Synergistic antinociceptive interaction between sevoflurane and intrathecal fentanyl in dogs

This study determined the nature of the antinociceptive interaction between sevoflurane and intrathecal fentanyl on somatosympathetic reflexes in anaesthetized dogs. Afferent A delta- and C-fibre-mediated somatosympathetic reflexes, evoked by supramaximal electrical stimulation of tibial nerves, were recorded from renal sympathetic nerves. The effect of fentanyl alone, administered intrathecally (i.t.) in incremental doses from 2 to 64 micrograms, was compared with the effect of the same doses during the administration of 1.5% sevoflurane. The mean ED50s for the depressant effect of fentanyl (i.t.) on A delta and C reflexes were 35.6 micrograms and 14.2 micrograms while 1.5% sevoflurane, when administered alone, depressed them by 15.5% (P < 0.05) and 27.5% (P < 0.01) respectively. During the administration of 1.5% sevoflurane, the mean ED50s of fentanyl (i.t.) for the depression of A delta and C reflexes were reduced by 76% and 75%, to 8.5 micrograms and 3.5 micrograms respectively. The combined antinociceptive effects of sevoflurane and intrathecal fentanyl were not additive but exhibited a high degree of synergistic interaction.      

The anesthetic efficacy of midazolam in the enflurane-anesthetized dog

This study determined the anesthetic efficacy of midazolam (MID) in terms of its ability to reduce enflurane MAC (EMAC). Control EMAC was determined by the tail-clamp method in 15 mongrel dogs. Each animal then received at least three incremental infusion rates of MID from among the following: 0.48, 2.4, 9.6, 19.2, 28.8, 48, or 151.2 micrograms.kg-1.min-1. MAC was determined during each infusion rate following a 1-h observation period, during which time MID concentration in plasma [( MID]) stabilized. [MID] was measured every 15 min beginning 45 min from the start of each new infusion rate. There was a linear relationship between MID infusion rates and the resulting [MID] (r = 0.995). In the range of [MID] from 14 to 14,118 ng/ml, there was a linear relationship between the log [MID] and the percent EMAC reduction. The slope of the line was very shallow, and the [MID] required to reduce EMAC by more than 50% exceeded the [MID] likely to be employed clinically in humans (750 ng/ml). Also, the 73 +/- 4% (mean +/- SEM) EMAC reduction produced by [MID] = 9,763 +/- 1213 ng/ml was not significantly greater than the 60 +/- 3% EMAC reduction achieved by [MID] = 1,464 +/- 293 ng/ml, a finding which suggests a ceiling effect to the anesthetic efficacy of midazolam. The authors conclude that, within the dose range of MID likely to be employed in humans, MID produced a concentration-dependent reduction of enflurane MAC in the dog. In doses above those likely to be employed clinically, a ceiling effect to the anesthetic efficacy of MID may become evident.     

Intrathecal midazolam and fentanyl in the rat: evidence for different spinal antinociceptive effects

The effects of intrathecal midazolam and fentanyl on electrical current threshold for pain were measured using stimulating electrodes in the neck and tail of rats with chronically implanted lumbar subarachnoid catheters. This involved the measurement of the minimum current (50 Hz 2 ms pulses 0-5 mA), which made the rat squeak when applied alternately to electrodes at each skin site. The responses measured in milliamperes were expressed as a number of times control readings. Equieffective doses of both midazolam and fentanyl produced a significant increase in electrical threshold for pain in the tail (mean +/- SEM 3.14 +/- 0.51 and 2.89 +/- 0.35: P less than 0.05; Wilcoxon sum rank test) in the absence of any change in the neck (mean +/- SEM 1.28 +/- 0.13 and 0.96 +/- 0.12, NS), thus demonstrating a spinal effect. Fentanyl caused a significant simultaneous increase in tail flick latency (mean +/- SEM 67.8 +/- 20.1%, P less than 0.05), but midazolam did not (mean +/- SEM 4.22 +/- 2.76%, NS). Intraperitoneal injections of naloxone (0.25 mg/kg) blocked the response to fentanyl in both tests and did not affect the response to midazolam. Intraperitoneal flumazenil (5 mg/kg) blocked the midazolam antinociceptive effect but did not affect the response to fentanyl in either test. Tail withdrawal in response to non-noxious stimulation was preserved in all animals with spinal analgesia, indicating that myelinated afferent and efferent pathways were still functioning. Righting reflex, coordination, motor power, and alertness were also preserved in the presence of both drugs. Both drugs caused spinally mediated antinociceptive effects that were qualitatively different.     

Reversal by naloxone of spinal antinociceptive effects of fentanyl, ketocyclazocine and midazolam.

Experiments using measurement of electrical-current threshold as a nociceptive test in the skin of the tail and neck in rats demonstrated that fentanyl, ketocyclazocine and midazolam caused spinally mediated antinociception when the drugs were administered intrathecally via chronically implanted lumbar subarachnoid catheters. The benzodiazepine antagonist flumazenil selectively suppressed the midazolam response, indicating that this benzodiazepine exerted its segmental antinociceptive effect via spinal-cord benzodiazepine receptors. Naloxone blocked the responses to both opioids and also midazolam. The dose of naloxone which suppressed the midazolam response was similar to that required to suppress the response to the kappa-opioid agonist. We suggest that the segmental antinociceptive effects of fentanyl and midazolam are mediated via different pathways; the benzodiazepine exerts its antinociceptive action via a spinal-cord opioid pathway which does not involve mu-receptors.     

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits

Background: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e. g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. Methods: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. on the effects of propofol and fentanyl respectively on PNA were studied. Results: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg · kg^?1 i. v. and 32 μg · kg^?1 i. v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg · kg^?1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg · kg^?1. The mean ED₅₀s, calculated from dose-response curves, were 5.4 mg · kg^?1, 3.9 μg · kg^?1 and 0.4 mg · kg^?1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg · kg^?1 and 8 μg · kg^?1, respectively. Conclusion: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.     

The additive antinociceptive interaction between WIN 55,212-2, a cannabinoid agonist, and ketorolac

Combinations of nonsteroidal antiinflammatory drugs (NSAIDs) and opioids are widespread in the management of pain, allowing better analgesia with reduced side effects. Cannabinoids are promising analgesic drugs that have pharmacological properties similar to those of opioids. However, the beneficial effects of cannabinoids for pain treatment are counterbalanced by their psychotomimetic side effects. We designed the present study to evaluate the antinociceptive interaction between cannabinoids and NSAIDs in mice, using the acetic acid-induced writhing test and tail-flick test. Interactions were analyzed using isobolographic analysis. WIN 55,212-2, a cannabinoid agonist, and the NSAID ketorolac, either alone or in combination, produced dose-dependent antinociception in the writhing test. Isobolographic analysis showed additive interactions between WIN 55,212-2 and ketorolac when they were coadministered systemically. Ketorolac is inactive in the radiant heat tail-flick test in which WIN 55,212-2 was active. Ketorolac did not influence WIN 55,212-2-induced antinociception in the tail-flick test. This study demonstrated an additive antinociceptive interaction between WIN 55,212-2 and ketorolac in an inflammatory visceral pain model. The combination of cannabinoids and NSAIDs may have utility in the pharmacotherapy of pain.     

The antinociceptive effects of fentanyl, midazolam and clonidine and their interactions in the spinal dorsal horn]

Lamina V-type neurons on the spinal dorsal horn which responded to the bradykinin injection into the femoral artery were studied neurophysiologically in the spinal transected cats by the tungsten microelectrode method. It has been demonstrated that the separate and combined antinociceptive effects of fentanyl, clonidine and midazolam administered intrathecally can produce reduction in response to noxious stimuli. Fentanyl (25 micrograms), clonidine (30 micrograms) and midazolam (1.0 mg) separately suppressed noxious evoked activity at the spinal level. On the other hand, fentanyl (5 micrograms), clonidine (5 micrograms) and midazolam (0.5 mg) each produced no significant suppression of the evoked activity. However, the combinations of drugs at lower doses produced supra-additive suppressive effect. These suppressive effects were reversed by each antagonist (naloxone, yohimbine and flumazenil). These findings suggest that when two of these drugs are combined at subanalgesic doses, a significant synergistic interaction is exerted. Therefore, the use of these drugs in combination can reduce the total amount of any one drug required for analgesia in the spinal cord and also reduce the side effects of these agents.     

Effects of pericardial lidocaine on hemodynamic parameters and responses in dogs anesthetized with midazolam and fentanyl

OBJECTIVE: Tachycardia during anesthesia should be avoided, especially during off-pump coronary artery bypass graft surgery. Decreasing heart rate without reducing cardiac contractility is an ideal goal. To achieve this, the authors attempted to block the cardiac nerves by pericardial administration of local anesthetic. DESIGN: A prospective study. SETTING: A laboratory. PARTICIPANTS: Anesthetized, mechanically ventilated dogs (n = 69). INTERVENTIONS: The pericardial space was infused with 2.5 or 5 mL of 1% lidocaine, 5 mL of 2% lidocaine, or normal saline solution. The hemodynamic changes and the cardiac responses to atropine or isoproterenol were measured during cardiac nerve blockade. To examine the inhibitory action of pericardial lidocaine on arrhythmias, an electrical fibrillator was installed. Furthermore, the blood level of lidocaine was measured. MEASUREMENTS AND MAIN RESULTS: Pericardial injection of lidocaine significantly decreased heart rate without a change in stroke volume. Under pericardial lidocaine, the tachycardia response to isoproterenol was similar to that observed without pericardial lidocaine, but response to atropine was significantly reduced. Pericardial lidocaine increased the voltage thresholds for inducing arrhythmias and ventricular fibrillation. Intravenous injection of lidocaine elevated the plasma concentration of lidocaine immediately, whereas the plasma concentration peaked at 10 minutes after pericardial administration. CONCLUSIONS: Pericardial lidocaine (1) decreased heart rate without affecting stroke volume, (2) preserved the tachycardiac response to isoproterenol but completely blocked the response to atropine, and (3) increased the voltage thresholds for arrhythmias and ventricular fibrillation induced by an electrical fibrillator. These results suggest that pericardial lidocaine may be useful for controlling heart rate during off-pump coronary artery bypass graft surgery.     

Hemodynamic interaction between midazolam and alfentanil in coronary patients

We studied the hemodynamic interaction between midazolam and alfentanil during induction of anaesthesia in 27 patients with coronary heart disease. Using alfentanil alone (93 +/- 6 micrograms/kg) the induction was associated with stable systemic haemodynamics but also with a pressure increase in pulmonary circulation, due to chest wall rigidity and respiratory acidosis. The administration of subhypnotic doses of midazolam (50 and 100 micrograms/kg) prior to alfentanil prevented chest wall rigidity and pulmonary vasoconstriction completely, suppressed the pressor response to intubation and reduced the dose of alfentanil required for induction. However the midazolam-alfentanil combination led to hypotension, which was primarily due to a decrease of peripheral systemic resistance. Thus the haemodynamic interaction between midazolam and alfentanil resembles the known interactions between other benzodiazepines and opiates, characterized by decreased sympathetic tone and suppressed baroreceptor reflex.     

不同剂量咪达唑仑与乳化异氟醚对大鼠催眠效应的相互作用

目的 评价不同剂量咪达唑仑与乳化异氟醚对大鼠催眠效应的相互作用.方法 成年雄性SD大鼠125只,体重240～300 g,随机分为5组(n=25),采用改良序贯法进行实验,M组和I组分别经尾静脉注射咪达唑仑、乳化异氟醚,首剂量分别为17.3 mg/kg、0.55 ml/kg;MI1组、MI2组和MI3组分别经尾静脉注射1/4、1/2、3/4咪达唑仑催眠效应半数有效剂量(ED50)+乳化异氟醚(首剂量分别为0.22、0.19、0.12 ml/kg),各组相邻剂量比值均为0.85,采用改良序贯法计算各组咪达唑仑、乳化异氟醚催眠效应的ED50,及其95%可信区间(95%CI).催眠有效的标准:前爪翻正反射消失.采用等辐射分析法判断不同剂量咪达唑仑与乳化异氟醚催眠效应的相互作用.结果 M组咪达唑仑催眠效应的ED50及其95%CI为26(22～30)mg/kg;I组、MI1组、MI2组及MI3组乳化异氟醚催眠效应的ED50及其95%CI分别为0.67(0.61～0.73)、0.30(0.28～0.33)、0.22(0.18～0.26)、0.18(0.16～0.20)ml/kg.MI1,组、MI1组、MI3组两药相互作用系数分别为1.51(P<0.01)、1.21(P<0.05)、0.98(P0.05).结论 咪达唑仑6.5、13 mg/kg复合乳化异氟醚时两药的催眠效应为协同作用,咪达唑仑19.5 mg/kg复合乳化异氟醚时两药的催眠效应为相加作用.     

不同剂量咪达唑仑与异丙酚催眠效应的相互作用

目的 评价不同剂量咪达唑仑与异丙酚催眠效应的相互作用.方法 择期全麻病人120例,ASA Ⅰ或Ⅱ级,年龄18～60岁,体重40～80 kg,随机分为4组(n=30),各组分别随机分为6个亚组,M组和P组各亚组分别静脉注射咪达唑仑0.04、0.06、0.08、0.10、0.12、0.15 mg/kg、异丙酚0.8、1.0、1.2、1.5、1.8、2.2 mg/kg;MP1组和MP2组各亚组分别按咪达唑仑与异丙酚ED50等效比1:13(咪达唑仑剂量分别为0.022、0.028、0.033、0.039、0.044、0.055 mg/kg)和临床常用比例1:10(咪达唑仑剂量分别为0.03、0.04、0.045、0.05、0.055、0.06 mg/kg)行麻醉诱导.M组、P组、MP1组和MP1组分别于注药后3、1,1、1 min时行警觉,镇静(OAA/S)评分,催眠有效标准:OAA/S评分≤2分.采用加权概率单位法计算半数有效剂量(ED50)及其95%可信区间(95%CI);采用等辐射分析法判断两药催眠效应的相互作用.结果 M组、MP1.2组咪达唑仑催眠效应的ED50及其95%CI分别为0.088(0.066～0.110)、0.031(0.026～0.036)、0.045(0.040～0.049)mg/kg;P组、MP1.2组异丙酚催眠效应的ED50及其95%CI为1.142(0.933～1.350)、0.421(0.343～0.480)、0.450(0.399～0.491)mg/kg.结论 麻醉诱导时咪达唑仑与异丙酚按ED50等效剂量比1:13给药,两药催眠效应为协同作用;按临床常用剂量比1:10给药时两药催眠效应为相加作用.     

Flumazenil in total intravenous anaesthesia using midazolam and fentanyl

Forty patients, scheduled for elective surgery in a thoracic and vascular surgical unit, were anaesthetized by a total intravenous anaesthesia technique using midazolam and fentanyl. Subsequent reversal of anaesthesia by the specific benzodiazepine antagonist flumazenil was evaluated in a double-blind trial. The patients were observed in the recovery room postoperatively until the next morning, and their recovery was repeatedly evaluated during the first 240 min after anaesthesia. Six patients in the placebo group required an oral airway or an endotracheal tube during the first hours of recovery, whereas none who received flumazenil did. The respiratory rate was significantly higher after flumazenil than placebo during the first 4 h postoperatively (Anova, P less than 0.01). Blood pressure and heart rate were not different between the two groups. The degree of sedation, orientation in time and space and the ability to cooperate were significantly superior after flumazenil than placebo (Anova, P less than 0.01). Some degree of resedation was observed in both groups, affecting 95% of the patients who received flumazenil against 30% after placebo (Mann-Whitney, P less than 0.05). No adverse reactions attributable to the use of flumazenil were encountered.     

咪唑安定和芬太尼对依托咪酯所致肌阵挛的影响

目的研究咪唑安定和芬太尼对依托咪酯所致肌阵挛的影响。方法全麻下行择期手术患者128例,根据麻醉诱导用药顺序和剂量的不同随机分为五组:Ⅰ组,咪唑安定0.05mg/kg、依托咪酯0.25mg/kg、芬太尼3μg/kg,22例;Ⅱ组,芬太尼3μg/kg、依托咪酯0.25mg/kg、咪唑安定0.05mg/kg,24例;Ⅲ组,咪唑安定0.05mg/kg、芬太尼3μg/kg、依托咪酯0.25mg/kg,32例;Ⅳ组,咪唑安定0.08mg/kg、依托咪酯0.25mg/kg、芬太尼3μg/kg,23例;Ⅴ组(对照组),依托咪酯0.25mg/kg、咪唑安定0.05mg/kg、芬太尼3μg/kg,27例。在静注依托咪酯后,观察并记录2min内肌阵挛阳性率及发生分级。结果五组肌阵挛阳性率分别为68.18%、41.67%、21.88%、21.74%、59.26%。与Ⅴ组比,Ⅲ、Ⅳ组肌阵挛阳性率及发生分级明显较低(P<0.05),Ⅰ、Ⅱ组肌阵挛阳性率及发生分级差异则无统计学意义。结论依次采用咪唑安定、芬太尼、依托咪酯诱导可减低依托咪酯引起的肌阵挛发生。     

Spinal and supraspinal midazolam potentiates antinociceptive effects of isoflurane

The effects of lumbar intrathecal (i.t.) and intracerebroventricular(i.c.v.) midazolam on nociception during isoflurane anaesthesiawere studied in rats using the tail-flick test. Rats receivedi.t. midazolam 2 and 4 µg or i.c.v. midazolam 4 and 8µg during 1.1, 1.2 and 1.3% isoflurane or without isoflurane.Neither i.t. nor i.c.v. midazolam alone at doses studied influencednociceptive responses. 1.1% isoflurane showed a minimum antinociceptiveeffect which was not influenced by i.t. or i.c.v. midazolam.1.2 and 1.3% isoflurane produced moderate antinociception whichwas markedly potentiated by both i.t. and i.c.v. midazolam.The effects of midazolam shown in the present study are differentfrom the reported effects of midazolam on opioid-induced antinociception;where spinally administered midazolam potentiates and supraspinalmidazolam inhibits the antinociceptive effects of morphine.The present results suggest that midazolam potentiates isoflurane-inducedantinociception at doses where no effect is seen alone. Br J Anaesth 2000; 85: 881–6     

Functional recovery of stunned myocardium is greater with halothane than fentanyl anaesthesia in dogs

We have compared the effects of halothane or fentanyl on recoveryof regional myocardial function in the postischaemic ventriclein dogs. The animals were followed for 120 min during reperfusionafter 15-min of occlusion of the left anterior descending coronaryartery. After 120 min of reperfusion, the fentanyl group hadrecovered only 54% and 50% of regional contractility and systolicshortening (P < 0.05), respectively, compared with halothane(63% and 86%). Intramyocardial tissue pressure was less thanbaseline 60 min after reperfusion in the fentanyl group (P <0.05), whereas the halothane group had returned to control values.We conclude that halothane is more effective than fentanyl inattenuating regional myocardial dysfunction associated withtransient episodes of ischaemia.     

Serotonin toxicity caused by an interaction between fentanyl and paroxetine

PURPOSE: To report a case of serotonin toxicity, presenting in the postoperative period, caused by an interaction between paroxetine (a selective serotonin reuptake inhibitor, SSRI) and fentanyl (a phenylpiperidine opioid). Serotonin toxicity precipitated by fentanyl is unusual and has not previously been described in combination with SSRIs in the perioperative setting. CLINICAL FEATURES: A 60-yr-old woman, established on paroxetine for depression, underwent excision of a chest wall myxofibrosarcoma and chest wall reconstruction. Fentanyl was administered for intraoperative and postoperative analgesia (1 mg intraoperatively, and 2.5 mg by infusion in the first 36 hr, postoperatively). She developed a vague affectation, intermittent agitation, bilateral hyper-reflexia, inducible clonus, and a period of hypertension, suggestive of serotonin toxicity. There was complete resolution after cessation of fentanyl and paroxetine.Conclusion: The co-administration of SSRIs and fentanyl may precipitate serotonin toxicity. There must be consideration of this unusual interaction when administering fentanyl to patients established on SSRIs. Physicians should be vigilant of the features of serotonin toxicity developing in such patients.     

靶控输注芬太尼复合异丙酚静脉麻醉的药效学

目的研究以血浆靶浓度(Ct)3μg/ml靶控输注(TCI)异丙酚时，50％和95％病人对切皮刺激无体动或心血管反应的芬太尼设定血浆靶浓度(Cp50和Cp95)及其量效关系。方法24例择期行全身麻醉手术的病人，ASAⅠ-Ⅱ级，年龄31—65岁，按芬太尼血浆靶浓度随机分为四组，每组6例。麻醉诱导时通过TCI系统使所有病人异丙酚血浆靶浓度达到和维持3μg/ml，使各组芬太尼的血浆靶浓度分别达到1．00、1．50、2．25、3．38ng/ml。观察和记录手术切皮刺激引起的体动反应和心血管反应。分别计算抑制切皮时体动反应和心血管反应的Cp50、Cp95，并建立对切皮刺激反应的芬太尼量-效关系曲线。结果切皮时体动无反应率随设定的芬太尼靶浓度(当异丙酚Ct=3μg/ml)增加而逐渐增高，病人对切皮刺激无体动反应的Cp50为1．84ng/ml，其95％可信区间为1．46—2．33ng/ml，相应的Cp9，为5．12ng/ml，靶浓度对数剂量(x)与体动无反应率的概率单位(Y)间的回归方程为：Y=2．45X 4．35。同样，病人心血管无反应率随设定的芬太尼靶浓度增加而逐渐增高,Cp50为2．67ng/ml，其95％可信区间为(1．96—3．62)ng/ml，相应的cp95为15．85ng/ml，靶浓度对数剂量(X)与心血管无反应率的概率单位(Y)间的回归方程为：Y=2．13X 4．09。结论靶控输注异丙酚(Ct=3μg／ml)复合芬太尼麻醉，设定芬太尼靶浓度至少为5．12ng/ml，切皮时可以达到满意的麻醉深度。     

全身麻醉诱导时咪唑安定与氯胺酮催眠相互作用的研究

目的 以等辐射分析法研究全身麻醉诱导时咪唑安定与氯胺酮之间催眠相互作用.方法 将90例择期上腹部手术患者随机分为:咪唑安定组(M组)、氯胺酮组(K组)、咪唑安定与氯胺酮复合组(C组),每组30例.麻醉诱导前各组以序贯方式给予不同剂量的咪唑安定、氯胺酮及两药复合药物(咪唑安定与氯胺酮剂量的数值比为1:10),给药2 min后开始催眠末点评估,患者对言语指令失去反应即进入催眠末点,对已进入催眠状态的患者进行麻醉末点评估,以序贯法测定三组催眠、麻醉末点半数有效剂量(ED50),以等辐射分析法分析两者之间催眠、麻醉相互作用.结果 在催眠末点:M组ED50为0.18 mg/kg(95%CI 0.09～0.31 mg/kg);K组ED50为0.50 nag/kg(95%CI 0.38～0.61 mg/kg);C组ED50为0.038/0.38 mg/kg(95%CI 0.024/0.24～0.073/0.73mg/kg),在催眠末点,C组ED50偏离相加线无统计学意义.结论 经等辐射分析法证实,咪唑安定与氯胺酮催眠效应上呈现相加作用.