The ED50and ED95of Dexmedetomidine For Inhibiting Postoperative Hyperalgesia After Remifentanil-based Anesthesia

As narcotic analgesics commonly used in surgery, opioid analgesics can reduce or eliminate the pain as well as change the emotional response to pain. With the in-depth clinical applications and laboratory research are continuously expanding, opioid analgesics have been found to increase postoperative pain sensitivity which not only can reduce the analgesic effect, but also increase pain perception and produce abnormal pain. Opioids induced hyperalgesia (OIH) is defined as an increased sensitivity to pain or a decreased pain threshold in response to opioid therapy.Studies showed that all of the opioids could cause hyperalgesia, such as remifentanil, fentanyl, morphine, pethidine and methadone. Various routes (local application, intrathecal injection, intravenous administration) and modes (single injection, repeated administration, chronic administration) of opioids administration have been reported to cause OIH. Remifentanil, an ultra-short-acting μ-opioid receptor agonist with an analgesic potency similar to that of fentanyl, has been widely used in the induction and maintenance of general anesthesia. Remifentanil has a predictable and rapid recovery that is independent of the dose and duration of infusion. Remifentanil is metabolized in blood and tissues by nonspecific esterases and its metabolism is unaffected by the occurrence of renal or hepatic disease. Remifentanil’s unique pharmacokinetic characteristics make it an ideal narcotic analgesic by continuous intravenous infusion. However, considerable evidence suggests that OIH are closely related to pharmacokinetic characteristics, long-term and high-dose administration, or rapid changes in blood concentration of opioid analgesic drugs. Remifentanil induced postoperative hyperalgesia is more serious than other opioids.Laparoscopic cholecystectomy (LC), which has advantages of less injury, rapid recovery and satisfactory curative effect, is a safe procedure providing high patient satisfaction. In laparoscopic cholecystectomy, compared with fentanyl/propofol, remifentanil/propofol provide a more stable hemodynamic status, a more rapid recovery and extubation. Compared with intravenous inhalational anesthesia, continuous infusion of remifentanil/propofol have profound sedative and analgesic effect, rapid onset,short duration of action and no significant adverse reactions. For laparoscopic cholecystectomy, continuous infusion of remifentanil with propofol is a safe and effective method. It is noteworthy that, pain scores after tracheal extubation are significantly higher under remifentanil/propofol anesthesia. The results are related not only to the rapid metabolism of remifentanil, but also to the OIH.Although the precise molecular mechanism of OIH is not yet understood, activation of the N-methyl-D-aspartate (NMDA)-receptor system has been proposed to play an important role in the occurrence of OIH. OIH can increase pain perception, affect circulatory, respiratory and endocrine systems, even cause psychological trauma, anxiety, fear and insomnia. All the above have a negative impact on patients. For best results, steps should have been taken preventatively before the patients feel pain postoperatively. Dexmedetomidine, a highly selective a2adrenergic receptor agonist with an a2/α1ratio of1,620:1, has combined functions of dose-dependent sedation and analgesia and have been widely used as premedication, general anesthetic adjuvant, postoperative analgesic. By acting on the locus ceruleus of the brainstem, dexmedetomidine initiates and maintains non-rapid eye movement; produces sedative, hypnotic and anxiolytic effects without respiratory depression. Dexmedetomidine can alleviate unpleasant emotional experience caused by the pain, reduce the use of perioperative opioid drugs. By inhibiting sympathetic nerve activity and catecholamine release caused by surgical stress, dexmedetomidine can attenuate the hemodynamic responses to tracheal intubation and surgical stimuli.In recent years, dexmedetomidine has increasingly been used for postoperative analgesia as well as the prevention and treatment of hyperalgesia. Recent studies have shown that dexmedetomidine could effectively relieve the postoperative hyperalgesia induced by remifentanil. At present, the prevention and treatment of OIH lack systematicness. How to obtain satisfactory analgesia and restore normal function of the patients’ organs as soon as possible, presents a challenge for our clinical analgesic. In this study,we investigate the dose-response relationship of dexmedetomidine for inhibiting postoperative hyperalgesia after remifentanil-based anesthesia in patients undergoing laparoscopic cholecystectomy surgery, in order to provide reference for clinical medication and to explore the possible mechanism.Research methods1Part One1.1General informationAfter approved by the ethics committee of Nangfan Hospital, we studied100patients undergoing laparoscopic cholecystectomy surgery under remifentanil-based general anesthesia from May to December2013. All genders, age30～65, weight 50-80kg, American Society of Anesthesiologists physical status Ⅰ～Ⅱ. Heart, lung, liver, kidney and blood coagulate functions are normal. No history of hormone application in a week before the operation. No history of alcohol or drug abuse, or opioid-containing pain or sedative medications. NYHA class Ⅰ～Ⅱ. EF>55%. The patients have no rheumatism activity. No acute infection. No diabetes. No history of immune system disease, nervous system disease and mental disease. No tuberculosis, hepatitis, syphilis and other infectious diseases. No contraindications to general anesthesia. The research subjects are han Chinese and there are no relationgship between them. All the patients were informed consent.1.2Anesthesia method and intraoperative monitoringPatients received10mg diazepam and0.5mg atropine intramuscularly30minutes before anesthesia. After entering the operating room, all patients have their ECG， heart rate, blood pressure, temperature, SpO2, PETCO2continuously monitored. Using bispectral index monitor continuously monitor BIS. Anesthesia was induced with midazolam0.05mg/kg, propofol2mg/kg, fentanyl4μg/kg and cisatracurium0.2mg/kg and maintained with infusion of remifentanil (0.25μg/kg/min) and propofol (4-12mg/kg/h). Cisatracurium was given intermittently. The patients were mechanically ventilated after tracheal intubation. Adjust the minute volume to maintain the PETCO2between35-45mmHg (1mmHg=0.133kPa). Adjust the dose of propofol during surgery so that the BIS value was maintained at40～50. Patients received0.05mg/kg cisatracurium intermittently to maintain muscle relaxation. Muscle relaxant should be stopped30min before the end of surgery. Stop propofol and remifentanil immediately after discontinuation of pneumoperitoneum. Extubation was conducted as the patient met the extubation indications:fully awake, restoration of spontaneous breathing, normal PETCO2, SpO2>95%, normal pharyngeal reflex and cough reflex recovery. Pain was assessed using VAS3times during30min after tracheal extubation. Interval between each VAS assessment is at least five minutes. Take the mean VAS scores as the final data.1.3Dexmedetomidine applicationPrior40min to the end of surgery, dexmedetomidine was given by a continuous infusion for20min to inhibit remifentanil-induced postoperative hyperalgesia. The dose of dexmedetomidine administered is determined by the sequential test method: initial dose is0.45μg/kg/h, dose gradient is0.05μg/kg/h. The mean VAS score<4was defined as effective. The optimal dose was determined by Dixon-Massey method. If the mean VAS score was<4, the next patient received a lower dose of Dexmedetomidine, or conversely if ineffective, a high dose was given in the next patient.1.4Observation target1.4.1VAS assessmentThe ruler which is ten centimeters long has one side marked with ten scales. One end of the ruler is "0" while the other end is "10".0points indicating no pain,10points indicating the most intense pain. The patients can mark the corresponding location on the ruler that representing their pain degree. Read the score according to the marked position.1.4.2Adverse reactionIf the subject investigated had arrhythmia, hypotension, hypertension, nausea, vomiting, fever, hypoxia, dizziness, sweating, shivering or respiratory depression, we should make a detailed description of the symptoms and signs, record the time, finally analysis of the causes.1.5StatisticsSPSS20.0software was used to analyze the data. Measurement data expressed as the mean±standard deviation and chi-square analysis was used for enumeration data. The up-and-down sequences were analyzed by using probit method that determines the ED50, ED95and95%confidence interval (CI).2Part Two2.1General information60American Society of Anesthesiologists physical status Ⅰ～Ⅱ patients aged30-65years who were scheduled for laparoscopic cholecystectomy were enrolled in this study. Exclusion criteria were as previously described.2.2Anesthesia method and intraoperative monitoringOn the day before surgery, patients were taught how to use the visual analog scale and the patient-controlled analgesia device. They were instructed to self-deliver analgesia whenever they began to feel pain. The patients were randomly assigned using a computer-generated random number table into one of two treatment groups, each of which received either dexmedetomidine (40minutes before the end of surgery, given by a continuous infusion of0.394μg/kg/h for20min) or placebo saline. General anesthesia procedure was same as Part One. Each patient was administered analgesics using a PC A pump containing sufentanil (100ug) and tropisetron (12mg) in a total volume of100ml of saline. This device was set to deliver a basal infusion of2ml/hr and bolus doses of0.5ml with a15min lockout period. Anesthetics were discontinued when the final surgical stitch had been placed. Immediately after completion of surgery the patient was connected to the PCA pump via an intravenous line. After completion of the surgical procedure, emergence from anesthesia and tracheal extubation, patients were transferred to the postanesthesia care unit.2.3Observation targetThe remifentanil dosage, liquid quantity, duration of operation and extubation time after surgery were recorded. Postoperative pain intensity was documented using a100mm linear VAS. The VAS consisted of a straight line with the left end of the line representing no pain and the right end of the line representing the worst pain. Patients were asked to mark the position on the line corresponding to their perception of pain. An i.v. dose of dezocine (5mg) was administered if patients reported a VAS score>40, and an appropriate amount of dezocine was added as needed during their postanesthesia care unit stay. The primary end points were the time to the first postoperative analgesic requirement, postoperative pain intensity using VAS, and cumulative volume of a PC A containing sufentanil and tropisetron over24hr. Side effects related to the study drugs included hypotension, bradycardia, dysrhythmia, shivering, postoperative nausea and vomiting (PONV).2.4StatisticsStatistical analysis was performed using the SPSS20.0software. The results are presented as mean±SD or number (percentage) of patients. Comparisons of age, body weight, duration of operation, time to first postoperative analgesic requirement, pain intensity, and cumulative PCA volume over24hr after surgery between the groups were conducted using one-way ANOVA (or independent-sample T-test). Chi-square tests were used to analyze categorical data, such as hypotension, bradycardia, shivering, dysrhythmia, and PONV. P<0.05was considered statistically significant.Results1Part one100patients were chosen,in which there are52female and48male.Mean age (44.6±7.8) years, weight (64.0±8.3) kg, remifentanil dosage (887.1±115.2) μg, operative duration(46.8±8.5) min. The ED50and ED95of dexmedetomidine for inhibiting postoperative hyperalgesia after remifentanil-based anesthesia in patients following laparoscopic cholecystectomy were0.394(95%CI=0.268～0.433) μg/kg/h and0.604(95%CI=0.543-0.848) μg/kg/h. Sinus bradycardia occured in one of three patients using0.60μg/kg/h dexmedetomidine. Of fourteen patients using0.55μg/kg/h dexmedetomidine, one patient had hypotension, two patients had sinus bradycardia. Adverse reaction of arrhythmia, hypotension, hypertension, nausea, vomiting, fever, dizziness, sweating, chills, hypoxia, respiratory inhibition were not found in other patients.2Part twoThere were no significant differences between the two groups with respect to age, weight, duration of operation, or infusion of fluid. Extubation time after surgery was significantly longer in the Dex group than in the control group (P<0.05). The time to first postoperative analgesic requirement was significantly shorter in the control group than in the Dex group. Compared with those in the Dex group, analgesic consumption during PACU stay, the dosage of dezocine, pain intensity using VAS were significantly higher or greater in the control group. The occurrence of adverse reactions like hypotension, bradycardia, arrhythmia, chills, and PONV between the two treatments had no significant difference.ConclusionThe ED50and ED95of dexmedetomidine for inhibiting postoperative hyperalgesia after remifentanil-based anesthesia in patients following laparoscopic cholecystectomy were0.394(95%CI=0.268-0.433) μg/kg/h and0.604(95%CI=0.543-0.848) μg/kg/h, which has guiding significances for clinically choosing medicine.