Masanori Yamauchi

Direct evidence for the role of nitric oxide on the glutamate-induced neuronal death in cultured cortical neurons

It has been reported that glutamate-induced neurotoxicity is related to an increase in nitric oxide (NO) concentration. An NO-sensitive electrode has been developed to measure NO concentration directly. Using this electrode, we examined NO concentration and neuronal survival after glutamate application in rat cultured cortical neurons. We also examined the effects of NMDA receptor antagonists, MK-801 and ketamine, and the NO synthetase inhibitor, L-NMMA on NO production and neuronal death. After 7 days in culture, application of glutamate (1 mM) or L-arginine (0.3 mM) to the cultured medium increased NO concentration, and decreased the number of anti-microtubule-associated protein 2 positive neurons. Both pretreatment with MK-801 (300 microns) and ketamine (300 microns) prevented glutamate-, but not L-arginine-induced increase in NO concentration and neuronal death. L-NMMA prevented both glutamate- and L-arginine-induced NO production and neuronal death. The nitric oxide donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP) also caused neuronal death, and MK-801, ketamine and L-NMMA did not prevent SNAP-induced toxicity. We have demonstrated excitatory amino acid-induced changes of NO concentration and the parallel relationship between changes of NO concentration and neuronal death. In conclusion, an increase in NO concentration does induce neuronal death, and the inhibition of the production of NO prevents glutamate-induced neuronal death.

Halothane suppression of spinal sensory neuronal responses to noxious peripheral stimuli is mediated, in part, by both GABAA and glycine receptor systems

Background A major effect of general anesthesia is lack of response in the presence of a noxious stimulus. Anesthetic depression of spinal sensory neuronal responses to noxious stimuli is likely to contribute to that essential general anesthetic action. The authors tested the hypothesis that &ggr;-aminobutyric acid receptor type A (GABAA) and strychnine-sensitive glycine receptor systems mediate halothane depression of spinal sensory neuronal responses to noxious stimuli. Methods Extracellular activity of single spinal dorsal horn wide dynamic range (WDR) neurons was recorded in decerebrate, spinal cord transected rats. Neuronal responses to noxious (thermal and mechanical) and nonnoxious stimuli were examined in the drug-free state. Subsequently, cumulative doses (0.1–2.0 mg/kg) of bicuculline (GABAA antagonist) or strychnine (glycine antagonist) were administered intravenously in the absence or presence of 1 minimum alveolar concentration (MAC) of halothane. Results Halothane, 1.1%, depressed the response of WDR neurons to both forms of noxious stimuli. Antagonists, by themselves, had no effect on noxiously evoked activity. However, bicuculline and strychnine (maximum cumulative dose, 2.0 mg/kg) partially but significantly reversed the halothane depression of noxiously evoked activity. Similar results were seen with most, but not all, forms of nonnoxiously evoked activity. In the absence of halothane, strychnine significantly increased neuronal responses to low threshold receptive field brushing. Conclusion Halothane depression of spinal WDR neuronal responses to noxious and most nonnoxious stimuli is mediated, in part, by GABAA and strychnine-sensitive glycine systems. A spinal source of glycine tonically inhibits some forms of low threshold input to WDR neurons.

Continuous low-dose ketamine improves the analgesic effects of fentanyl patient-controlled analgesia after cervical spine surgery.

BACKGROUND:The effects of fentanyl with ketamine for postoperative pain are unknown. We investigated the adjuvant effects of ketamine for fentanyl patient-controlled analgesia. METHODS:Cervical and lumbar spine surgery patients were divided into three groups: ketamine 1 mg/kg followed by 42 and 83 &mgr;g · kg−1 · h−1 in ketamine-1 and ketamine-2 group, respectively, and a control group. Postoperative patient-controlled analgesia fentanyl was administered with a background infusion. RESULTS:Pain scores and analgesia requirement in the ketamine-2 group were significantly lower than those of the control group after cervical surgery. Ketamine partially improved the analgesic effects of fentanyl after lumbar surgery. CONCLUSION:Small-dose ketamine improved the analgesic effects of fentanyl after cervical surgery.

Ultrasound‐Guided Cervical Nerve Root Block: Spread of Solution and Clinical Effect

OBJECTIVES We investigated the clinical effects and accuracy of ultrasound-guided cervical nerve root block. Additionally, spinal level and spread of injected solution were confirmed by anatomic dissection of fresh cadavers. DESIGN SETTING, PATIENTS, AND INTERVENTIONS: Twelve patients diagnosed with mono-radiculopathy between C5-7 underwent ultrasound-guided nerve root block. An insulated needle was advanced with an in-plane approach using nerve stimulation and 2 mL of 0.375% ropivacaine with 4 mg of dexamethasone was injected using nerve stimulation. Ultrasound-guided C5-7 nerve root block was also performed in ten fresh cadavers. Blue dye (2 mL) was injected onto each nerve root and anatomic dissection was performed to confirm the exact spinal level and spread pattern of the dye. RESULTS   Pain score before the procedure (65 [46-80], median [interquartile range]) was decreased to 25 [3-31] at 24 hours (P = 0.003) and 40 [28-66] at 30 days (P = 0.02) after the root block. Obvious side effects were not seen. All target nerve roots in patients and cadavers were correctly identified by ultrasound imaging. The needle tip did not reach the pedicle of the vertebral arch in the anteroposterior view of fluoroscopy, and spread pattern of contrast medium was extraforaminal and extraneural. CONCLUSIONS This study suggests that injected solution by ultrasound-guided cervical nerve root block mainly spreads to the extraforaminal direction compared with conventional fluoroscopic technique. Therefore, present clinical study involves possibility of safer selective nerve root block with sufficient analgesic effects by ultrasound guidance, despite the absence of intraforaminal epidural spread of solution.

Effects of systemic administration of lidocaine and QX-314 on hyperexcitability of spinal dorsal horn neurons after incision in the rat.

Abstract Although systemic lidocaine has been shown to suppress postoperative pain in a clinical setting, the mechanisms of action of lidocaine have not been elucidated. The present study was therefore designed to determine the relative contribution of central and peripheral sites to the action of lidocaine on incision‐induced hyperexcitation of spinal dorsal horn (SDH) neurons in the rat. Receptive field (RF) areas, spontaneous activities, and responses of single wide‐dynamic‐range (WDR) neurons of the SDH to nonnoxious and noxious stimuli were recorded before and after longitudinal incisions of 1 cm through the skin, fascia, and muscle had been made in the center of their RFs of the hindquarters. Significant increases in spontaneous activities, RF sizes, and responses of WDR neurons to both nonnoxious and noxious stimuli were observed at 30 min after the incision (P < 0.001). Systemic administration of lidocaine (1 mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) and QX‐314 (1 mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) significantly but temporarily suppressed and reversed the increases in spontaneous activity, responses to nonnoxious, and noxious stimuli and RF sizes (P < 0.01). Systemic administration of the same doses of lidocaine and QX‐314 did not affect responses of WDR neurons to nonnoxious or noxious stimuli or their RF sizes in sham‐operated animals in which an incision had not been made. The results suggest that systemic administration of lidocaine has suppressive effects on postoperative pain mainly through peripheral sites of action.

Identification of the lumbar intervertebral level using ultrasound imaging in a post-laminectomy patient.

A spinal block was performed in a post-laminectomy patient, using both ultrasound imaging and X-ray imaging. Ultrasound imaging clearly identified the L3/4 intervertebral level, the spinal canal, the corpus vertebrae, and the dura mater. Using ultrasound imaging, we measured the distance from the skin surface to the dura mater (39 mm). A 25-G needle for the spinal block was accurately advanced into the spinal canal with the use of X-ray imaging (43 mm from the skin to the subarachnoid space). We report here that ultrasound imaging was useful for performing a spinal block in a post-laminectomy patient in whom there was anatomical change around the spine.

A Prospective, Open-Label, Multicenter Study to Assess the Efficacy of Spinal Cord Stimulation and Identify Patients Who Would Benefit

Objective:  To identify patients likely to benefit from spinal cord stimulation (SCS).

The effect of cardiac output on the onset of neuromuscular block by vecuronium.

A relationship between cardiac output and the onset time of neuromuscular blockade administered into a peripheral vein was evaluated in 41 adult patients. Anaethesia was induced with midazolam and fentanyl and maintained with intermittent doses of fentanyl and 66% nitrous oxide in oxygen. After immobilisation of the forearm in a splint, the ulnar nerve in the other arm was stimulated supramaximally every 10 s and the adduction force of the thumb was recorded. The times from administration of vecuronium 0.08mg.kg‐1 to first and 95% depression of twitch response was 82.4(18.0) s and 191.7(33.5) s (mean, SD), respectively. A significant correlation between cardiac index and the onset time of blockade was observed. This study demonstrated that the rapidity of the onset of paralysis in the adductor pollicis muscle after vecuronium injection into a peripheral vein is clearly related to cardiac output.

Differential effects of propofol, thiamylal and ketamine on the cricothyroid and posterior cricoarytenoid muscles of the canine larynx

PurposeTo measure the electromyographic (EMC) responses of the phasic discharge in the cricothyroid (CT; a tensor muscle of the vocal folds) and the posterior cricoarytenoid (PCA; sole abductor muscle of the vocal folds) following intravenous infusion of propofol 1.0 mg · kg−1 · min−1, thiamylal 1.0 mg · kg−1 · min−1, or ketamine 0.5 mg · kg−1 · min−1 for five minutes.DesignProspective, nonrandomized, controlled animal study. Setting: University research laboratory. Subjects: Fifteen mongrel dogs, including three groups of five animals in each group.InterventionsUnder 0.2–0.3% halothane and oxygen anesthesia with spontaneous ventilation, phasic EMG activities of the CT and PCA muscles were recorded in an identical manner after the administration of each drug.Measurements and main resultsPropofol infusion produced almost equal suppression of EMG activity of the CT and the PCA with lime and three minutes after the start of infusion of propofol there was a significant depression of the phasic activities in the both muscles; EMG activity of the CT and the PCA was 33.8 ± 21.2 and 36.6 ± 22.9% (% of control, mean ± SD) respectively P < 0.05). Thiamylal selectively reduced rhythmic discharges in the CT muscle during spontaneous breathing and significant depression of discharge in the CT muscle was observed three minutes after the drug (47.3 ± 24.9%, P < 0.05). In contrast, both phasic EMG activities of the CT and the PCA were rhythmically active and the differential sensitivity between the CT and the PCA muscles was not observed after ketamine, even after ten minutes of administration.ConclusionsThis study confirms a difference in sensitivity between the CT and the PCA muscles, demonstrating that the intrinsic laryngeal muscles do not behave similarly after the administration of conventional intravenous anaesthetic agents.RésuméObjectifMesurer la réponse électromyographique (EMG) de la décharge phasique du muscle cricothyrodien (CT: un des muscles tenseurs des cordes vocales) et la cricoaryténodien postérieur (CAP: le seul muscle abducteur des cordes vocales) après une perfusion intraveineuse de propofol 1,0 mg · kg−1· min−1, de thyamilal 1,0 mg · kg−1 · min−1 ou de kétamine 0,5 mg · kg−1 · min−1 pendant cinq minutes.Organisation de l’étudeProspective, non aléatoire, contrôlée, sur des animaux.MilieuLaboratoire de recherche universitaire.SujetsQuinze chiens de race commune divisés en trois groupes de cinq.InterventionsSous anesthésie en ventilation spontanée à l’halothane 0,2–0,3% en oxygène, l’activité phasique EMG des muscles CT et CAP est enregistrée de manière identique après l’administration de chaque agent.Mesures et principaux résultatsLa perfusion de propofol produit une suppression presque identique de l’activité EMG du CT et CAP avec le temps. Trois minutes après le début de la perfusion de propofol, on constate une dépression importante de l’activité phasique des deux muscles; l’activité phasique du CT et du CAP est respectivement de 33,8 ± 21,2 et 36,6 ± 22,9 (% du contrôle, moyenne ± ET, P < 0,05). Par contre, l’activité EMG phasique du CT et du CAP était en harmonie et une différence de sensibilité entre les muscles CT et CAP n’a pas été observée avec la kétamine, même après dix minutes d’administration.ConclusionCette étude confirme la différence de sensibilité qui existe entre les muscles CT et CAP et démontre que les muscles intrinseques du larynx ne se comportent pas de la même façon après l’administration des anesthésiques intraveineux usuels.

Annual FEV1 changes and numbers of circulating endothelial microparticles in patients with COPD: a prospective study

Objective Growing evidence suggests that endothelial injury is involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). Circulating endothelial microparticles (EMPs) increase in patients with COPD because of the presence of endothelial injury. We examined the relationship between EMP number and changes in forced expiratory volume in 1 s (FEV1) in patients with COPD. Design Prospective study. Setting One hospital in Japan. Participants A total 48 outpatients with stable COPD coming to the hospital from September 2010 to September 2011. Primary and secondary outcomes measured Blood samples were collected and vascular endothelial (VE)-cadherin EMPs (CD144+ EMPs), E-selectin EMPs (CD62E+ EMPs) and platelet endothelial cell adhesion molecule EMPs (CD31+/CD41− EMPs) were measured using fluorescence-activated cell sorting. Annual FEV1 changes were evaluated using FEV1 data acquired a year before and a year after sample collection. Results The number of E-selectin and VE-cadherin EMPs showed significant negative correlations with annual FEV1 changes (rs=−0.65, p<0.001, rs=−0.43, p=0.003, respectively). Leucocyte counts tended to be correlated with annual FEV1 changes, but this correlation was not significant (rs=−0.28, p=0.057). There were significant differences in annual FEV1 changes between with and without history of frequent exacerbation (p=0.006), and among Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages (p=0.009). Multiple linear regression analysis revealed E-selectin EMP to be the only significant parameter associated with annual FEV1 changes, independent of VE-cadherin EMP, GOLD stages, leucocyte counts, and history of frequent exacerbation. Receiver operating characteristic curves showed the optimum E-selectin EMP cut-off level for prediction of rapid FEV1 decline (>66 mL/year) to be 153.0/µL (areas under curve 0.78 (95% CI 0.60 to 0.89); sensitivity, 67%; specificity, 81%). Conclusions The high E-selectin EMP levels in stable patients with COPD are predictive of rapid FEV1 decline. Trial registration number UMIN000005168.