Delia Aguado

Reduction of the minimum alveolar concentration of isoflurane in dogs using a constant rate of infusion of lidocaine–ketamine in combination with either morphine or fentanyl

The objective of this study was to determine the effects of a constant rate of infusion of lidocaine and ketamine in combination with either morphine or fentanyl on the minimum alveolar concentration of isoflurane (MAC(ISO)) during ovariohysterectomy in dogs. Female dogs (n=44) were premedicated with acepromazine and midazolam. Anaesthesia was induced with propofol and maintained with isoflurane. Dogs received ketamine (0.6 mg/kg/h) and lidocaine (3 mg/kg/h) together with morphine (0.24 mg/kg/h; MLK) or fentanyl (0.0036 mg/kg/h; FLK). The control group received Ringers lactate solution. A skin incision was used as the noxious stimulus. The MAC(ISO) value was obtained with Dixons up-and-down method. MAC(ISO) was 0.7±0.0 vol.% in the control group, 0.3±0.0 vol.% in the MLK group (45% MAC reduction) and 0.0±0.0 vol.% in the FLK group (97% MAC reduction). A combination of fentanyl with lidocaine and ketamine decreased the MAC(ISO) in dogs; this decrease was more pronounced than that produced by morphine, lidocaine and ketamine.

Opioid Tolerance Blunts the Reduction in the Sevoflurane Minimum Alveolar Concentration Produced by Remifentanil in the Rat

Background:Acute opioid tolerance is a known entity leading to reduced analgesic efficacy of these drugs in the postoperative period. However, the development of acute opioid tolerance in the very short term, i.e., during the intraoperative period when opioids are being administered, has not been reported. Therefore, the aim of this study was to determine if acute opioid tolerance could develop and limit the opioid-induced reduction in the minimum alveolar concentration (MAC) for inhalant anesthetics. Methods:Male Wistar rats were randomly allocated to receive two doses of remifentanil (120 and 240 &mgr;g · kg−1 · h−1) under sevoflurane anesthesia, and the sevoflurane MAC was determined before and at two time intervals afterwards. In a second experiment, the low dose of remifentanil was increased once an acute opioid tolerance effect was observed. The sevoflurane MAC was determined from alveolar gas samples at the time of tail clamp. Results:A remifentanil constant rate of infusion dose-dependently reduced the sevoflurane MAC from 2.4 to 1.8 ± 0.2 vol% and from 2.3 ± 0.3 vol% to 1.5 ± 0.3 vol%, at the low and high doses, respectively. However, 90 min later, when the sevoflurane MAC was redetermined, the observed reduction was blunted to nearly 50% of the previous sevoflurane MAC values. When this acute opioid tolerance effect was observed with the low dose, the sevoflurane MAC reduction originally achieved could be reattained by doubling the dose; i.e., giving the high dose. Conclusions:Remifentanil efficacy in reducing the sevoflurane MAC diminishes within a short term, suggesting that increased opioid doses may be required to maintain intraoperative analgesia during sevoflurane anesthesia.

Effects of Naloxone on Opioid-induced Hyperalgesia and Tolerance to Remifentanil under Sevoflurane Anesthesia in Rats

Background:Opioid antagonists at ultra-low doses have been used with opioid agonists to prevent or limit opioid tolerance. The aim of this study was to evaluate whether an ultra-low dose of naloxone combined with remifentanil could block opioid-induced hyperalgesia and tolerance under sevoflurane anesthesia in rats. Methods:Male adult Wistar rats were allocated into one of four treatment groups (n = 7), receiving remifentanil (4 µg·kg−1·min−1) combined with naloxone (0.17 ng·kg−1·min−1), remifentanil alone, naloxone alone, or saline. Animals were evaluated for mechanical nociceptive thresholds (von Frey) and subsequently anesthetized with sevoflurane to determine the baseline minimum alveolar concentration (MAC). Next, treatments were administered, and the MAC was redetermined twice during the infusion. The experiment was performed three times on nonconsecutive days (0, 2, and 4). Hyperalgesia was considered to be a decrease in mechanical thresholds, whereas opioid tolerance was considered to be a decrease in sevoflurane MAC reduction by remifentanil. Results:Remifentanil produced a significant decrease in mechanical thresholds compared with baseline values at days 2 and 4 (mean ± SD, 30.7 ± 5.5, 22.1 ± 6.4, and 20.7 ± 3.7g at days 0, 2, and 4, respectively) and an increase in MAC baseline values (2.5 ± 0.3, 3.0 ± 0.3, and 3.1 ± 0.3 vol% at days 0, 2, and 4, respectively). Both effects were blocked by naloxone coadministration. However, both remifentanil-treated groups (with or without naloxone) developed opioid tolerance determined by their decrease in MAC reduction. Conclusions:An ultra-low dose of naloxone blocked remifentanil-induced hyperalgesia but did not change opioid tolerance under inhalant anesthesia. Moreover, the MAC increase associated with hyperalgesia was also blocked by naloxone.

Reduction of the sevoflurane minimum alveolar concentration induced by methadone, tramadol, butorphanol and morphine in rats.

This study aimed to estimate the reduction in the minimum alveolar concentration (MAC) of sevoflurane induced by low and high doses of methadone (5 and 10 mg/kg), tramadol (25 and 50 mg/kg), butorphanol (5 and 10 mg/kg) or morphine (5 and 10 mg/kg) in the rat. A control group received normal saline. Sixty-three adult male Sprague-Dawley rats were anaesthetized with sevoflurane (n = 7 per group). Sevoflurane MAC was then determined before and after intraperitoneal administration of the opioids or saline. The duration of the sevoflurane MAC reduction and basic cardiovascular and respiratory measurements were also recorded. The baseline MAC was 2.5 (0.3) vol%. Methadone, tramadol and morphine reduced the sevoflurane MAC (low dose: 31 ± 10, 38 ± 15 and 30 ± 13% respectively; high dose: 100 ± 0, 83 ± 17 and 77 ± 25%, respectively) in a dose-dependent manner. The low and high doses of butorphanol reduced the sevoflurane MAC to a similar extent (33 ± 7 and 31 ± 4%, low and high doses, respectively). Two rats developed apnoea following administration of high-dose butorphanol and methadone. These anaesthetic-sparing effects are clinically relevant and may reduce the adverse effects associated with higher doses of inhalational anaesthetics.

Ketamine and remifentanil interactions on the sevoflurane minimum alveolar concentration and acute opioid tolerance in the rat.

BACKGROUND: Ketamine is used at low doses for its analgesic and antihyperalgesic properties when combined with opioids but also when opioid-induced hyperalgesia and tolerance appear. In this study we determined the interaction of ketamine and remifentanil on the minimum alveolar concentration (MAC) of sevoflurane in rats and to determine whether ketamine may block acute opioid tolerance (AOT). METHODS: Male Wistar rats were anesthetized with sevoflurane, and the MAC was determined before and after ketamine administration (10, 20, 40, and 80 mg kg−1 or saline) alone or combined with remifentanil (120 and 240 &mgr;g kg−1 h−1, low and high doses, respectively). One additional group received the lowest ketamine dose after starting a remifentanil infusion. Finally, naloxone was administered to determine the potential action of ketamine on opioid receptors. MAC was determined from intratracheal gas samples, and tail clamping was used as a supramaximal stimulus. End-tidal anesthetic concentrations were assayed using a side stream gas analyzer. Statistical analysis was performed with an analysis of variance. RESULTS: Ketamine and remifentanil dose-dependently reduced the MAC. Adding the low dose of remifentanil to ketamine did not improve the MAC reduction, whereas the high dose of remifentanil enhanced ketamine reduction in a subadditive fashion. Nevertheless, ketamine was unable to block the development of AOT to remifentanil at either dose. Finally, naloxone blocked the MAC reduction produced by ketamine. CONCLUSIONS: A subadditive effect between ketamine and remifentanil was found on the sevoflurane MAC reduction rats. In addition, ketamine was unable to block AOT. The clinical relevance of these findings should be elucidated in future studies to reduce anesthetic requirements.

Remifentanil and cyclooxygenase inhibitors interactions in the minimum alveolar concentration of sevoflurane in the rat

BACKGROUND Intraoperative opioids reduce anaesthetic requirements and thus limit the side-effects derived from high doses of the latter. Cyclooxygenase (COX) inhibitors can also be given but it remains unclear whether they further reduce the anaesthetic requirements. Our aim was to determine whether COX inhibitors potentiate the effect of remifentanil on the minimum alveolar concentration (MAC) of sevoflurane anaesthetized rats. METHODS Male Wistar rats received remifentanil under sevoflurane anaesthesia, and the MAC was determined before and at two time intervals after, separated by 1.5 h. Rats were randomly allocated to receive paracetamol, metamizole, ketoprofen, or parecoxib just before one of the two studied time intervals. The MAC was determined from alveolar gas samples at the time of tail clamp. Data were analysed with an analysis of variance for repeated measures. RESULTS Paracetamol potentiated the MAC reduction produced by remifentanil in rats (P=0.002), whereas metamizole, ketoprofen, and parecoxib failed to produce such an effect. Furthermore, paracetamol and remifentanil produced a maximum degree of MAC reduction [35 (10)%] even when a tolerance effect to remifentanil was observed in animals given remifentanil alone (P<0.001). A tolerance to remifentanil was not observed when metamizole, ketoprofen, or parecoxib was given once the opioid infusion has been started (P>0.05). CONCLUSIONS COX inhibitors differentially potentiate the analgesic effect produced by remifentanil on the sevoflurane MAC, and paracetamol was the most effective drug. However, since all COX inhibitors prevented a tolerance effect to opioids once it was established, intraoperative rather than preoperative administration of these drugs is suggested.

Pressure safety range of barotrauma with lung recruitment manoeuvres: A randomised experimental study in a healthy animal model

CONTEXT Recruitment manoeuvres aim at reversing atelectasis during general anaesthesia but are associated with potential risks such as barotrauma. OBJECTIVE To explore the range of pressures that can be used safely to fully recruit the lung without causing barotrauma in an ex-vivo healthy lung rabbit model. DESIGN Prospective, randomised, experimental study. SETTING Experimental Unit, La Paz University Hospital, Madrid, Spain. ANIMALS Fourteen healthy young New Zealand rabbits of 12 weeks of age. INTERVENTIONS Animals were euthanised, the thorax and both pleural spaces were opened and the animals were allocated randomly into one of two groups submitted to two distinct recruitment manoeuvre strategies: PEEP-20 group, in which positive end-expiratory pressure (PEEP) was increased in 5-cmH2O steps from 0 to 20 cmH2O and PEEP-50 group, in which PEEP was increased in 5-cmH2O steps from 0 to 50 cmH2O. In both groups, a driving pressure of 15 cmH2O was maintained until maximal PEEP and its corresponding maximal inspiratory pressures (MIPs) were reached. From there on, driving pressure was progressively increased in 5-cmH2O steps until detectable barotrauma occurred. Two macroscopic conditions were defined: anatomically open lung and barotrauma. MAIN OUTCOME MEASURES We measured open lung and barotrauma MIP, PEEP and driving pressure obtained using each strategy. A pressure safety range, defined as the difference between barotrauma MIP and anatomically open lung MIP, was also determined in both groups. RESULTS Open lung MIP was similar in both groups: 23.6 ± 3.8 and 23.3 ± 4.1 cmH2O in the PEEP-50 and PEEP-20 groups, respectively (P = 0.91). However, barotrauma MIP in the PEEP-50 group was higher (65.7 ± 3.4 cmH2O) than in the PEEP-20 group (56.7 ± 5 0.2 cmH2O) (P = 0.003) resulting in a safety range of pressures of respectively 33.3 ± 8.7 and 42.1 ± 3.9 cmH2O (P = 0.035). CONCLUSION In this ex-vivo model, we found a substantial difference between recruitment and barotrauma pressures using both recruitment strategies. However, a higher margin of safety was obtained when a higher PEEP and lower driving pressure strategy was used for recruiting the lung.

The effects of gabapentin on acute opioid tolerance to remifentanil under sevoflurane anesthesia in rats.

BACKGROUND: Tolerance to remifentanil during sevoflurane anesthesia may blunt the ability of this drug to reduce anesthetic requirements. Gabapentin has been shown to be effective in reducing postoperative narcotic usage, a reduction that may be associated with a reduction in opioid-induced tolerance and hyperalgesia. We sought to determine whether gabapentin might prevent the observed acute opioid tolerance (AOT) produced by remifentanil in sevoflurane minimum alveolar concentration (MAC). METHODS: Wistar rats were anesthetized with sevoflurane and the effects of gabapentin alone on sevoflurane MAC were determined at doses of 150 and 300 mg · kg−1. In a second experiment, gabapentin 300 mg · kg−1 was administered before remifentanil (120 and 240 &mgr;g · kg−1 · h−1). The MAC was determined before gabapentin administration and 3 more times at 1.5-hour intervals after drug administration to assess AOT. MAC was determined from intratracheal gas samples using a sidestream gas analyzer; tail clamping was used as a supramaximal stimulus. Statistical analysis was performed with the 1-way analysis of variance test. RESULTS: Remifentanil reduced MAC (2.5 ± 0.2%) by 16% ± 5% and 36% ± 6% (120 and 240 &mgr;g · kg−1 · h−1, respectively, P < 0.01) with a further reduction produced by coadministration with gabapentin 300 mg · kg−1 to 39% ± 12% and 62% ± 14%, respectively (P < 0.01 versus remifentanil alone). Gabapentin given alone at 150 and 300 mg · kg−1 reduced MAC by 26% (both doses, P < 0.01). AOT was observed with remifentanil and characterized by a lower degree of MAC reduction, approximately 1.5 hours later (P < 0.05). However, when remifentanil was administered with gabapentin, the AOT to remifentanil was not observed (P > 0.05). CONCLUSIONS: Gabapentin reduced the sevoflurane MAC and enhanced the MAC reduction produced by remifentanil. This enhancement may limit AOT in rats.

Hyperalgesia and increased sevoflurane minimum alveolar concentration induced by opioids in the rat A randomised experimental study

BACKGROUND Perioperative opioids reduce inhalational anaesthetic requirements. The initial hypoalgesia may, however, be followed by a rebound hyperalgesia. OBJECTIVES To determine whether prior opioid administration influences inhalational anaesthetic requirements, which might be associated with opioid-induced hyperalgesia. DESIGN A prospective, randomised, experimental study. SETTING Experimental Surgery, La Paz University Hospital, Madrid, Spain. ANIMALS Seventy-nine adult male Wistar rats. INTERVENTIONS Sevoflurane minimum alveolar concentration (MAC) and mechanical nociceptive thresholds (MNTs) were assessed at baseline and 7 days later following opioid treatment with remifentanil 120 &mgr;g kg−1 h−1, buprenorphine 150 &mgr;g kg−1, methadone 8 mg kg−1 or morphine 10 mg kg−1. The duration of the effect of remifentanil on MAC and MNT was evaluated in addition to the preventive effect of ketamine 10 mg kg−1 on remifentanil-induced hyperalgesia. MAIN OUTCOME MEASURES The effect of different opioid treatments on MAC and MNT was evaluated using analysis of variance (ANOVA). RESULTS All studied opioids produced an immediate reduction in sevoflurane MAC, followed by an increase (16%) in baseline MAC 7 days later (P < 0.05), although the immediate MAC reduction produced by these opioids at that time was not different. Remifentanil produced a decrease in MNT (P < 0.05), which was associated with an increase in the MAC (P < 0.05) that persisted at 21 days. The effect of remifentanil on MNT and MAC was blocked by ketamine. CONCLUSION Opioid-induced hyperalgesia was associated with an increase in the MAC in normal rats who had not undergone surgery. Both effects lasted 21 days and were prevented by ketamine.

Clinical comparison of the effects of isoflurane or propofol anaesthesia on mean arterial blood pressure and ventilation in dogs undergoing orthopaedic surgery receiving epidural anaesthesia

The aim of this study was to compare the effects on mean arterial pressure (MAP) and ventilation of propofol total IV anaesthesia (TIVA) and isoflurane as anaesthetic maintenance in healthy dogs undergoing orthopaedic surgery, with epidural anaesthesia. Dogs were premedicated IM with dexmedetomidine (4μg/kg) and methadone (0.3mg/kg), induced with IV propofol (0.65-5mg/kg) and randomly assigned to be maintained with isoflurane (group I) or propofol (group P). Isoflurane end-tidal concentration (EtISO) and propofol infusion rate were adjusted during the surgery to maintain a suitable anaesthetic depth. All dogs received bupivacaine (1mg/kg) and morphine (0.1mg/kg) in the lumbosacral epidural space (total volume 0.2mL/kg). MAP was recorded every 5min during the procedure. Statistical analysis was performed using parametric (Students t test) and nonparametric (Mann-Whitney U-test, chi-square) tests, as appropriate. Anaesthetic maintenance in groups I and P was accomplished by providing a mean EtISO of 1.12±0.15% and a mean propofol infusion rate of 15.0±4.7mg/kg/h, respectively. MAP was significantly higher in group P than in group I (92±17mmHg versus 78±10mmHg; P=0.021). Eleven dogs in group P and two dogs in group I reached an EtCO2>7.3kPa, requiring mechanical ventilation (P=0.001). In combination with epidural anaesthesia, propofol TIVA improved MAP and is a suitable alternative to isoflurane in orthopaedic surgery of the hind limb in healthy dogs. Nevertheless, since it was associated with increased respiratory depression, mechanical ventilation should be available.