receptors is implicated in the mechanisms of OIH, and NMDA receptor blockers can reduce its incidence [1,4,23]. Different studies demonstrated that the addition of ketamine to remifentanil prevented OIH in major abdominal surgeries, resulting in improved and longer lasting postoperative analgesia [5,23]. This study investigated the benefit of adding ketamine to remifentanil in laparoscopic cholecystectomy, a minimally invasive procedure, to reduce OIH. Low-dose ketamine has the advantage of reducing adverse effects, reason why it was chosen for this study. The same dose of 5 μg/kg per minute without an initial bolus was also used by Koppert et al [2], and they were able to demonstrate reduction in the extent of hyperalgesia surrounding a transcutaneous electrical stimulation in healthy volunteers. However, they also used a lower
Table 6
Ketamine-associated adverse
Unrest Hallucination Diplopia/nystagmus a Dysphoria Nausea Loss of reality Itching Vertigo Vomiting* χ2 test. a P value b .05.
G1 (n = 28)
G2 (n = 28)
5 5 5 1 22 1 3 11 16
3 2 0 0 21 1 3 17 8
dose of remifentanil (0.1 μg/kg per minute), which could explain the difference in their final results. Therefore, the use of low-dose ketamine might have caused the lack of observed OIH prevention [24]. Different infusion rates and the use of an induction bolus and of postoperative maintenance of ketamine may have promoted the positive results of other studies. Joly et al [5] demonstrated a reduction in the consumption of opioids and in the incidence of hyperalgesia assessed with monofilaments with the addition of ketamine to remifentanil; however, they used a ketamine bolus of 0.5 mg/kg and a postoperative maintenance of 2 μg/kg per minute in addition to the same infusion rate of this study. Cytokine levels have been associated with the development of OIH [25,26]. IL-6 is a known relevant marker of the degree of tissue damage during surgery [25,26]. Interleukin 6 can stimulate the production of IL-8, which has been described as a marker of several inflammatory conditions [27]. Interleukin 10 is a primary antiinflammatory cytokine with a similar half-life to IL-6. Previous studies have demonstrated increased production of IL-10 with the use of ketamine [10,28]. There are no publications to current date looking at the association between remifentanil, ketamine, and inflammatory response. In the present study, serum levels of IL-6, IL-8, and IL-10 were measured; and serum concentrations were obtained before the surgery, between hours 4 and 6 (peak) and at 24 hours after surgery. It was expected that the addition of ketamine would reduce IL-6 and IL-8 and increase IL-10 serum concentrations, with a significant difference in IL levels between groups, but no differences between groups were observed for any of the cytokines measured. One reason for this finding could be that the impact of ketamine on cytokine levels is more evident for major surgeries, such as cardiac surgery [10]. One possible explanation for the lack of a preventative effect on OIH in the surgical area could be due to the times when hyperalgesia was assessed. However, the time intervals of hyperalgesia manifestation after surgical trauma are well known, and the assessments performed in this study were done accordingly. In a previous study of remifentanilinduced hyperalgesia, patients were evaluated up to 48 hours after surgery; however, hyperalgesia was always present within the first 24 hours if it were to happen in the 48-hour evaluation period [5]. Others have shown that hyperalgesia can last from 2-10 days [4]. The conflicting results reported in various studies may also reflect different methods of evaluation. Other sensory tests could possibly demonstrate an effect for the studied medication (ie, heat, cold, and vibration), but they have not been reproducible in clinical practice because of the longer testing time required (N 30 minutes) and because they can be confusing to patients [13]. The absence of a placebo group not receiving remifentanil is a limitation of this study, preventing remifentanil to being directly implicated in the induction of hyperalgesia in both
Effect of ketamine associated with remifentanil groups. The lack of difference could simply be due to no OIH in either group. However, the vast majority of studies demonstrates that remifentanil induces postoperative hyperalgesia at high doses, as it was used in this study [5,12,13]. The use of a lower dose of remifentanil and/or the use of a bolus dose of ketamine before maintenance with a continuous infusion might be interesting approaches for the prevention of OIH that require further investigation. Future studies with different doses and protocols should be conducted to identify the most appropriate algorithm to prevent OIH, a phenomenon that negatively affects postoperative pain control.
4.1. Final considerations The addition of ketamine (5 μg/kg per minute) to remifentanil during laparoscopic cholecystectomy reduced remifentanilinduced hyperalgesia at a site distant from the primary injury but not at the incision site. It did not affect postoperative pain intensity, opioid consumption, or cytokine levels. Different outcomes reported in the literature may be due to the intensity of pain stimulus, timing of assessment, doses of ketamine and remifentanil, and study protocol. In conclusion, it was not possible to demonstrate that ketamine (5 μg/kg per minute) in addition to remifentanil has an effect in preventing or reducing remifentanil-induced hyperalgesia after laparoscopic cholecystectomy.
Acknowledgments Fundação de Amparo à Pesquisa do Estado de São Paulo and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
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