Hideaki Tsuchida

Clonidine and Lidocaine Inhibition of Isoflurane-induced Tachycardia in Humans

Background:A rapid increase in isoflurane concentration can induce tachycardia and hypertension and increase plasma catecholamine concentrations. To investigate a possible mechanism, we measured hemodynamic responses to isoflurane administered via mask; we also administered clonidine for premedication, lidocaine topically to the nasal mucosa, or lidocaine intravenously to evaluate the effect of these drugs on the hemodynamic responses. Methods:Forty ASA physical status 1 patients (aged 20-30 yr) scheduled for elective oral surgery participated in the study. Thirty patients were randomly allocated to one of three groups: a control group, a group receiving 3-4 µg · kg-1 of oral clonidine for premedicatlon, and a group receiving 2 ml of 4% lidocaine spray to the nasal mucosa. Ten patients were assigned nonrandomly to a group receiving intravenous lidocaine continuously (0.4 mg · kg-1 bolus followed by 30 µg · kg-1 · min-1 ) after the initial randomized experiments were done to test whether systemic lidocaine blunts the responses to inhaled isoflurane. Anesthesia was induced with thlamylal, after which inhalation of 1% isoflurane in 100% oxygen via mask was begun. The inspired concentration of isoflurane was increased by 1% every 5 min to a maximum of 4%. During normocapnia and without surgical stimulation, heart rate and systolic blood pressure were measured every minute for 20 min before and during isoflurane inhalation. Plasma catecholamine concentrations were measured before and at each isoflurane concentration. Results:In the control and Intravenous lidocaine groups, an increase in isoflurane concentration from 2% to 3% significantly increased systolic blood pressure (peak changes of 16 ± 5 and 15 ± 6 mmHg, respectively) and heart rate (peak changes of 23 ± 3 and 13 ± 4 beats · min -1, respectively). A change in concentration to 4%, however, did not significantly alter hemodynamics. Blood pressure and heart rate responses to a change to 3% Isoflurane were significantly blunted in the groups receiving clonidine (peak changes of 4 ± 4 mmHg and 8 ± 3 beats · min-1, respectively) or nasal lidocaine (peak changes of 2 ± 1 mmHg and 4 ± 2 beats · min-1, respectively) compared with the control group. In all groups, plasma epinephrine and norepinephrlne concentrations increased after administration of 2% and 1% Isoflurane, respectively. Plasma lidocaine concentrations were 0.3-1.3 µg · kg-1 in the nasal lidocaine group and 0.6-1.5 µg · kg-1 in the intravenous lidocaine group. Conclusions:Stepwise increases in isoflurane concentration elicited hypertension and tachycardia as well as increments in plasma catecholamine concentrations during mask anesthesia. Nasal administration of lidocaine and clonidine premedicatlon significantly blunted the circulatory responses to isoflurane. intravenous lidocaine did not significantly weaken the responses to changes in isoflurane concentration.

The effects of sevoflurane, isoflurane, halothane, and enflurane on hemodynamic responses during an inhaled induction of anesthesia via a mask in humans.

A rapid increase in isoflurane or desflurane concentration induces tachycardia and hypertension and increases plasma catecholamine concentration.Little information is available as to whether sevoflurane, halothane, and enflurane induce similar responses during anesthesia induction via mask. Fifty ASA physical status I patients, aged 20-40 yr, and scheduled for elective minor surgery, received one of four volatile anesthetics: sevoflurane, isoflurane, halothane, or enflurane. Anesthesia was induced with thiamylal, followed by inhalation of 0.9 minimum alveolar anesthetic concentration (MAC) of the anesthetic in 100% oxygen via mask. The inspired concentration of anesthetic was increased by 0.9 MAC every 5 min to a maximum of 2.7 MAC. Heart rate (HR) and systolic blood pressure (SBP) were measured before and every minute for 15 min during anesthetic inhalation. In the sevoflurane and isoflurane groups, venous blood samples were drawn to determine the concentrations of plasma epinephrine and norepinephrine 3 min after each increase in anesthetic concentration. Sustained increments in HR were observed after increases in inspired isoflurane concentration to 1.8 MAC and 2.7 MAC (peak changes of 15 +/- 3 and 17 +/- 3 bpm, respectively). Isoflurane also increased SBP transiently after the inspired concentration was increased to 2.7 MAC (peak change of 10 +/- 4 mm Hg). Enflurane increased HR after the inspired concentration was increased to 2.7 MAC (peak change of 9 +/- 2 bpm). In contrast, changes in sevoflurane and halothane concentrations did not induce hyperdynamic responses. Plasma norepinephrine concentration in the isoflurane group was significantly higher than that in the sevoflurane group during 2.7 MAC (P = 0.022). We propose that there is a direct relationship between airway irritation of the anesthetic and immediate cardiovascular change during an inhaled induction of anesthesia. (Anesth Analg 1996;82:821-6)

Effects of Halothane and Isoflurane on Cytosolic Calcium Ion Concentrations and Contraction in the Vascular Smooth Muscle of the Rat Aorta

BackgroundHalothane and isoflurane have been reported to suppress the contraction of vascular smooth muscle, although the exact mechanism has not been explained fully. This study examined the effect of halothane and isoflurane on cytosolic calcium ion (Ca2+) concentrations ([Ca2+]cyt), which was measured simultaneously with muscle tension in the vascular smooth muscle of the rat aorta to improve the understanding of the anesthetics effect on vascular smooth muscle. MethodsIsolated spiral strips of rat thoracic aorta were suspended for isometric tension recordings in physiologic salt solution. The [Ca2+]cyt was measured concomitantly by using fura-2-Ca2+ fluorescence. During exposure to 0%, 1%, 2%, or 396 halothane or 096, 2%, or 4% isoflurane, increases in muscle tension and [Ca2+]cyt induced by 32.8 mil K+ or 30 nm norepinephrine were measured and compared with the reference values. In the other series, the 396 halothane-induced increase in [Ca2+]cyt was measured in Ca2+-free solution without and with a pretreatment of ryanodlne, caffeine, or norepinephrine. ResultsHalothane and isoflurane increased resting-state [Ca2+]cyt, although only 3% halothane elicited a transient increase in muscle tension during the resting state. By contrast, both anesthetic agents attenuated the high K+- and norepi-nephrine-induced increases in [Ca2+]cyt and muscle tension in a concentration-dependent manner. During 3% halothane or 4% isoflurane exposure, the pretreatment of the muscle strip with a 10-6-M dose of Bay K 8644 augmented the high K+-induced increase in [Ca2+]cyt to the level observed in the control (0% anesthetic exposure) state. However, the increase in muscle tension in the presence of Bay K 8644 was low; it was still attenuated from the control level during 3% halothane or 4% isoflurane administration. These results indicate that, not only [Ca2+]cyt-dependent, but also [Ca2+]cyt-independent, mechanisms arc involved in the anesthetic-induced suppression of smooth muscle contraction. A 396 halothane-induced increase in [Ca2+]cyt was observed in the Ca2+-free solution even when the muscle strip was pretreated with a 10-6-M dose of ryanodine and a 20-mM dose of caffeine, whereas it was abolished completely after the muscle strip was pretreated with ryanodine, caffeine, and 100 nM norepinephrine. These results indicate that halothane can release Ca2+ from an intracellular Ca2+ store other than the caffeine-releasable site. ConclusionsHalothane and isoflurane have multiple effects on the [Ca2+]cyt and induce [Ca2+]cyt-dependent and [Ca2+]cyt-in-dependent suppression of the contraction in the vascular smooth muscle.

The hemodynamic effects of landiolol, an ultra-short-acting beta1-selective blocker, on endotracheal intubation in patients with and without hypertension.

BACKGROUND:The ultra-short-acting &bgr;1-selective blocker, landiolol, is widely used in Japan. We investigated the effects of landiolol on intubation-induced adrenergic response in 88 patients. METHODS:General anesthesia was induced and maintained with target-controlled infusion of propofol at an effect–site concentration of 5 &mgr;g/mL. Muscle relaxation was obtained with 0.1 mg/kg vecuronium, and endotracheal intubation was performed 4 min after vecuronium injection. We first investigated the optimal time point for landiolol to be administered before intubation in 43 normotensive patients. Then we examined whether landiolol was as effective as fentanyl to prevent tachycardia after intubation in 45 hypertensive patients. RESULTS:Landiolol at 0.1 mg/kg was most effective against intubation-induced tachycardia when infused 4 min before intubation in normotensive patients. However, 0.2 mg/kg landiolol was necessary to prevent tachycardia after intubation in hypertensive patients. Landiolol had no significant effects on arterial blood pressure or bispectral index at any dose throughout the study period. In contrast, 2 &mgr;g/kg fentanyl frequently caused hypotension just before and 5 min after intubation. CONCLUSION:Low doses of landiolol can effectively prevent tachycardia after intubation without significant effects on arterial blood pressure.

Baroreflex control of heart rate during cardiac sympathectomy by epidural anesthesia in lightly anesthetized humans.

To evaluate the effects of acute sympathetic denervation on the baroreflex control of heart rate, baroreflex sensitivities were compared in lightly anesthetized humans who had either cervical (N = 20) or lumbar epidural anesthesia (N = 18), or neither (N = 18). Levels of anesthesia during cervical block using 10 ml of 2% mepivacaine without epinephrine were C3-T7 and T7-S1 during lumbar epidural block. Baroreflex sensitivity was assessed with a pressor test using phenylephrine infusion to increase systolic blood pressure by 60 mm Hg within 2 min. There were no statistically significant differences in the baroreflex sensitivities in the absence of epidural block and during lumbar epidural block, the slopes of the regression line (in msec of RR interval change per mm Hg increase in systolic blood pressure, i.e., msec/mm Hg) relating systolic pressure and the succeeding pulse interval being 3.8 ± 1.4 (mean ± SD) and 3.7 ± 1.7, respectively. The mean slope during cervical block, 1.1 ± 1.2 msec/mm Hg, was significantly different from the slopes observed in the absence of epidural block and during lumbar epidural block (P < 0.01). The results suggest that cardiac sympathectomy induced by epidural anesthesia can suppress partially baroreceptor function by interrupting sympathetic efferent fibers innervating the heart during high levels of epidural anesthesia, but that lumbar sympathectomy during epidural anesthesia is unlikely to affect baroreceptor activity.

The usefulness of celiteactivated thromboelastography for evaluation of fibrinolysis

PurposeAlthough thromboelastography is useful for measuring both coagulability and fibrinolysis, it takes about two hours to measure all parameters including fibrinolytic rate. The present study aimed to investigate the usefulness of celite-activated thromboelastography (TEGc)to evaluate fibrinolytic status in non-cardiac surgery.MethodsWhole blood samples were obtained from 30 patients for non-cardiac surgery, and used for measurements of both native TEG (TEGn) and TEGc. The final concentration of 1% (w/v) celite was used for TEGc.ResultsTime for measurement of the fibrinolytic rate (FR) of TEGc in patients (56.7 ± 4.0 min) was less than half that of FR of TEGn (123.3 ± 15.6 min) (P < 0.05), suggesting a more rapid assessment of fibrinolytic status. A linear relationship was observed between FR values of TEGc and those of TEGn (r = 0.93,P < 0.0001), suggesting the usefulness of the fibrinolytic parameter of TEGc.ConclusionTEGc is a useful technique for a more rapid assessment of fibrinolytic status.RésuméObjectifBien que la thromboélastographie soit utile pour mesurer la coagulabilité et la fibrinolyse, il faut environ deux heures pour mesurer tous les paramètres, y compris la vitesse fibrinolytique. L’étude actuelle avait pour but d’examiner l’utilité de la thromboélastographie activée par les diatomées (TEGd) pour évaluer l’état fibrinolytique lors d’une chirurgie non cardiaque.MéthodeDes échantillons de sang total ont été prélevés chez 30 patients devant subir une chirurgie non cardiaque et utilisés pour les mesure de TEG non dénaturée (TEGn) et de TEGd. La concentration finale de 1% (p/v) de diatomées a été utilisée pour la TEGd.RésultatsLe temps de mesure de la vitesse fibrinolytique (VF) de la TEGd chez les patients (56,7 ± 4,0 min) représentait moins de la moitié du temps de la VF de la TEGn (123,3 ± 15,6 min) (P < 0,05), ce qui indique une évaluation plus rapide de l’état fibrinolytique. Une relation linéaire a été observée entre les valeurs de VF de la TEGd et celles de la TEGn® = 0.93,P < 0,0001), suggérant ainsi l’utilité du paramètre fibrinolytique de la TEGd.ConclusionLa TEGd est une technique utile pour obtenir plus rapidement l’évaluation de l’état fibrinolytique.

Role of intracellular Ca2+ pools in the effects of halothane and isoflurane on vascular smooth muscle contraction.

We examined the effect of halothane and isoflurane on contraction in the vascular smooth muscle of rat thoracic aorta simultaneously with the cytosolic Ca2+ levels ([Ca2+]i). Isolated spiral strips of rat thoracic aorta were suspended for isometric tension recordings in physiologic salt solution. The [Ca2+]i was measured concomitantly using fura-2-Ca2+ fluorescence. Muscle tension was elicited either by 51 mM K+ solution or 30 nM norepinephrine, and the muscle was exposed to 0%, 1%, 2%, 3% halothane or 0%, 1%, 2%, 3%, 4% isoflurane. The effects of the anesthetics were compared with the effects of verapamil, an L-type voltage-dependent Ca2+ channel blocker, also administered during K(+)-induced muscle contraction. In another series, the effects of the anesthetics on caffeine- or norepinephrine-induced muscle contraction were determined in Ca(2+)-free solution. Finally, 3% halothane or 4% isoflurane was administered during K(+)-induced contraction in muscle strips pretreated with ryanodine and caffeine. During K(+)-induced contraction, halothane evoked a transient increase followed by a decrease in both muscle tension and [Ca2+]i. The biphasic change in muscle tension was not elicited by isoflurane or by any agent under norepinephrine-induced contraction. Both halothane and isoflurane ultimately suppressed both K(+)- and norepinephrine-induced increases in muscle tension and the [Ca2+]i in a concentration-dependent manner. The slopes of the [Ca2+]i-tension regression lines under the two anesthetics were significantly steeper than that under verapamil during K(+)-induced contraction. Halothane, but not isoflurane, augmented 4 mM caffeine-induced tension and [Ca2+]i transients in the Ca(2+)-free solution in a concentration-dependent manner. However, neither anesthetic influenced norepinephrine-induced tension and [Ca2+]i transients. In the muscle strips pretreated with ryanodine and caffeine, the difference observed between the anesthetics was abolished. In conclusion, halothane, but not isoflurane, enhances Ca2+ release predominantly from the caffeine-releasable Ca2+ stores in vascular smooth muscle; this release may modify the effect of halothane. The intracellular Ca2+ pools can be affected differently by volatile anesthetic drugs, depending on the nature of the stimulus for smooth muscle contraction.

Propofol improves recovery from paraquat acute toxicity in vitro and in vivo.

Objective: To investigate whether the antioxidative sedatives propofol and thiopental can improve recovery from acute paraquat toxicity in A549 cells and in mice.¶Design: Prospective, controlled, dose-response, in vitro study and prospective, controlled animal study. Setting: A university animal research laboratory.¶Subjects: Established human lung cultured cells and male SPF ICR mice. Interventions: Paraquat-treated (0.2 mM) A549 cells were incubated either with the antioxidative sedatives propofol (0–0.56 mM) or thiopental (0–2.0 mM), or the non-antioxidative sedatives diazepam (0–3.0 mM), midazolam (0–3.0 mM) and ketamine (0–9.0 mM), as well as the antioxidative drugs, trolox (0–2.0 mM), α-tocopherol (0–4.4 mM), antioxidative-processed food (AOB; 0–1.0 mg/ml), superoxide dismutase (SOD; 0 and 3,000 U/ml) and ulinastatin (0 and 50,000 U/ml), for 48 h. Paraquat-treated mice received i. v. injections of 10 mg/kg propofol, 5 mg/kg thiopental, 4.0 mg/kg trolox, 100 mg/kg α-tocopherol, 10 mg/kg AOB or 5,000 U/kg SOD, b. i. d. for 4 days (n = 10 each). Measurements and results: Post-administered propofol and thiopental, as well as the antioxidative drugs, trolox, α-tocopherol and AOB, improved A549 cell survival in vitro. The non-antioxidative sedatives SOD and ulinastatin were not protective. An i. p. injection of 50 mg/kg of paraquat resulted in a survival rate of 40 % in mice at day 6. Propofol, trolox, α-tocopherol and AOB significantly lowered the mortality rate (80 % survival), while thiopental did not.¶Conclusion: Post i. v. injection of propofol is protective against paraquat-induced damage. Propofol can be given during mechanical ventilatory support after paraquat poisoning.

Effect of volatile anesthetics with and without verapamil on intracellular activity in vascular smooth muscle.

Background Although halothane and isoflurane inhibit receptor agonist‐induced smooth muscle contraction by inhibiting Calcium2+ influx via the L‐type voltage‐dependent Calcium2+ channels, their effects on pharmacomechanical coupling remained to be clarified. The intracellular action of both anesthetics was studied during agonist‐induced contractions using the Calcium2+ channel blocker verapamil. Methods Isolated spiral strips of rat thoracic aorta with endothelium removed were suspended for isometric tension recordings in physiologic salt solution. Cytosolic concentration of Calcium2+ ([Ca sup 2+]i) was measured concomitantly using fura‐2‐Calcium2+ fluorescence. Muscle contraction was evoked by the receptor agonists with 30 nM norepinephrine or 10 micro Meter prostaglandin F2 alpha (PGF2 alpha), followed by exposure to halothane, at 0%, 1%, 2%, and 3% or isoflurane, at 2% and 4%. The effects of the anesthetics were compared with those of 0.1–1 micro Meter verapamil (n = 8 for each condition). To clarify the intracellular action of the volatile anesthetics on agonist‐induced contractions, this procedure was repeated for the anesthetics only in the presence of 1 micro Meter verapamil (n = 8 for each condition). The effects of both anesthetics were also examined in nonreceptor‐mediated contractions evoked with a 1‐micro Meter dose of the protein kinase C activator, 12‐deoxyphorbol 13‐isobutylate, which increases the Calcium2+ sensitivity of the contractile elements (n = 8 for each). Results Halothane, isoflurane, and verapamil suppressed norepinephrine‐ and PGF2 alpha‐induced increases in muscle tension and [Ca sup 2+]i in a concentration‐dependent manner. The Calcium2+ ‐tension regression lines suggested that the volatile anesthetics reduced Calcium2+ sensitivity of the contractile elements during PGF2 alpha‐induced contraction. Pretreatment of the muscle strip with verapamil revealed that halothane and isoflurane released Calcium2+ during norepinephrine‐induced contraction and that [Ca2+]i ‐tension relationship was modulated during PGF2 alpha‐induced contractions. Halothane at 2% and 3% and isoflurane at 4% suppressed 12‐deoxyphorbol 13‐isobutylate‐induced increases in muscle tension, whereas they enhanced increases in [Ca2+]i, indicating that both anesthetics suppressed Calcium2+ sensitivity during 12‐deoxyphorbol 13‐isobutylate‐induced contraction. Conclusions Verapamil pretreatment unmasked the intracellular action of the anesthetics. Halothane and isoflurane influenced pharmacomechanical coupling during agonist‐induced contraction.

Effects of halothane and isoflurane on β-adrenoceptor-mediated responses in the vascular smooth muscle of rat aorta

Background Although previous studies have proposed that anesthetics may influence signal transduction systems, their effects on the [small beta, Greek]‐adrenoceptor‐mediated system have not been fully characterized in vascular smooth muscle. The aim of this study was to determine how halothane and isoflurane affect [small beta, Greek]‐adrenoceptor‐mediated vasodilation in rat aorta and what mechanisms were involved. Methods Isometric tension and the intracellular calcium ion concentration ([Ca2+]i) were measured concomitantly in rat aortic strips from which the endothelium was removed. Strips precontracted with norepinephrine were dilated with the [small beta, Greek]‐adrenoceptor agonists, isoproterenol; the adenylyl cyclase activator, forskolin; or the membrane‐permeable dibutyryl cyclic adenosine monophosphate (cAMP) with or without halothane or isoflurane. The effects of the anesthetics on each vasodilator were compared with the control responses. [small beta, Greek]‐adrenoceptor binding characteristics and affinity for agonists were determined with [(125) I]‐iodocyanopindolol with and without halothane or isoflurane. Furthermore, concentrations of cAMP induced by either isoproterenol or forskolin were measured with or without the anesthetics using an enzyme immunoassay procedure. Results Halothane and isoflurane attenuated vasodilation and [Ca2+]i decreases induced by isoproterenol, whereas both anesthetics only slightly affected vasodilation and [Ca2+]i decreases induced by forskolin and dibutyryl cAMP. Halothane and isoflurane had no effect on [small beta, Greek]‐adrenoceptor binding characteristics and affinity for agonists. Three percent halothane or 4% isoflurane significantly reduced cAMP levels induced by isoproterenol but not by forskolin. Conclusions Halothane and isoflurane, at clinically relevant concentrations, can interfere with [small beta, Greek]‐adrenoceptor‐mediated responses in the rat aorta at the steps after the agonist‐receptor binding but before the adenylyl cyclase activation.