Ketamine is an N-methyl-d-aspartate (NMDA) antagonist1 with anesthetic properties, but it is also associated with clinically relevant adverse effects that have limited its use.2 Therefore, ketamine is used at lower doses for its analgesic3 and for its antihyperalgesic properties.4,5 Intraoperative use of low doses of ketamine improve postoperative pain relief and decrease morphine requirements during the first 24 hours. These results are obtained whether ketamine is administered via an epidural catheter or systemically, but it is preferably given at a constant rate of infusion.3,6–9 Despite the strong evidence-based improvement in pain therapy and reduction in opioid requirements produced by ketamine,10–14 a lack of improved postoperative analgesia has also been reported.15 Besides the antiopioid-induced hyperalgesia action of ketamine, this drug has been used for its antitolerance action.5,8,16–18 Therefore, because acute opioid tolerance may develop during anesthesia,19–21 ketamine might be useful to limit or prevent it.22,23
A method to determine the relative analgesic potency of analgesic drugs used in the intraoperative period is the determination of the reduction in the minimum alveolar concentration (MAC) of inhalation anesthetics.24 We hypothesized that the MAC reduction by ketamine and remifentanil would be additive or synergistic but also that ketamine, in combination with opioids, would block AOT. Therefore, the purpose of this study was to determine the effect of ketamine, administered alone or in combination with remifentanil, on the sevoflurane MAC (MACSEV) in rats and to determine whether ketamine may blunt or prevent AOT.
After obtaining the approval of the Institutional Animal Care Committee (La Paz University Hospital, Madrid, Spain), the reduction of MACSEV in response to ketamine and remifentanil was evaluated in rats. Sevoflurane was obtained from Abbott (Sevorane; Abbott Laboratories, Madrid, Spain), ketamine from Parke-Davis (Ketolar 500; Parke-Davis-Pfizer, Madrid, Spain), remifentanil from Glaxo-Wellcome (Ultiva; Glaxo-Wellcome Laboratories, Madrid, Spain), and naloxone from Sigma-Aldrich (naloxone hydrochloride dehydrate; Sigma-Aldrich, St. Quentin Fallavier, France).
One hundred two adult male Wistar rats (Charles River Laboratories, Barcelona, Spain), weighing 321 ± 34 g, were housed in groups of 4 to 6 animals per cage (macrolon type IV) with a 12-hour light, 12-hour dark cycle, relative humidity of 40%–70%, and 20° ± 2°C ambient temperature. Food (B&K Universal; Grimston, UK) and water were provided ad libitum. Animals were allowed to acclimatize for at least 1 week. All of the studies were performed during the morning (starting at 8:30 am).
Rats were placed in an induction chamber, into which 8% sevoflurane in a continuous oxygen flow of 3 L min−1 was directed (Sevoflurane Vaporizer; Sevorane Dragër Vapor 2000, Lubeck, Germany). Endotracheal intubation was performed using a 14-gauge polyethylene catheter (Terumo Surflo IV Catheter; Terumo Europe NV, Leuven, Belgium) with the animal positioned in sternal recumbency. A flexible, blunt-tipped wire guide was inserted into the trachea with an otoscope and used to direct the endotracheal catheter. After the catheter was properly positioned, it was connected to a small T piece breathing system with minimum dead space. Fresh gas flow to the T piece was adjusted to 1 L min−1 of oxygen (100%), and the sevoflurane concentration was adjusted to 1.5 × MAC (3.5%–4%). Rats were kept under spontaneous ventilation during the whole experiment, because these remifentanil doses did not produce hypercapnia (Paco2 below 45 mm Hg),25 which might have modified the MAC.26,27 However, when signs of hypoventilation occurred, spontaneous ventilation was stimulated by touching the rat's thorax softly. Remifentanil was administered with an infusion pump (syringe pump, model Sep11S; Ascor S.A., Medical Equipment, Warsaw, Poland) by a 22-gauge polyethylene catheter inserted in a tail vein.
The carotid artery was catheterized (Venocath-18, Venisystems; Hospira, Sligo, Ireland) via the surgical cut-down approach. This access point allowed for arterial blood sampling and blood pressure measurement via a calibrated pressure transducer (Transpac IV; Abbott Laboratories, Abbott Park, IL). Systolic, diastolic, and mean arterial blood pressures, arterial oxygen hemoglobin saturation (via pulseoximetry), and heart and respiratory rates were recorded continuously (RGB; Medical Devices, Madrid, Spain). Arterial blood (1 mL) was collected for blood gas analysis (Rapidlab 1265; Bayer AG, Leverkusen, Germany) at the end of the study to ensure that values at that time were within normal limits of pH (7.35 to 7.47), oxygen (Pao2; >120 mm Hg), and carbon dioxide arterial partial pressures (Paco2; 35 to 55 mm Hg). Rectal temperature was also monitored and maintained between 37.0°C and 38.5°C by means of a water-circulating warming blanket (Heat Therapy Pump, Model TP-220; Gaymar, Orchand Park, NY) and a heating lamp.
Determination of the Minimum Alveolar Concentration
Intratracheal gas sampling was used to measure anesthetic gas concentration and to determine the MAC. This method has been described in detail.28 In brief, a fine catheter with a 0.9-mm external diameter was inserted through the endotracheal catheter with the fine catheter tip located at the level of the carina. The proximal end of the catheter was connected to a 10-mL gas-tight glass syringe (Hamilton Syringe, 1000 series Gastight, model 26,211-U; Sigma-Aldrich, St. Quentin Fallavier, France). Samples were obtained by withdrawing 10 mL of gas over a 5-minute period using an infusion pump (model KDS-210; Harvard Apparatus, Millis, MA). The fine catheter was withdrawn between samples. After every step change in anesthetic concentration delivered by the anesthetic circuit, at least 10 minutes were allowed for equilibration before the noxious stimulus was applied. The samples were assayed using a side-stream infrared analyzer (Capnomac Ultima; Datex-Ohmeda, Hertfordshire, UK).
MACSEV was established according to a method described elsewhere.29 A supramaximal noxious stimulus was applied with a long hemostat (8-inch Rochester Dean Hemostatic Forceps) clamped to the first ratchet lock on the tail for 60 seconds, immediately before the gas sample was obtained from the trachea. The tail was always stimulated proximally to a previous test site when the previous response was negative, or it was stimulated distally if it was positive, starting 6 cm from the tail base. A positive response was considered to be a gross purposeful movement of the head, extremities, or body. A negative response was considered to be the lack of movement or grimacing, swallowing, chewing, or tail flicking. When a negative response was seen, the sevoflurane concentration was reduced in decrements of 0.2% until the negative response became positive. Similarly, when a positive response was seen, the sevoflurane concentration was increased until the positive response became negative. The MAC was considered to be the concentration midway between the highest concentration that permitted movement in response to the stimulus and the lowest concentration that prevented such movement. Determination of the MAC was performed in a laboratory at 650 m above sea level.
Experimental Design and Drug Groups
The MACSEV was determined 4 times in every animal. Once the animals were anesthetized and instrumented, a baseline MAC (MACSEV) was determined, and each animal acted as its own control. In the first experiment, ketamine was then administered intraperitoneally, and remifentanil (high and low doses or saline) was continuously infused into the tail vein 30 minutes later with no initial loading dose. The MAC was redetermined (MAC-2), and again approximately 90 minutes later (MAC-3). Finally, the remifentanil infusion was stopped, and the MAC was determined once more (MAC-4). Periods of 30 minutes were allotted between MAC determinations, and periods of 40 to 60 minutes were usually necessary to determine the MAC value. Overall, every experiment lasted >6 hours. Fifteen groups (drug × dose; n = 6 per group) were established in the first experiment according to the drug administered: ketamine (4 doses and saline), remifentanil (2 doses), or a combination of the 2. Therefore, 5 groups were administered ketamine at doses of 10, 20, 40, and 80 mg kg−1 or saline intraperitoneally once the MACSEV was determined. Ten additional groups were given the same doses of ketamine or saline and were also administered remifentanil at either 120 or 240 μg kg−1 h−1 (low and high doses, respectively) during the MAC-2 and MAC-3 determinations.
In a second experiment, to evaluate the potential blocking action of ketamine in AOT, another group of animals (n = 6) was administered the lowest dose of ketamine (10 mg kg−1) after the MAC-2 was determined with remifentanil at 120 μg kg−1 h−1.
In a third experiment, we aimed to assess whether the observed effects of ketamine on the MAC would have been mediated, at least in part, through opioid receptors. To test this, we administered naloxone 10 mg kg−1, without remifentanil, to a group of rats treated with ketamine 40 mg kg−1 (n = 6), 15 minutes after the determination of the MAC-2.
Animals were euthanized with an overdose of potassium chloride given IV while they were still deeply anesthetized (Fig. 1).
Sample size calculations indicated an n value of 6 necessary to determine differences with a power of 80% and a P value of 0.05. Mean and SD was obtained from a previous study,21 and the statistical package used was N Query Advisor (version 2.0; Statistical Solutions. Saugus, MA).
Results are presented as mean ± sd. Rats in every experiment were randomly allocated using a random number generator (Excel 2007, Microsoft Office). Data were tested for normality with the Kolmogorov–Smirnov test. To assess the interaction between remifentanil and ketamine in the MAC, a 2-way analysis of variance (ANOVA) was used. A 1-way ANOVA was used to determine the effect of ketamine on the prevention of AOT (experiments 1 and 2) as well as the effect of naloxone and ketamine in the MAC (Experiment 3). The Bonferroni test was used to compare groups. A P value of <0.05 was set to indicate statistical significance. All analyses were performed using the SPSS statistical package (version 15 for Windows, 2006; SPSS Inc., Chicago, IL).
The baseline MACSEV determined in all rats was 2.3% ± 0.3% volume (n = 102) and was similar among groups (P = 1.00).
Effects of Ketamine and Remifentanil on the MAC (Experiment 1; Fig. 2)
Ketamine dose-dependently reduced the MAC with a maximum reduction (MAC-2) of 4% ± 8%, 12% ± 8%, 25% ± 2%, and 41% ± 10% with 10, 20, 40, and 80 mg kg−1, respectively. The MAC reduction observed in a further MAC determination (MAC-3) was similar to that determined in MAC-2 in all groups (MAC reduction of 6% ± 10%, 13% ± 9%, and 16% ± 11% with 10, 20, and 40 mg kg−1, respectively; P > 0.05), with the exception of the group that was administered ketamine 80 mg kg−1 (MAC reduction of 29% ± 12%; P = 0.008). In the last MAC determination (MAC-4), values were not different from baseline (as percentage of variation from baseline; P > 0.05) in all groups, with the exception of the ketamine 80 mg kg−1 group in which MAC-4 was lower than baseline values (P < 0.001).
Remifentanil, given alone, dose-dependently reduced the MAC (MAC-2) by 20% ± 9% and 30% ± 6% with the low and high doses, respectively. However, an AOT effect to remifentanil was observed approximately 1.5 hours later (MAC-3) as determined by a lower MAC reduction, 14% ± 4% and 18% ± 2% with the low and high doses, respectively (P = 0.001 and P = 0.004, respectively), even though the same remifentanil constant rate of infusion had been maintained (Table 1).
Effects of Combined Action of Ketamine and Remifentanil on the MAC and AOT (Experiment 1; Fig. 2)
There was no significant interaction between remifentanil and ketamine, and individual doses of ketamine were not compared (P = 0.32). The high dose of remifentanil (P < 0.001), but not the low dose (P = 0.12), significantly increased the MAC reduction produced by ketamine (all doses) combined with saline. Individual MAC-2 reductions were 5% ± 10%, 17% ± 5%, 28% ± 6% ,and 38% ± 9% with remifentanil at 120 μg kg−1 h−1, and 23% ± 5%, 38% ± 12%, 47% ± 16%, and 62% ± 10% with remifentanil at 240 μg kg−1 h−1, combined with ketamine at 10, 20, 40, and 80 mg kg−1, respectively.
Remifentanil administration produced an AOT effect in all groups determined by a significantly lower MAC reduction (MAC-2 vs. MAC-3; P < 0.05), with the exception of the remifentanil low-dose (120 μg kg−1 h−1) and the ketamine lowest-dose group (10 mg kg−1) (Table 1).
A Delayed Administration of A Low Dose of Ketamine did not Prevent Remifentanil-induced AOT in the MAC (Experiment 2, Table 2)
A remifentanil-induced AOT was observed when remifentanil was administered alone at 120 μg kg−1 h−1 (1.7% ± 0.2% volume and 1.9% ± 0.3% volume MAC-2 and MAC-3, respectively; P = 0.01). When the lowest dose of ketamine, 10 mg kg−1, was administered after the remifentanil infusion was started and the MAC-2 determined, an AOT to remifentanil was observed because MAC-3 (2.0% ± 0.2% volume) was different from MAC-2 (1.8% ± 0.2% volume) (P = 0.007).
Naloxone Blunted the MAC Reduction Produced by Ketamine (Experiment 3; Fig. 3)
Naloxone (10 mg kg−1) significantly blocked (MAC reduction of 4% ± 1%) the MAC reduction produced by ketamine (40 mg kg−1) (MAC reduction of 20% ± 1%) (P = 0.001).
Given alone, ketamine and remifentanil both dose-dependently reduced the MACSEV in the rats. However, the combination of both drugs during sevoflurane anesthesia enhanced the MAC reduction produced by either drug alone in a subadditive fashion. In fact, the dose-dependent anesthetic-sparing effect of ketamine was not improved by the low dose of remifentanil, and a 20% further reduction in the MAC was observed after the high dose of this opioid with every ketamine dose given to the rats.
There is evidence suggesting that ketamine in subanesthetic doses (a dose below that required to produce anesthesia) administered in the perioperative period is effective in reducing opioid requirements postoperatively in humans3,4,6–9,15,30–32 and animals.33–35 However, controversial results have been reported regarding the efficacy of ketamine in improving pain relief when combined with opioids. A recent qualitative review of randomized trials concluded that the benefit of adding ketamine to morphine in IV patient-controlled analgesia for orthopedic or abdominal surgery remains unclear with 5 clinical trials of 11 failing to demonstrate improved postoperative analgesia.15 Besides, although most studies have assessed postoperative pain, no study has screened the effects of these drugs in the intraoperative period during inhaled anesthesia. Results from our study suggest a subadditive interaction between remifentanil and ketamine in terms of MAC reduction because the effects of the combination are less than the sum of the expected effects of the 2 drugs alone. Furthermore, the low dose of remifentanil, which reduced the MAC by 20%, did not improve the anesthetic-sparing action of ketamine.
The use of opioids is associated with a gradual decrease in their analgesic efficacy due to opioid tolerance, and eventually a dose escalation is necessary to maintain the same net analgesic effect in the long term.21,36 A link between opioid tolerance and NMDA activity has been proposed by which opioids might enhance NMDA receptor function37,38 in cancer16 or surgical patients.4,5 Remifentanil not only acts on opioid receptors but also on NMDA receptors, potentially triggering opioid tolerance.37,39 Morphine induces up-regulation of the spinal NMDA receptor NR2B subunit expression, and activation of JNK in the spinal cord, leading to morphine antinociceptive tolerance,40 which can be prevented or reversed by NMDA antagonists.1,22,23,41 Therefore, remifentanil-induced hyperalgesia and acute tolerance19,20 might be thwarted by the administration of ketamine. However, although an AOT effect has been observed that leads to blunting of the MAC reduction produced by remifentanil in rats,21 a preventive action of ketamine could not be determined from the results of the present study.
A potential explanation for the limited additive action of ketamine and remifentanil, in comparison with morphine, is a potential variable degree of interaction of ketamine with opioids at the μ receptor. Ketamine binds to μ opioid receptors,42–44 and their activation can reduce the MACSEV45 while their blockade by the opioid antagonist naloxone46 determined the suppression of the ketamine-induced MAC reduction. Additional evidence for a differential interaction of opioids with ketamine has been found at the spinal cord. Epidural ketamine selectively enhances epidural morphine but may antagonize the antinociceptive activity of fentanyl in rats.35 Also, a lack of analgesic interaction has been determined with epidural meperidine in dogs.47 The combination of 2 lipophilic and fast-acting drugs, such as ketamine42,48 and remifentanil, might cause competition for the μ receptor, with less μ receptor occupancy by remifentanil and thus potential antagonism of the remifentanil-induced antinociception by ketamine. Other potential explanations35 may involve a variable binding affinity for the opioid receptor by morphine and fentanyl, a competitive impairment in the passive diffusion of both drugs, a competition for binding to the same transporter through the blood-brain barrier, or reduced metabolism through the inhibition of morphine glucuronidation by ketamine.49
Another relevant issue when determining the enhancement between ketamine and opioids is the measurement method. Previous studies have reported an improvement in analgesic efficacy in the postoperative period, whereas our study determined the MAC. The MAC is a standard measure of the potency of inhalation anesthetics,29 and comparison among different analgesic substances can be made by determining the degree of MAC reduction they produce. Furthermore, this method is of clinical value because it better mimics the intraoperative period. However, the MAC reduction is not only the result of the antinociceptive effects of the drugs but also the result of complex interactions between the analgesic drugs and volatile anesthetics.24 The MAC actually measures immobility to a noxious stimulus,50 immobility that is considered to be the result of anesthetic effects at the spinal cord.51
The noxious stimulus used for the determination of MAC may also influence the observed interaction between remifentanil and ketamine. Remifentanil increases all thresholds for pain detection and tolerance to pressure as well as to electrical nociceptive stimuli.5 Ketamine failed to prevent tolerance to remifentanil and opioid-induced hyperalgesia in healthy volunteers when a nociceptive pressure stimulus, similar to that used in the MAC method, was applied. However, a preventive action of ketamine was observed with repeated electrical stimulation,52 inducing central temporal summation and involving NMDA receptors.53
Differences in the doses of drugs between people and rats may account for the observed effects. Extrapolation of doses from rats to humans should be based on allometric escalation, and refer to body surface rather than body weight. Doses of ketamine below 80 mg kg−1 should be considered subanesthetic,41,54 and actually higher doses necessary to produce anesthesia should be combined with sedatives such as α-2 adrenoceptor agonists. The doses of remifentanil that we used25 were based on their ability to produce a significant MAC reduction.55 Nevertheless, the observed results should not be directly extrapolated between species because the same opioids and doses may actually account for large variations in the MAC.50,56
In conclusion, a subadditive effect between ketamine and remifentanil was found on the MACSEV reduction in rats, and in addition, ketamine was unable to block the acute tolerance to remifentanil, leading to a blunting effect on the MAC reduction produced by the opioid. Further studies should determine whether the interaction observed in rats is of clinical relevance.
Name: Delia Aguado, DVM.
Contribution: Study design, conduct of study, data analysis, and manuscript preparation.
Name: Mariana Abreu, DVM.
Contribution: Conduct of study.
Name: Javier Benito, DVM.
Contribution: Study design and manuscript preparation.
Name: Javier García-Fernández, MD, PhD.
Contribution: Study design and manuscript preparation.
Name: Ignacio A. Gómez de Segura, DVM, PhD, DECLAM, DECVA.
Contribution: Study design, data analysis, and manuscript preparation.
This manuscript was handled by Marcel E. Durieux, MD, PhD.
The authors thank Drs. E. de Miguel and C. Largo, Department of Experimental Surgery, La Paz University Hospital, Madrid, Spain.
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