Effects of sevoflurane versus propofol on QT interval.

BACKGROUND: Prolongation of the QT interval is an alteration of the electrocardiogram (ECG) that may result in a potentially dangerous polymorphic ventricular tachycardia known as torsade de pointes. Michaloudis et al. investigated the effect of isoflurane and halothane on the QT interval in premedicated and non premedicated children, and in premedicated adults. Isoflurane significantly prolonged the QTc interval, in contrast to halothane, which shortened the QTc interval. The aim of the study was to evaluate the effect of sevoflurane on the QT interval in patients undergoing non-cardiac surgery. METHODS: One hundred and eighty patients classified as ASA physical status I-III were enrolled and 102 were excluded. Patients had been scheduled for elective non cardiac surgery. Exclusions criteria were: cardiovascular impairment or chronic obstructive lung disease, medication affecting QT interval, and an abnormal prolongation of the QTc interval (440 ms). The patients were then randomly allocated to one of two groups, one receiving sevoflurane anesthesia and the other receiving propofol anesthesia. In all patients, a 12 lead ECG was recorded before surgery, after intubation, after extubation. The investigators reading the ECG were blinded to the type of induction and anesthesia used. The following variables were recorded or calculated: heart rate, P-R interval, QRS interval, QT interval, QTc interval according to Bazett's formula, systolic, diastolic and mean blood pressure. RESULTS: The sevoflurane significantly prolongs the QT and the QTc interval, whereas the induction and total intravenous anesthesia with propofol significantly shortens the QT but not the QTc interval. CONCLUSIONS: The amount the sevoflurane-associated QT prolongation may possibly be of clinical significance in some patients presenting long QT syndrome, hypokalemia, or in presence of other agents or factors that lengthen QT.     

The effects of propofol and sevoflurane on the QT interval and transmural dispersion of repolarization in children

Prolongation of the QT interval is associated with torsades de pointes (TdP), especially in children or young adults with long QT syndromes. Susceptibility to TdP arises from increased transmural dispersion of repolarization (TDR) across the myocardial wall. Several anesthetic drugs prolong the QT interval, but their effect on TDR is unknown. TDR can be measured on the electrocardiograph (ECG) as the time interval between the peak and end of the T wave (Tp-e). We investigated the effects of propofol and sevoflurane on the corrected QT (QTc) and Tp-e intervals in 50 unpremedicated ASA physical status I-II children, aged 1-16 yr, who were randomized to receive propofol (group P) or sevoflurane (group S). Twelve-lead ECGs were recorded preoperatively and intraoperatively. Sevoflurane significantly prolonged the preoperative QTc; propofol did not. Neither anesthetic had any significant effect on the preoperative Tp-e. Sevoflurane increases the duration of myocardial repolarization in children to a larger extent than does propofol, but as the dispersion of repolarization appears unaffected, the risk of TdP is likely to be minimal with either anesthetic.     

The effects of sevoflurane, isoflurane and desflurane on QT interval of the ECG

BACKGROUND AND OBJECTIVE: To determine if there is any significant difference between the effects of desflurane, isoflurane and sevoflurane on the QT interval, QT dispersion, heart rate corrected QT interval and QTc dispersion of the electrocardiogram. METHODS: The study was conducted in a prospective, double blind and randomized manner in a teaching hospital. Ninety ASA I patients, aged 16-50 yr, undergoing general anaesthesia for noncardiac surgery were studied. RESULTS: There was no significant change in QT intervals during the study in any group (P > 0.05). QT dispersion in the sevoflurane group 49+/-14 ms vs. 37+/-10 ms; in the desflurane group 55+/-16 and 62+/-21 ms vs. 35+/-14 ms and in the isoflurane group 54+/-26 and 59+/-24 ms vs. 42+/-19 ms were significantly increased at 3 and 10 min after 1 MAC of steady end-tidal anaesthetic concentration compared with baseline values (P < 0.05). QTc values in the sevoflurane group were 444+/-24 and 435+/-2 1ms vs. 413+/-19 ms (P < 0.05), in the isoflurane group were 450+/-26 and 455+/-34 ms vs. 416+/-34 ms (P < 0.05), in the desflurane group were 450+/-26 and 455+/-34 ms vs. 416+/-34 ms (P < 0.05) at 3 and 10 min after reaching 1 MAC of anaesthetic concentration and significantly increased compared with baseline values. QTc dispersion increased significantly with sevoflurane 62+/-14 ms vs. 45+/-16 ms (P < 0.05); isoflurane 70+/-36 ms at 3 min and 75+/-36 ms at 10 min after reaching 1 MAC of anaesthetic concentration vs. 50+/-24 ms (P < 0.05); desflurane 67+/-25 ms at 3 min and 74+/-27 ms at 10 min after 1 MAC concentration vs. 41+/-22 ms (P < 0.05). CONCLUSION: Sevoflurane, isoflurane and desflurane all prolonged QTd, QTc and QTcd but there were no significant intergroup differences.     

The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes

Substance P receptors (SPR) modulate nociceptive transmission within the spinal cord. The effects of IV anesthetics on SPR are not clear. In this study, we investigated the effects of IV anesthetics on SPR expressed in Xenopus oocytes. We examined the effects of ketamine, pentobarbital, propofol, and tramadol on SP-induced Ca(2+)-activated Cl(-) currents mediated by SPR expressed in Xenopus oocytes using a whole-cell voltage clamp. Ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, but propofol and tramadol had little effect on the currents. We also studied the effects of ketamine and pentobarbital on [(3)H]-SP to SPR. Ketamine and pentobarbital inhibited the specific binding of [(3)H]-SP to SPR expressed in Xenopus oocytes. Scatchard analysis of [(3)H]-SP binding revealed that ketamine and pentobarbital decreased the apparent dissociation constant for binding and maximal binding, indicating noncompetitive inhibition. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ketamine and pentobarbital on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that ketamine and pentobarbital inhibit SPR function. The mechanism of their inhibition on SPR function could not be through activation of the PKC pathway and may be due to noncompetitive displacing the SP binding. IMPLICATIONS: We investigated the effects of IV anesthetics on substance P receptors (SPR) expressed in Xenopus oocytes. Ketamine and pentobarbital inhibit SPR function via noncompetitive displacing SP binding. The findings imply that the inhibition of SPR function by these compounds may play a role in the analgesic effects of these IV anesthetics.     

Idiopathic prolonged QT interval and QT dispersion: the effects of propofol during implantation of cardioverter-defibrillator

Local anaesthesia combined with conscious sedation is becoming a popular technique for implantation of cardioverter-defibrillator devices. Propofol was given to provide loss of consciousness during defibrillation shock administration, for induced ventricular fibrillation testing. Propofol was found to decrease QT interval and QT dispersion in two patients with idiopathic prolonged QT interval and QT dispersion. The findings of the procedure are reported.     

The inhibitory effects of anesthetics and ethanol on substance P receptors expressed in Xenopus oocytes.

The neuropeptide substance P (SP) modulates nociceptive transmission within the spinal cord. SP is unique to a subpopulation of C fibers found within primary afferent nerves. However, the effects of anesthetics on the SP receptor (SPR) are not clear. In this study, we investigated the effects of volatile anesthetics and ethanol on SPR expressed in Xenopus oocytes. We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents mediated by SPR expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the volatile anesthetics tested, and ethanol, inhibited SPR-induced Ca(2+)-activated Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C inhibitor bisindolylmaleimide I (bisindolylmaleimide) enhanced the SP-induced Cl(-) currents. However, bisindolylmaleimide abolished the inhibitory effects on SPR of the volatile anesthetics examined and of ethanol. These results demonstrate that halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit the function of SPR and suggest that activation of protein kinase C is involved in the mechanism of action of anesthetics and ethanol on the inhibitory effects of SPR. IMPLICATIONS: We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on substance P receptor (SPR) expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the anesthetics and ethanol inhibited SPR function, and the protein kinase C (PKC) inhibitor abolished these inhibitions. These results suggest that anesthetics and ethanol inhibit SPR function via PKC.     

Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes

BACKGROUND: Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-D-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva directly stimulates human NMDA receptors. METHODS: To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. RESULTS: Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nM-1 mM each) or Ultiva (0.01 pM-0.1 mM) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 microM/12 microM for glutamate/glycine and 3.5 nM for Ultiva, and NR1A/2B EC50 values were 3.9 microM/1.9 microM for glutamate/glycine and 0.82 microM for Ultiva. Glycine in combination with Ultiva showed no additive effect compared with Ultiva alone. Ultiva-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 microM) did not stimulate NMDA receptors. CONCLUSION: These data indicate that Ultiva but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.     

The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes

Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT(2C)R) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomotion. In this study, we used a whole-cell voltage clamp to examine the effects of tramadol on 5-HT-induced Ca(2+)-activated Cl(-) currents mediated by 5-HT(2C)R expressed in Xenopus oocytes. Tramadol inhibited 5-HT-induced Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor, bisindolylmaleimide I (GF109203x), did not abolish the inhibitory effects of tramadol on the 5-HT(2C)R-mediated events. We also studied the effects of tramadol on [(3)H]5-HT binding to 5-HT(2C)R expressed in Xenopus oocytes, and found that it inhibited the specific binding of [(3)H]5-HT to 5-HT(2C)R. Scatchard analysis of [(3)H]5-HT binding revealed that tramadol altered the apparent dissociation constant for binding without changing maximal binding, indicating competitive inhibition. The results suggest that tramadol inhibits 5-HT(2C)R function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT(2C)R, rather than via activation of the PKC pathway. IMPLICATIONS: We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT(2C)R) expressed in Xenopus oocytes. Tramadol inhibited 5-HT(2C)R function and the specific binding of [(3)H]5-HT to 5-HT(2C)R in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT(2C)R might involve the competitive displacement of 5-HT binding to the 5-HT(2C)R.     

Effects of sevoflurane on voltage-gated sodium channel Nav1.8, Nav1.7, and Nav1.4 expressed in Xenopus oocytes

Sevoflurane is widely used as a volatile anesthetic in clinical practice. However, its mechanism is still unclear. Recently, it has been reported that voltage-gated sodium channels have important roles in anesthetic mechanisms. Much attention has been paid to the effects of sevoflurane on voltage-dependent sodium channels. To elucidate this, we examined the effects of sevoflurane on Na_v 1.8, Na_v 1.4, and Na_v 1.7 expressed in Xenopus oocytes. The effects of sevoflurane on Na_v 1.8, Na_v 1.4, and Na_v 1.7 sodium channels were studied by an electrophysiology method using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. Sevoflurane at 1.0 mM inhibited the voltage-gated sodium channels Na_v1.8, Na_v1.4, and Na_v1.7, but sevoflurane (0.5 mM) had little effect. This inhibitory effect of 1 mM sevoflurane was completely abolished by pretreatment with protein kinase C (PKC) inhibitor, bisindolylmaleimide I. Sevoflurane appears to have inhibitory effects on Na_v1.8, Na_v1.4, and Na_v 1.7 by PKC pathways. However, these sodium channels might not be related to the clinical anesthetic effects of sevoflurane.     

Comparison of single-breath vital capacity rapid inhalation with sevoflurane 5% and propofol induction on QT interval and haemodynamics for laparoscopic surgery

BACKGROUND AND OBJECTIVE: To compare two techniques to achieve induction of anaesthesia for laparoscopic surgery. A single-breath vital capacity rapid inhalation induction with sevoflurane was compared to intravenous propofol. Their effects on haemodynamics and the QT interval of the electrocardiogram were assessed. METHODS: Forty-four ASA I-II patients scheduled to undergo elective laparoscopic gynaecological surgery were divided into two groups. In the sevoflurane group (Group S, n = 22), general anaesthesia was induced with a single-breath vital capacity rapid inhalation of sevoflurane 5% with nitrous oxide (N2O) 65% in O2 and then anaesthesia was maintained with sevoflurane 1-1.5% with N2O 65% in O2. In the propofol group (Group P, n = 22), general anaesthesia was induced with propofol 2 mg kg(-1) intravenously and maintained with propofol 6 mg kg(-1) h(-1). Systolic, diastolic and mean arterial pressures, heart rate and end-tidal CO2 values were recorded before anaesthesia (basic value), during the induction period (time X), at 10 min (time Y) and at 30 min (time Z) of CO2 insufflation in all patients. QT intervals were calculated using Bazett's equation. RESULTS: Systolic, diastolic and mean arterial pressure values during the induction period (time X) were lower than the basic value in both groups (P < 0.05). In Group S, QTc intervals were significantly longer during the induction period (time X) and at the tenth min of CO2 insufflation (time Y) than Group P (P < 0.05). Five patients at time X and two patients at time Y developed ventricular dysrhythmias, which improved spontaneously in Group S. In Group P, there was no significant difference in QTc intervals and only one patient developed a ventricular dysrhythmia at time Y. CONCLUSIONS: Single-breath vital capacity rapid inhalation induction technique with sevoflurane can cause prolongation of the QT interval and dysrhythmias, compared with induction and maintenance of anaesthesia with propofol in laparoscopic surgery.     

七氟醚和丙泊酚对成人心电跨壁复极离散度的影响

目的 比较吸入麻醉药七氟醚和静脉麻醉药丙泊酚对成人心电跨壁复极离散度的影响.方法 ASA Ⅰ或Ⅱ级择期普外科手术患者60例,男、女各30例.根据性别随机分为四组:女性七氟醚组(FS组),女性丙泊酚组(FP组),男性七氟醚组(MS组),男性丙泊酚组(MP组),每组患者均为15例,随机接受七氟醚或丙泊酚的麻醉诱导.麻醉诱导前行12导联同步ECG;检查为对照.FS、MS组采用8%七氟醚,氧气流量4 L/min诱导,七氟醚浓度以呼出浓度为准,入睡后七氟醚呼出浓度改为3%维持;FP、MP组采用丙泊酚靶控输注(TCI)诱导,血浆浓度3.5μg/ml.每组均采用BIS监测,以BIS值达45～50后维持15 min为观察终点,并获取麻醉诱导后12导联同步ECG.测量并记录麻醉诱导前后ECG的校正的QT间期(QTc间期)、T波峰-末间期(Tp-e间期)、HR、MAP、SpO<,2>.结果 七氟醚组(FS、MS组)麻醉诱导后QTc间期比诱导前延长(P<0.05),Tp-e间期差异无统计学意义;在丙泊酚组(FP、MP组)麻醉诱导前、诱导后QTc间期、Tp-e间期差异无统计学意义.结论 七氟醚延长患者QTc间期,但七氟醚和丙泊酚诱导对跨壁复极离散度不产生影响.     

The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes

We assessed the effects of tramadol, a centrally acting analgesic, and its major metabolite, on neurotransmitter-gated ion channels. Tramadol binds to mu-opioid receptors with low affinity and inhibits reuptake of monoamines in the central nervous system. These actions are believed to primarily contribute to its antinociceptive effects. However, little is known about other sites of tramadol's action. We tested the effects of tramadol and its M1 metabolite (0.1-100 microM) on human recombinant neurotransmitter-gated ion channels, including glycine, gamma-aminobutyric acid(A) (GABA(A)), and N-methyl-D-aspartate (NMDA) receptors, expressed in Xenopus oocytes. Tramadol and M1 metabolite did not have any effects on glycine receptors. GABA(A) receptors were significantly inhibited only at large concentrations (100 microM). NMDA receptors were inhibited in a concentration-dependent manner. Tramadol and M1 metabolite inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a noncompetitive inhibition. This study suggests that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABA(A) receptors at large concentration might correlate with convulsions. The inhibitory effect on NMDA receptors may contribute to the antinociceptive effect of tramadol at relatively large concentrations.     

The effects of spinal anesthesia on QT interval in preeclamptic patients

In this study, we measured the effects of spinal anesthesia on the corrected QT (QTc) interval in women with severe preeclampsia. Twenty-five preeclamptic (preeclamptic group) and 25 healthy pregnant women with normal arterial blood pressure and QTc interval (control group) were enrolled in this prospective, case-controlled study. Arterial blood pressure, heart rate, and QTc interval values were obtained before (baseline value) and at 5, 10, 20, 30, 60, and 120 min after initiation of spinal anesthesia. Total ephedrine dose, time elapsed until sensory block, and Apgar scores were recorded. Prior to spinal anesthesia, QTc interval values were significantly higher in the preeclamptic group (452 +/- 17.5 ms) when compared with that in controls (376 +/- 21.4 ms). Although the QTc interval shortened during spinal anesthesia when compared with baseline value in the preeclamptic group (P < 0.05), it showed no significant change in the control group. In conclusion, the QTc interval may be prolonged in severe preeclamptic patients who have hypertension and hypocalcemia. Spinal anesthesia for cesarean delivery may normalize that prolonged QTc interval due to sympathetic blockade.     

Mechanism of QT interval prolongation induced by sevoflurane in guinea-pig ventricular myocyte

BACKGROUND: Sevoflurane causes QT interval prolongation clinically, but its precise mechanism has not been clarified. We examined the mechanism of QT interval prolongation induced by sevoflurane by means of electrophysiological technique in guinea-pig ventricular myocyte. METHODS: Electrocardiogram was recorded in guinea-pig and effect of sevoflurane (1, 2, 4%) was examined. Action potential (AP), delayed rectified potassium current (IKr), and L-type calcium channel current (ICa) were monitored as whole-cell current and by voltage clamp techniques in guinea-pig single ventricular myocytes. Sevoflurane was applied by bubbling into the bathing solution. RESULTS: Sevoflurane (1, 2, 4%) increased QTc value. Sevoflurane prolonged the duration of AP at 2%, but shortened it at 6%. IKr was reduced to 35% of control in the presence of 2% sevoflurane, but a higher concentration (6%) did not show further inhibition. ICa was reduced only to 87% of control in the presence of 2% sevoflurane and the reduction was dose-dependent (4, 6%). CONCLUSIONS: Sevoflurane 2% inhibited IKr, but it showed only slight inhibition on ICa. Because the duration of AP is regulated by ICa (plateau phase) and IKr (repolarization), greater inhibition of IKr than ICa could result in prolongation of AP. It is suggested that this mechanism may play a role in QT interval prolongation under sevoflurane anesthesia.     

Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects

Methadone is a strong opioid analgesic that is finding increasing use in chronic pain therapeutics. We explored its reported efficacy for inhibiting N-methyl-D-aspartate (NMDA) receptors in a functional electrophysiologic assay (Xenopus laevis oocyte expression). Racemic methadone inhibited all subtypes of rat NMDA receptors with derived 50% inhibitory concentrations in the low micromolar range. These concentrations overlap with clinically achievable concentrations reported in pharmacokinetic studies. In contrast, morphine inhibited these functional ion channels only at 8-16 times larger concentrations. The NR1/2A and NR1/2B subtype combinations were in general significantly more sensitive to inhibition by methadone and morphine compared with the NR1/2C and NR1/2D subtypes. In the presence of racemic methadone, the maximum NMDA-stimulated currents were markedly decreased, but the NMDA concentration producing 50% of maximal activation was altered only slightly, indicating that methadone blocks by a noncompetitive mechanism. Although stereoisomers of methadone showed minimal stereoselectivity in most subtypes, R(-) methadone was highly selective in its inhibition of the NR1/2A combination. These results provide further functional data describing the NMDA receptor inhibitory actions of methadone and support the hypothesis that methadone acts through both opioid and NMDA receptor mechanisms. IMPLICATIONS: At clinically achievable concentrations, methadone inhibits functional N-methyl-D-aspartate receptors. These results indicate a unique mode of action by this opioid that may enhance its ability to treat chronic pain and to limit opioid tolerance.