Kiyonobu Nishikawa

The short-acting beta1-adrenoceptor antagonists esmolol and landiolol suppress the bispectral index response to tracheal intubation during sevoflurane anesthesia.

In this randomized, double-blind, controlled study, we tested the hypothesis that the short-acting &bgr;1-adrenoceptor antagonists esmolol and landiolol suppress hemodynamic changes and bispectral index (BIS) increases, both of which are induced by tracheal intubation under general anesthesia with sevoflurane alone. Forty-five patients were randomly assigned to the control, esmolol, and landiolol groups (n = 15 each). Anesthesia was induced with sevoflurane in oxygen, with an end-tidal concentration maintained at 1 minimum alveolar anesthetic concentration (MAC). Infusion of saline (control group), esmolol (bolus of 1 mg/kg and then 0.25 mg · kg−1 · min−1; esmolol group), or landiolol (bolus of 0.125 mg/kg and then 0.04 mg · kg−1 · min−1; landiolol group) was started 5 min after the induction of anesthesia and was continued throughout the study. Tracheal intubation was performed 12 min after anesthesia induction. There were no differences in overall changes of mean arterial blood pressure among the three groups, whereas, at 1–5 min after tracheal intubation, heart rate increased in all groups but was significantly slower in the esmolol and landiolol groups than in the control group (P < 0.05). BIS was between 96 and 98 for all patients at baseline and decreased during the induction of anesthesia. There were no differences in BIS among the three groups before laryngoscopy (39 ± 5, 39 ± 5, and 38 ± 4 in the control, esmolol, and landiolol groups, respectively). BIS increased significantly in the control group (54 ± 10; P < 0.05) 1 min after intubation, whereas it remained unchanged in the esmolol and landiolol groups (45 ± 10 and 41 ± 6, respectively). In conclusion, the increase in both heart rate and BIS after tracheal intubation under 1 MAC sevoflurane anesthesia was suppressed by the concomitant administration of either esmolol or landiolol.

Systemic vascular resistance has an impact on the reliability of the Vigileo-FloTrac system in measuring cardiac output and tracking cardiac output changes

BACKGROUND The aim of this study was to examine the ability of the Vigileo-FloTrac system to measure cardiac output (CO) and track changes in CO induced by increased vasomotor tone, under different states of systemic vascular resistance (SVR). METHODS Forty patients undergoing cardiac surgery were enrolled. Haemodynamic variables including CO measured by the Vigileo-FloTrac system (version 3.02) (APCO), CO measured by a pulmonary artery catheter (ICO), and SVR index (SVRI) were recorded before (T1) and 2 min after (T2) phenylephrine administration (100 μg). Bland and Altman analysis was used to compare ICO and APCO at T1. We used four-quadrant plots and polar plots to compare the trending abilities between ICO and APCO. Patients were divided into three groups according to the SVRI value at T1, with low (<1200 dyn cm(-5) m(2)), normal (1200-2500 dyn cm(-5) m(2)), and high (>2500 dyn cm(-5) m(2)) SVRI states. RESULTS A total of 155 paired data were collected. The adjusted percentage error was 46.3%, 26.4%, and 61.4%, and the concordance rate between ΔICO and ΔAPCO was 67.5%, 28.8%, and 7.7% in the low, normal, and high SVRI state, respectively. The polar plot analysis showed that the mean angular bias was -22.3°, -46.0°, and -3.51°, and the radial limits of agreement were 70°, 85°, and 87°, in the low, normal, and high SVRI state, respectively. CONCLUSIONS These results indicate that the reliability of the Vigileo-FloTrac system to measure CO and track changes in CO induced by phenylephrine administration was not clinically acceptable.

Advance of age decreases the minimum alveolar concentrations of isoflurane and sevoflurane for maintaining bispectral index below 50

BACKGROUND We investigated age-related differences in the minimum alveolar concentration (MAC) of isoflurane and sevoflurane for maintaining bispectral index (BIS) below 50 (MAC(BIS50)). METHODS One hundred and twenty young (<or=40 yr), middle-aged (41-69 yr), and elderly (>or=70 yr) patients were randomly allocated to one of the six groups. Anaesthesia was induced with isoflurane or sevoflurane in oxygen. After tracheal intubation, we arbitrarily started maintenance of anaesthesia in each group with end-tidal isoflurane and sevoflurane concentrations of 0.8 and 1.2 vol%, respectively. After 10 min at predetermined end-tidal isoflurane or sevoflurane concentrations, BIS was measured for 1 min. MAC(BIS50) of isoflurane or sevoflurane for each group was determined by up-down methodology. RESULTS MAC(BIS50) of isoflurane in young, middle-aged, and elderly patients was 0.82% end-tidal (95% confidence intervals 0.76-0.88), 0.67% (0.61-0.73), and 0.56% (0.51-0.61), respectively, and that of sevoflurane in young, middle-aged, and elderly patients was 1.28% (1.24-1.32), 0.97% (0.89-1.05), and 0.87% (0.84-0.90), respectively. For both isoflurane and sevoflurane, the MAC(BIS50) was significantly higher (P=0.002 and 0.001, respectively) in young patients and significantly lower (P=0.02 for both) in elderly patients than those in middle-aged patients. CONCLUSIONS Advance in age significantly decreased the concentrations of isoflurane and sevoflurane required to maintain BIS below 50. BIS correctly reflected age-associated decrease of end-tidal concentrations of isoflurane and sevoflurane required for maintaining adequate depth of anaesthesia during resting state.

Landiolol has a less potent negative inotropic effect than esmolol in isolated rabbit hearts

PurposeWe compared the negative chronotropic and inotropic effects of landiolol and esmolol, two clinically available short-acting β1-blockers with high β1-selectivity, using whole isolated rabbit heart preparations.MethodsTachycardia was induced by continuous perfusion of 10−7 M isoproterenol, and we used concentrations of landiolol or esmolol in ascending steps (1 · 10−6, 3 · 10−6, 1 · 10−5, 3 · 10−5, and 1 · 10−4 M). Heart rate (HR), left ventricular developed pressure (LVDP), the maximal rates of left ventricular force development (LVdP/dtmax), and myocardial oxygen consumption (MVO2) were measured and compared.ResultsBoth landiolol and esmolol produced dosedependent decreases in HR, LVDP, LVdP/dtmax, and MVO2. The HR lowering effects of the two agents were comparable. At concentrations of 3 · 10−5 and 1 · 10−4 M, esmolol produced more profound depression of LVDP (47 ± 26 and 12 ± 11 mmHg, respectively; mean ± SD) and reduction of LVdP/dtmax (650 ± 287 and 120 ± 103 mmHg·s−1) than landiolol (68 ± 20 and 64 ± 20 mmHg, and 897 ± 236 and 852 ± 240 mmHg·s−1, respectively). At the same concentrations, esmolol caused more profound reduction in MVO2 (40 ± 11 and 35 ± 10 μl·min−1 · g−1) than landiolol (50 ± 8 and 48 ± 8 μl·min−1 · g−1), respectively.ConclusionOur results indicate that in the isolated rabbit heart, landiolol and esmolol had equipotent negative chronotropic effects, however, landiolol had a less potent negative inotropic effect than esmolol.

The effects of general anesthetics on P2X7 and P2Y receptors in a rat microglial cell line.

BACKGROUND: Microglial cells play important roles in coordinating the inflammatory brain responses to hypoxia and trauma. Ionotropic P2X receptors and metabotropic P2Y receptors (P2YRs) expressed in microglia can be activated by extracellular adenosine triphosphate (ATP) derived from damaged cells or astrocytes, and participate in the signaling pathways evoked in brain insult. Although several inhaled and IV anesthetics produce neuroprotective effects through neuronal mechanisms, little is known about how general anesthetics modulate microglial responses in the pathological state. We examined the effects of various general anesthetics on purinergic responses in a rat microglial cell line. METHODS: Currents were consistently activated by applications of ATP via a U-tube system under the whole-cell configuration. ATP-induced nondesensitizing currents observed after several applications of ATP exhibited characteristics of P2X7 receptors. The P2YRs-mediated mobilization of intracellular Ca2+ was measured using a Ca2+-sensitive fluorescent dye (fura-2). RESULTS: Inhaled anesthetics (sevoflurane, isoflurane, and halothane) at doses three times as high as minimum alveolar concentrations had no effect on the P2X7Rs-mediated currents. IV anesthetics (ketamine, propofol, and thiopental) enhanced the P2X7Rs-mediated currents reversibly. The potencies for activation of P2X7Rs were not correlated with the octanol/buffer partition coefficients. Thiopental, at low concentrations, slightly inhibited the P2X7Rs-mediated currents, suggesting its dual actions on P2X7Rs. The P2YRs-mediated mobilization of intracellular Ca2+ was not affected by any of the general anesthetics tested. CONCLUSIONS: Our results suggest that IV anesthetics, particularly thiopental and propofol, may modulate microglial functions through P2X7Rs in pathological conditions.

Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: An in vivo patch-clamp analysis of analgesic mechanisms

Summary A novel analgesic mechanism of systemic dexmedetomidine (&agr;2‐agonist) revealed by in vivo patch‐clamp analysis: paradoxical activation of descending noradrenergic system enhances spinal inhibitory synaptic transmission. ABSTRACT &agr;2‐Adrenoceptors are widely distributed throughout the central nervous system (CNS) and the systemic administration of &agr;2‐agonists such as dexmedetomidine produces clinically useful, centrally mediated sedation and analgesia; however, these same actions also limit the utility of these agents (ie, unwanted sedative actions). Despite a wealth of data on cellular and synaptic actions of &agr;2‐agonists in vitro, it is not known which neuronal circuits are modulated in vivo to produce the analgesic effect. To address this issue, we made in vivo recordings of membrane currents and synaptic activities in superficial spinal dorsal horn neurons and examined their responses to systemic dexmedetomidine. We found that dexmedetomidine at doses that produce analgesia (<10 &mgr;g/kg) enhanced inhibitory postsynaptic transmission within the superficial dorsal horn without altering excitatory synaptic transmission or evoking direct postsynaptic membrane currents. In contrast, higher doses of dexmedetomidine (>10 &mgr;g/kg) induced outward currents by a direct postsynaptic action. The dexmedetomidine‐mediated inhibitory postsynaptic current facilitation was not mimicked by spinal application of dexmedetomidine and was absent in spinalized rats, suggesting that it acts at a supraspinal site. Furthermore, it was inhibited by spinal application of the &agr;1‐antagonist prazosin. In the brainstem, low doses of systemic dexmedetomidine produced an excitation of locus coeruleus neurons. These results suggest that systemic &agr;2‐adrenoceptor stimulation may facilitate inhibitory synaptic responses in the superficial dorsal horn to produce analgesia mediated by activation of the pontospinal noradrenergic inhibitory system. This novel mechanism may provide new targets for intervention, perhaps allowing analgesic actions to be dissociated from excessive sedation.

Intrathecal gabapentin and clonidine synergistically inhibit allodynia in spinal nerve-ligated rats

AIMS The objective of this study was to elucidate the interaction between intrathecally administered gabapentin and clonidine on neuropathic pain associated with allodynia in the spinal nerve ligation model in the rat. MAIN METHODS Thresholds for hind paw responses to mechanical stimuli were determined by delivering von Frey filaments to the plantar surface. The left L5 spinal nerve was ligated and a fine catheter was intrathecally implanted at the L3-4 interspace under sevoflurane anesthesia. After confirmation of the established allodynia, gabapentin at 10, 30, 60 and 100μg or clonidine at 5, 15, 30 and 50μg was injected as a monotherapy in conscious rats through the intrathecal catheter to obtain the dose-response curve of %MPE (maximum possible effect) of the antiallodynic effect and its ED(50). Gabapentin and clonidine were concomitantly administered in a fixed-dose ratio proportional to the predetermined ED(50) of these drugs, thereby obtaining a dose-response curve for the drug combination and its ED(50). The profile of the interaction between these drugs was analyzed using an isobolographic analysis. KEY FINDINGS The ED(50) for gabapentin and clonidine were 57.3±4.0 and 20.2±1.0μg, respectively (mean±SEM). However, the co-administration of gabapentin and clonidine at a ratio of 20:7 contributed to a much smaller experimental ED(50) values (gabapentin 10.1±1.1μg, and clonidine 3.6±0.3μg) compared with their theoretical ED(50)s on the additive line in the isobologram. SIGNIFICANCE In the L5 spinal nerve-ligated rats, the intrathecal co-administration of gabapentin and clonidine exerted a synergistic action on the mechanical antiallodynic effect.

Improved Performance of the Fourth-Generation FloTrac/Vigileo System for Tracking Cardiac Output Changes

OBJECTIVES The aims of this study were to compare cardiac output (CO) measured by the new fourth-generation FloTrac™/Vigileo™ system (Version 4.00) (COFVS) with that measured by a pulmonary artery catheter (COREF), and to investigate the ability of COFVS to track CO changes induced by increased peripheral resistance. DESIGN Prospective study. SETTING University Hospital. PARTICIPANTS Twenty-three patients undergoing cardiac surgery. INTERVENTIONS Phenylephrine (100 µg) was administered. MEASUREMENTS AND MAIN RESULTS Hemodynamic variables, including CO(REF) and CO(FVS), were measured before and after phenylephrine administration. Bland-Altman analysis was used to assess the discrepancy between CO(REF) and CO(FVS). Four-quadrant plot and polar-plot analyses were utilized to evaluate the trending ability of CO(FVS) against CO(REF) after phenylephrine boluses. One hundred thirty-six hemodynamic interventions were performed. The bias shown by the Bland-Altman analysis was-0.66 L/min, and the percentage error was 55.4%. The bias was significantly correlated with the systemic vascular resistance index (SVRI) before phenylephrine administration (p<0.001, r(2) = 0.420). The concordance rate determined by four-quadrant plot analysis and the angular concordance rate calculated using polar-plot analysis were 87.0% and 83.0%, respectively. Additionally, this trending ability was not affected by SVRI state. CONCLUSIONS The trending ability of the new fourth-generation FloTrac™/Vigileo™ system after increased vasomotor tone was greatly improved compared with previous versions; however, the discrepancy of the new system in CO measurement was not clinically acceptable, as in previous versions. For clinical application in critically ill patients, this vasomotor tone-dependent disagreement must be decreased.

Nitrous oxide induces paradoxical electroencephalographic changes after tracheal intubation during isoflurane and sevoflurane anesthesia

In this randomized, double-blind, controlled study, we tested the hypothesis that nitrous oxide (N2O) affects bispectral index (BIS) and 95% spectral edge frequency (SEF95) in response to tracheal intubation during anesthesia with isoflurane and sevoflurane. In protocol 1, we randomly allocated 90 ASA physical status I patients to 6 groups (n = 15 each). Anesthesia was induced with isoflurane or sevoflurane with 0%, 33%, or 66% N2O. The concentration of isoflurane and sevoflurane was gradually increased and end-tidal concentrations were maintained at 1.1% and 1.7%, respectively. Tracheal intubation was performed 12 min after induction of anesthesia. BIS was significantly increased 1 min after tracheal intubation compared before laryngoscopy in patients receiving only isoflurane or sevoflurane (P = 0.001 and 0.007, respectively). In patients receiving 66% N2O-isoflurane or 66% N2O-sevoflurane, both BIS and SEF95 were significantly decreased after tracheal intubation and significantly lower than in those patients receiving only isoflurane or sevoflurane, respectively (P < 0.01 for both). In protocol 2, 3 &mgr;g/kg of IV fentanyl completely abolished the decrease of BIS and SEF95 after tracheal intubation during anesthesia with 66% N2O-isoflurane and 66% N2O-sevoflurane (n = 10). We conclude that 66% N2O induced a paradoxical decrease of BIS in response to tracheal intubation during anesthesia with isoflurane and sevoflurane.

Effects of intravenous administration of local anesthetics on the renal sympathetic nerve activity during nitrous oxide and nitrous oxide‐halothane anesthesia in the cat

The effects of subseizure doses of lidocaine and bupivacaine administered intravenously (i.v.) on mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were studied in cats anesthetized with nitrous oxide (N2O)‐O2 and N2O‐O2‐halothane (1 %). In cats anesthetized with N2O‐O2, MAP decreased briefly (P<0.01) and then returned to the initial level within a minute after the i.v. injection of lidocaine (5 mg/kg, 10 mg/kg). RSNA increased at first and then decreased slightly. In cats with denervated baroreceptors, the change in RSNA after lidocaine 5 mg/kg i.v. was similar to that in cats with intact baroreceptors. In contrast, MAP, HR and RSNA decreased significantly (P<0.01) after i.v. injection of lidocaine during N2O‐O2‐halothane anesthesia. The effects of bupivacaine on RSNA were similar to those of lidocaine. It is concluded that cardiovascular depression following intravenous local anesthetics during N2O‐O2‐halothane anesthesia may be caused by both a decreased sympathetic activity and a direct depressant effect on the myocardium.