Tomoharu Funao

Dexmedetomidine decreases the convulsive potency of bupivacaine and levobupivacaine in rats : involvement of α2-adrenoceptor for controlling convulsions

Dexmedetomidine, a highly selective &agr;2-adrenoceptor agonist, is used in combination with local anesthetics for sedation and analgesia. We tested the hypothesis that dexmedetomidine used for sedation alters the convulsive potency of racemic bupivacaine and levobupivacaine in awake, spontaneously breathing rats. In the first experiments, male Sprague-Dawley rats were randomly divided into six groups: bupivacaine with no dexmedetomidine (bupivacaine control; BC), bupivacaine with small-dose dexmedetomidine (BS), bupivacaine with large-dose dexmedetomidine (BL), levobupivacaine with no dexmedetomidine (levobupivacaine control; LC), levobupivacaine with small-dose dexmedetomidine (LS), and levobupivacaine with large-dose dexmedetomidine (LL) (n = 10 for each group). Continuous infusion of dexmedetomidine (Groups BC and LC, 0 &mgr;g · kg−1 · h−1; Groups BS and LS, 3.6 &mgr;g · kg−1 · h−1; and Groups BL and LL, 10.8 &mgr;g · kg−1 · h−1) was started after bolus injection (Groups BC and LC, 0 &mgr;g/kg; Groups BS and LS, 0.5 &mgr;g/kg; and Groups BL and LL, 1.5 &mgr;g/kg). Fifteen minutes after the start of the dexmedetomidine infusion, continuous infusion of bupivacaine (Groups BC, BS, and BL) or levobupivacaine (Groups LC, LS, and LL) at 1 mg · kg−1 · min−1 was started and continued until tonic/clonic convulsions occurred. Dexmedetomidine achieved significantly different sedation levels both in Groups BC, BS, and BL and in Groups LC, LS, and LL (P < 0.05). Convulsive doses of bupivacaine and levobupivacaine were significantly larger in Groups BL and LL than in Groups BC and LC, respectively (P < 0.01 for both). Concentrations of bupivacaine and levobupivacaine in plasma and in brain at the onset of convulsions were also larger in Groups BL and LL than in Groups BC and LC (P < 0.01 for both). In the second experiment, yohimbine (1 mg/kg) administered 10 min before and 5 min after the start of dexmedetomidine infusion completely reversed the sedative effect of dexmedetomidine (bolus 1.5 &mgr;g/kg, followed by 10.8 &mgr;g · kg−1 · h−1). Convulsive doses and plasma and brain concentrations of bupivacaine and levobupivacaine at the onset of convulsions in rats receiving yohimbine and dexmedetomidine were significantly smaller than in those receiving only dexmedetomidine (P < 0.05 for all) and were similar to those without dexmedetomidine or yohimbine. We conclude that dexmedetomidine used for sedation decreases the convulsive potency of both bupivacaine and levobupivacaine in rats. &agr;2-Adrenoceptor agonism may be involved in this anticonvulsant potency.

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.

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.

Relationship between noradrenaline release in the locus coeruleus and antiallodynic efficacy of analgesics in rats with painful diabetic neuropathy.

AIMS In animal models of neuropathic pain, the noradrenergic descending pain inhibitory pathways from the locus coeruleus (LC) may be suppressed. However, no study has investigated the correlation between noradrenaline (NA) release in the LC and efficacy of analgesics in rats with painful diabetic neuropathy. Using microdialysis and analysis of mechanical hypersensitivity, we investigated the correlation between NA release in the LC and efficacy of morphine, tramadol, and clomipramine in rats with diabetic mellitus (DM). MAIN METHODS In freely moving rats, basal NA concentrations in LC perfusate were quantitated 72 to 96 h after microdialysis probe implantation. Following intravenous administration of each drug, NA concentrations were expressed as a percentage of basal values. We concurrently measured the threshold to elicit a paw withdrawal response every 20 min for 80 min. KEY FINDINGS NA concentrations in the LC perfusate were significantly higher in the tramadol and clomipramine groups compared to the morphine group. Naloxone administration did not significantly affect NA concentrations. In the morphine group, NA release in the LC was not significantly correlated with the pain threshold. In contrast, in the tramadol and clomipramine groups, NA release in the LC was significantly correlated with the pain threshold. The correlation coefficient was higher in the clomipramine group than in the tramadol group. SIGNIFICANCE Our results suggest that the descending noradrenergic pathway can play an important role in analgesia for DM neuropathy and that there is a significant correlation between NA release in the LC and the efficacy of tramadol and clomipramine.

The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats

PurposeTo examine whether inhibition of P-glycoprotein (P-gp) activity by quinidine affects the central nervous system toxicity of lidocaine and racemic bupivacaine (bupivacaine).MethodsForty male Sprague-Dawley rats were randomly divided into four groups (n = 10). Fifteen minutes following administration of 15 mg·kg−1 of quinidine (QL and QB groups) or saline (L and B groups), lidocaine (L and QL groups, 4 mg·kg−1·min−1) or bupivacaine (B and QB groups, 1 mg·kg−1·min−1) was infused until convulsions occurred. Concentrations of lidocaine and its primary metabolite, monoethylglycinexylidide (MEGX) and bupivacaine in plasma and in the brain at the onset of convulsions were measured by high-performance liquid chromatography.ResultsThere were no differences in the dose of lidocaine required to induce convulsions between the L and QL groups. There were no differences in the concentrations of total (L = 17.2 ± 3.5, QL = 16.6 ± 2.6 μg·mL−1) or unbound lidocaine (L = 7.8 ± 2.5, QL = 7.3 ± 2.3 μg·mL−1), total (L = 1.2 ± 0.5, QL = 1.3 ± 0.7 μg·mL−1) or unbound MEGX (L = 0.9 ± 0.5, QL = 0.8 ± 0.4 μg·mL−1) in plasma, total lidocaine or MEGX in the brain at the onset of convulsions between the L and QL groups. The dose of bupivacaine required to induce convulsions was comparable in the B and QB groups. At the onset of convulsions, plasma concentrations of both total (B = 4.9 ± 1.1, QB = 4.0 ± 0.6 μg·mL−1, P = 0.03) and unbound bupivacaine (B = 1.4 ± 0.6, QB = 0.9 ± 0.2 μg·mL−1, P = 0.02) were significantly lower in the QB group than in the B group. There were no differences in concentration of total bupivacaine in the brain between the B and QB groups.ConclusionThese results suggest that quinidine inhibited P-gp activity, resulting in increased brain/plasma concentration ratio of bupivacaine, but not of lidocaine, and decreased the threshold of plasma concentration for bupivacaine-induced convulsions.RésuméObjectifVérifier si l’inhibition de l’activité des P-glycoprotéines (P-gp) par la quinidine agit sur la toxicité de la lidocaïne et de la bupivacaïne racémique (bupivacaïne) sur le système nerveux central.MéthodeQuarante rats mâles Sprague-Dawley ont été répartis au hasard en quatre groupes (n = 10). Quinze minutes après l’administration de 15 mg·kg−1 de quinidine (groupes QL et QB) ou de solution saline (groupes L et B), des perfusions de lidocaïne (groupes L et QL, 4 mg·kg−1·min−1) ou de bupivacaïne (groupes B et QB, 1 mg·kg−1·min 1) ont été administrées jusqu’à l’apparition de convulsions. On a mesuré par chromatographie liquide haute performance les concentrations plasmatiques et cérébrales de lidocaïne, et de son principal métabolite, le monoéthylglycinexylidide (MEGX), et de bupivacaïne.RésultatsLa dose de lidocaïne nécessaire à l’induction des convulsions entre les rats des groupes L et QL n’a pas présenté de différence. Aucune différence n’a été notée entre les concentrations plasmatiques de lidocaïne totale (L = 17,2 ± 3,5, QL = 16,6 ± 2,6 μg·mL−1) et libre (L = 7,8±2,5,QL = 7,3±2,3 μg·mL−1), entre le MEGX total (L= 1,2 ± 0,5, QL= 1,3 ± 0,7μg·mL−1) et libre (L = 0,9± 0,5, QL = 0,8± 0,4 μg·mL−1), entre les concentrations cérébrales de lidocaïne totale et de MEGX total, au déclenchement des convulsions chez les rats des groupes L et QL. La dose de bupivacaïne nécessaire pour induire les convulsions a été comparable pour les rats des groupes B et QB. Au début des convulsions, les concentrations plasmatiques de bupivacaïne totale (B = 4,9 ± 1, 1, QB = 4,0 ± 0,6 μg·mL−1, P = 0,03) et libre (B = 1,4 ±0,6, QB = 0,9 ± 0,2 μg·mL−1, P = 0,02) ont été significativement plus faibles dans le groupe QB que dans le groupe B. Aucune différence de concentration de bupivacaïne totale cérébrale n’a été notée entre les groupes B et QB.ConclusionLa quinidine a inhibé l’activité de la P-gp, entraînant une hausse du ratio de la concentration cérébrale/plasmatique de bupivacaïne, mais non de lidocaïne, et une baisse du seuil de concentration plasmatique pour les convulsions induites par la bupivacaïne. Les anesthésiques locaux sont couramment utilisés pour l’anesthésie régionale et le traitement de l’arythmie.

The Vigileo-FloTracTM System: Arterial Waveform Analysis for Measuring Cardiac Output and Predicting Fluid Responsiveness: A Clinical Review

Surgical mortality rates range from 0.4% to 4%, with the occurrence of perioperative complications ranging from 3% to 17%. 2–5 These perioperative complications typically lead to an increase in the “unnecessary” days of hospitalization after surgery. Therefore, identifying high-risk patients and developing strategies aimed at decreasing perioperative complications are issues of great importance for anesthesiologists. Various interventions aimed at improving surgical outcomes have been examined by previous studies, including goal-directed therapy (GDT), 6–10 glycemic control, 11,12 and neuraxial blockade. 13–15 In a recent review, it has been suggested that interventions such as hemodynamic optimization, oxygen, glycemic control, and neuraxial anesthesia might decrease perioperative mortality. 16 Inadequate tissue perfusion has been indicated to be the strongest intraoperative predictor of perioperative complications. 17 For high-risk surgical patients, the main cause of perioperative mortality is more often related to inadequate tissue perfusion than to cardiac events. 18 Perioperative hemodynamic management can lead successfully to the optimization of cardiac output and ensure adequate oxygen delivery to the tissues; this has been shown to improve postoperative outcomes and reduce the length of the hospital stay. 7,10,19–23 In several studies that focused on cardiac output optimization, a cardiac output monitor was used to bring the patient to the plateau of the Frank-Starling curve. A pulmonary artery catheter (PAC) with intermittent thermodilution has been used as a clinical standard for cardiac output measurement. However, the use of invasive cardiac output monitoring has decreased, and, consequently, there has been an increased use of minimally invasive monitoring techniques in operating rooms and intensive care units (ICU). The term, “minimally invasive monitoring,” indicates any monitoring technique that is less invasive than, PAC; currently, minimally invasive monitoring techniques include the Vigileo-FloTrac TM system, PiCCO TM monitor, LiDCO TM system, transesophageal echocardiography, and pressure recording analytic method (PRAM). 24 The Vigileo-FloTrac TM system (Edwards LifeSciences, Irvine, CA) requires a proprietary transducer, which is attached to a standard radial or femoral arterial catheter and is connected to the Vigileo TM monitor. The Vigileo-FloTrac TM system requires no external calibration. For estimation of the cardiac output, the standard deviation (SD) of pulse pressure sampled in 20 seconds is related to normal stroke volume (SV) based on the patients’ demographic data (height, weight, age, and gender). Further, it also is correlated with a database that contains information regarding cardiac output measured using a PAC in various clinical settings. Vascular resistance and compliance are estimated by arterial waveform analysis. In the last 5 years, these cardiac output measurement algorithms have been improved repeatedly after conflicting data from early validation studies. Further software improvements have addressed the problem of limited accuracy under low systemic vascular resistance (SVR) states, and recent data have shown improvements in cardiac output measurement under these specific conditions. However, the accuracy of this system after acute SVR changes remains an issue of major concern. Some studies have raised questions about the validity of the data provided by the Vigileo-FloTrac TM system. 25,26 Therefore, the authors performed a review about the reliability of this system. The aim of this review was to provide data regarding the ability of the Vigileo-FloTrac TM system to measure cardiac output and track changes in cardiac output after hemodynamic interventions as well as to assess the reliability of stroke volume variation (SVV) measured by this system.

Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.

Background:Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol. Methods:Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6). Results:Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P < 0.01), while intracerebroventricular methysergide lowered the seizure threshold (P < 0.05 vs. saline). Conclusions:The authors determined that serotonin-reduced rats were predisposed to tramadol-induced seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.

Discrepancy between superior vena cava oxygen saturation and mixed venous oxygen saturation can predict postoperative complications in cardiac surgery patients.

OBJECTIVE To determine if increases in discrepancy between ScvO2 and SvO2 (ScvO2 - SvO2 = ΔSO2) during surgery in cardiac surgery patients can predict postoperative complications. DESIGN Prospective, observational study. SETTING University hospital. PARTICIPANTS One hundred two patients undergoing cardiac surgery were enrolled. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Central venous oxygen saturation (ScvO2) and mixed venous oxygen saturation (SvO2) values during surgery automatically were collected. The average value of ΔSO2 for every minute was calculated. The area under the receiver operating characteristic curve for prolonged postoperative ICU stay (≥3 days) was 0.745 for ΔSO2, which was significantly different from those of ScvO2 and SvO2 (p<0.05) (ScvO2; 0.584, SvO2; 0.598). The optimal threshold value of ΔSO2 to predict prolonged ICU stay (≥3 days) was 12% (sensitivity: 72.0%, specificity: 76.9%). Postoperative ICU duration, ventilation time, and hospital stay were significantly longer in Group D patients (intraoperative maximum ΔSO2 ≥12%) than those in Group N patients (intraoperative maximum ΔSO2<12%). As for postoperative complications, the number of patients with postoperative use of intra-aortic balloon pumping, delirium, respiratory failure requiring tracheotomy, and severe complications was significantly higher in Group D patients. Multivariate logistic regression models were used to evaluate the independent effects of perioperative variables on the risk of developing prolonged ventilation (>24 hours) and prolonged ICU stay (≥3 days). A discrepancy in intraoperative ΔSO2 was an independent risk factor for prolonged postoperative ventilation and ICU stay. CONCLUSION The discrepancy between ScvO2 and SvO2 during cardiac surgery is an independent risk factor of postoperative complications such as prolonged ICU stay and ventilation time.

The utility of intra-operative three-dimensional transoesophageal echocardiography for dynamic measurement of stroke volume

Measurement of left ventricular stroke volume and cardiac output is very important for managing haemodynamically unstable or critically ill patients. The aims of this study were to compare stroke volume measured by three‐dimensional transoesophageal echocardiography with stroke volume measured using a pulmonary artery catheter, and to examine the ability of three‐dimensional transoesophageal echocardiography to track stroke volume changes induced by haemodynamic interventions. This study included 40 cardiac surgery patients. Haemodynamic variables were measured before and 2 min after haemodynamic interventions, which consisted of phenylephrine 100 μg or ephedrine 5 mg. We used Bland–Altman analysis to assess the agreement between the stroke volume measured by three‐dimensional transoesophageal echocardiography and by the pulmonary artery catheter. Polar‐plot and 4‐quadrant plot analyses were used to assess the trending ability of three‐dimensional transoesophageal echocardiography compared with the pulmonary artery catheter. Bias and percentage error were −1.2 ml and 20%, respectively. The concordance rate in the 4‐quadrant analysis after phenylephrine and ephedrine administration was 75% and 84%, respectively. In the polar‐plot analysis, the angular concordance rate was 66% and 73% after phenylephrine and ephedrine administration, respectively. Three‐dimensional transoesophageal echocardiography was clinically acceptable for measuring stroke volume; however, it was not sufficiently reliable for tracking stroke volume changes after haemodynamic interventions.