Effect of Remifentanil on the Tpeak-Tend Interval During Electroconvulsive Therapy.

INTRODUCTION: QT interval dispersion, which reflects the regional heterogeneity of ventricular repolarization, increases during electroconvulsive therapy (ECT). Tpeak-Tend (TpTe) is considered a new marker of the transmural dispersion of ventricular repolarization (TDR). This study aimed to evaluate the effect of remifentanil on TpTe during ECT. METHODS: Forty-two patients who were scheduled to undergo ECT with American Society of Anesthesiologists physical status I or II randomly received 0.1 µg/kg remifentanil (group R: n = 21) or saline (group C: n = 21). After the induction of general anesthesia, we measured the TpTe, TpTe/QT, TpTe/QTc, TpTe/RR, TpTe/√RR and TpTe/3√RR every minute during ECT (QT: QT interval, QTc: corrected QT interval, RR: RR interval). Statistical analysis was performed using two-way analysis of variance (ANOVA). RESULTS: Immediately (T0) and 1 min (T1) after electrical stimulation, the RRs (group C: T0; 654.2 ± 145.9 ms, T1; 657.3 ± 114.8 ms, group R: T0; 849.6 ± 249.3 ms, T1; 885.4 ± 213.6 ms, p < 0.05) were significantly increased, while systolic (group C: T0; 177.1 ± 35 mmHg, group R: T0; 129 ± 27.2 mmHg, p < 0.05) and diastolic blood pressures (group C: T0; 107.1 ± 22.4 mmHg, T1; 101.3 ± 23.2 mmHg, group R: T0; 75.4 ± 19.3 mmHg, T1; 80.6 ± 18.3 mmHg, p < 0.05) were significantly decreased in group R compared to group C. The TpTe/RR was significantly lower at T1 in group R compared to group C (group C: 101.5 ± 28.2, group R: 76.8 ± 21.8, p < 0.05). However, there was no significant difference in TpTe, TpTe/QT, TpTe/QTc, TpTe/√RR or TpTe/3√RR between the two groups throughout the study. CONCLUSION: Pretreatment with remifentanil suppressed the increase of TpTe/RR after electrical stimulation. Our results imply that remifentanil may lead to a decrease in TDR during ECT. TRIAL REGISTRATION: This trial was registered with the University Hospital Medical Information Network (registration number: UMIN000051958).

Remimazolam Compared to Propofol for Total Intravenous Anesthesia with Remifentanil on the Recovery of Psychomotor Function: A Randomized Controlled Trial.

INTRODUCTION: This study aimed to compare remimazolam to propofol in psychomotor recovery after total intravenous anesthesia (TIVA) using the Trieger dot test. METHODS: Sixty-six patients who were scheduled to undergo endoscopic sinus surgery with American Society of Anesthesiologists (ASA) physical status I or II were randomly allocated to the remimazolam (group R) or propofol group (group P). In group R, all patients received flumazenil postoperatively. After discontinuation of anesthetic agents, the time to eye opening, response to verbal commands, extubation, and discharge from the operation room were measured. Psychomotor recovery was assessed using the Trieger dot test before induction and at 0, 30, 60, 90, 120, 150, and 180 min after anesthesia. RESULTS: The time to eye opening, response to verbal commands, extubation, and discharge from the operation room were significantly longer in group P compared to group R (group P: 9.8 ± 3.2 min, 11.5 ± 3.4 min, 12.7 ± 3.4 min, 18.1 ± 4.2 min; group R: 6.5 ± 2 min, 7.3 ± 2.6 min, 8.4 ± 2.9 min, 13.2 ± 3.2 min; respectively, p < 0.05). In the Trieger dot test, the number of dots missed was significantly increased in group R compared to group P at 30, 60, 90, and 120 min after discharge from the operation room (group R: 20.5 ± 9.3, 16 ± 8.8, 14.9 ± 11.1, 14.3 ± 10.8; group P: 14.6 ± 7.8, 10 ± 7.1, 8.7 ± 7.3, 7.3 ± 5.7; respectively, p < 0.05). The maximum distance of dots missed was significantly increased in group R compared to group P at 30 min after discharge from the operation room (group R: 3.9 ± 2.8; group P: 2.7 ± 1.6; p < 0.05). CONCLUSION: Our results suggest that remimazolam with flumazenil leads to rapid recovery following anesthesia; however, it may cause delayed psychomotor decline. CLINICAL TRIAL REGISTRATION: This trial is registered with the University Hospital Medical Information Network (registration number UMIN000044900).

Predictors of high-cost patients with acute whiplash-associated disorder in Japan.

INTRODUCTION: The proportion of neck injuries due to traffic accidents is increasing. Little is known about high-cost patients with acute whiplash-associated disorder (WAD). The present study aimed to investigate whether time to first visit for conventional medicine, multiple doctor visits, or alternative medicine could predict high-cost patients with acute WAD in Japan. METHODS: Data from a compulsory, no-fault, government automobile liability insurance agency in Japan between 2014 and 2019 were used. The primary economic outcome was the total cost of healthcare per person. Treatment-related variables were assessed based on the time to first visit for conventional and alternative medicine, multiple doctor visits, and visits for alternative medicine. Patients were categorized according to total healthcare cost (low, medium, and high cost). The variables were subjected to univariate and multivariate analysis to compare high-cost and low-cost patients. RESULTS: A total of 104,911 participants with a median age of 42 years were analyzed. The median total healthcare cost per person was 67,366 yen. The cost for consecutive medicine, for consecutive and alternative medicine, and total healthcare costs were significantly associated with all clinical outcomes. Female sex, being a homemaker, a history of WAD claim, residential area, patient responsibility in a traffic accident, multiple doctor visits, and visits for alternative medicine were identified as independent predictive factors for a high cost in multivariate analysis. Multiple doctor visits and visits for alternative medicine showed large differences between groups (odds ratios 2673 and 694, respectively). Patients with multiple doctor visits and visits for alternative medicine showed a significantly high total healthcare cost per person (292,346 yen) compared to those without (53,587 yen). CONCLUSIONS: A high total healthcare cost is strongly associated with multiple doctor visits and visits for alternative medicine in patients with acute WAD in Japan.

Prevalence of and Risk Factors for Prescription Opioid Misuse, Abuse, Diversion and Doctor Shopping in Japan: A Survey Study.

INTRODUCTION: Opioid use disorder is a global problem. Although opioid analgesics are prescribed less frequently in Japan than in many other countries, the rate of aberrant prescription opioid-taking behaviors in Japan is unknown. METHODS: An internet survey was conducted to estimate the prevalence of and risk factors for prescription opioid misuse, abuse, diversion and doctor shopping in Japanese subjects with chronic pain who had been prescribed opioid analgesics. RESULTS: The proportion of respondents (n = 387) who reported opioid misuse was 45.5% (95% confidence interval [CI]: 40.4-50.6); rates were: 24.6% (95% CI: 20.3-29.2) for abuse; 15.0% (95% CI: 11.6-19.0) for diversion; and 10.6% (95% CI: 7.7-14.1) for doctor shopping. Aberrant prescription opioid-taking behaviors were higher in participants with chronic post-cancer treatment pain (misuse, 64.2%; abuse, 52.2%) or chronic cancer pain (misuse, 57.4%; abuse, 26.2%) than in those with chronic noncancer pain (misuse, 37.8%; abuse, 17.0%). Younger age, male sex, smoking, habitual drinking, diagnosis of psychiatric disease, use of opioids other than tramadol, and use of opioids for chronic post-cancer treatment pain and chronic cancer pain were identified as risk factors for aberrant prescription opioid-taking behaviors. CONCLUSION: Even in Japan, which has not experienced the surge in opioid consumption documented in other countries, aberrant prescription opioid-taking behaviors were observed. When prescribing opioid analgesics, universal precautions should always be taken for both cancer and non-cancer patients. TRIAL REGISTRATION: UMIN000041788.

Assessment of the ECG T-Wave in Patients With Subarachnoid Hemorrhage.

BACKGROUND: Prolongation of the interval from the peak to the end of the T wave (Tp-Te) on a 12-lead electrocardiogram (ECG) is associated with ventricular arrhythmias. The aim of this study was to clarify associations between Tp-Te, Tp-Te/QT, and Tp-Te/rate-corrected QT (QTc) with clinical severity of subarachnoid hemorrhage (SAH) and clinical outcomes. METHODS: This retrospective study included 222 patients with acute SAH (group S) and 306 patients with unruptured cerebral aneurysms (group U). Tp-Te, Tp-Te/QT, and Tp-Te/QTc were manually measured in standard 12-lead ECG recordings on admission and comparisons made between patients in groups S and U. The relationships of these ECG parameters with Hunt and Hess grade and Glasgow outcome scale were analyzed using multiple logistic regression analysis after adjustment for confounding factors. RESULTS: Tp-Te, Tp-Te/QT, and Tp-Te/QTc were significantly greater in group S than in group U (group S: 109±30, 0.26±0.07, and 0.24±0.06 ms; group U: 84±12, 0.22±0.03, and 0.21±0.03 ms, respectively; P < 0.0001). In addition, in the multiple logistic regression analyses these variables were positively correlated with the Hunt and Hess grade (Tp-Te odds ratio [95% confidence interval], 2.414 [1.375-4.238], P=0.002; Tp-Te/QT, 1.886 [1.085-3.277], P = 0.024; Tp-Te/QTc, 1.873 [1.07-3.278], P=0.028, and negatively correlated with Glasgow outcome scale Tp-Te odds ratio [95% confidence interval], 4.168 [2.409-7.209], P<0.001; Tp-Te/QT, 2.434 [1.413-4.192], P=0.001; Tp-Te/QTc 2.953 [1.703-5.123], P<0.001). CONCLUSIONS: Tp-Te, Tp-Te/QT, and Tp-Te/QTc are associated with disease severity and clinical outcome in patients with SAH.

Effect of Methadone on Cardiac Repolarization in Japanese Cancer Patients: A Longitudinal Study.

INTRODUCTION: Methadone is known to prolong the QT interval, which could induce lethal arrhythmias such as torsades de pointes. To determine the risk of ventricular arrhythmias in cancer patients using methadone, we measured QT dispersion (QTD) and Tpeak-Tend (TpTe) before and after methadone administration and evaluated the correlations between methadone dosage and cardiac repolarization. METHODS: We conducted a retrospective observational study with 19 patients undergoing follow-up for cancer pain with methadone. Electrocardiogram (ECG) recordings were obtained from the patients at methadone initiation and 1 week, 1 month, and 2 months later. The QT, corrected QT (QTc), QTD, QTc dispersion (QTcD), TpTe, TpTe/QT, and TpTe/QTc were measured manually via ECG records and analyzed using a repeated measures one-way ANOVA. The correlations between these ECG parameters and each methadone dosage were determined using Spearman's rank correlation coefficient. RESULTS: The QTD, QTcD, TpTe/QT, and TpTe/QTc remained unchanged, while TpTe was prolonged significantly at 2 months (initiation: 82 ± 17 ms; 2 months: 106 ± 20 ms, p = 0.018). In addition, there was a positive correlation between TpTe and methadone dosage (rs = 0.4, p = 0.041). CONCLUSIONS: The findings suggested that small or modest doses of methadone could exert dose-dependent effects on cardiac repolarization in cancer patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000034519.

Comparison of Cardiac Repolarization After Transcatheter Aortic Valve Implantation and Surgical Aortic Valve Replacement: A Longitudinal Study.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) has been established as an alternative to surgical aortic valve replacement (SAVR) for high-risk patients. To assess the impact of TAVI on cardiac repolarization, we compared QT dispersion (QTD) and the interval from the peak to the end of the T wave (Tpeak-Tend: TpTe) between the patients who underwent TAVI and those who underwent SAVR and TpTe between the patients who underwent TAVI or SAVR. METHODS: This retrospective study was approved by the ethics committee of Dokkyo Medical University Hospital. The study included 45 patients who underwent TAVI and 45 patients who underwent SAVR. The QT, corrected QT (QTc), QTD, QTc dispersion (QTcD), Tp-Te, Tp-Te/QT, and Tp-Te/QTc were manually measured in standard 12-lead electrocardiogram (ECG) recordings obtained before surgery, immediately after surgery, 1 month, 3 months, and 6 months after surgery and compared between the two groups. RESULTS: No change was observed in RR, QT, QTc, Tp-Te, Tp-Te/QT, and Tp-Te/QTc in the two groups throughout the study. The QTD and QTcD significant decreased immediately after surgery in the TAVI group as compared to the SAVR group (P < 0.001). In contrast, QTD and QTcD in the SAVR group gradually, but not significantly declined 6 months after surgery. CONCLUSIONS: QTD and QTcD immediately decreased after TAVI as compared to SAVR. Our findings indicate that TAVI more rapidly improved dispersion of spatial repolarization than SAVR.

Impact of thoracic epidural sympathetic block on cardiac repolarization.

PURPOSE: The interval from the peak to the end of the T wave (Tp-Te) on electrocardiography is considered a marker of ventricular arrhythmias. A previous study suggested that right stellate ganglion block prolonged QT and QT dispersion (QTD). We investigated the effect of thoracic epidural sympathetic block with 1% mepivacaine on QT, QTD, Tp-Te, and Tp-Te/QT by using computerized measurement. PATIENTS AND METHODS: After obtaining the approval of the ethics committee of Dokkyo Medical University Hospital, 23 patients with American Society of Anesthesiologists physical status I or II who were scheduled to undergo thoracic surgery were enrolled. An epidural catheter was inserted at the Th4-5 or 5-6 level and then used for injection of 7 mL of 1% mepivacaine. Changes in RR interval, QT, corrected QT (QTc), QTD, QTc dispersion (QTcD), Tp-Te, Tp-Te/QT, and Tp-Te/QTc before and after epidural injection were assessed by computerized measurement. Statistical analysis was performed by one-way ANOVA. RESULTS: Systolic blood pressure was consistently suppressed 10-15 minutes after injection (baseline: 136±10 mmHg, 11 minutes: 113±12 mmHg, 12 minutes: 112±13 mmHg, 13 minutes: 112±12 mmHg, 14 minutes: 108±17 mmHg, 15 minutes: 111±14 mmHg; P<0.05). However, RR interval, QT, QTc, QTD, QTcD, Tp-Te, Tp-Te/QT, and Tp-Te/QTc were not changed after epidural block. CONCLUSION: Thoracic epidural injection of 1% mepivacaine did not alter QT, QTc, QTD, QTcD, Tp-Te, Tp-Te/QT, or Tp-Te/QTc. These results emphasize the safety of thoracic epidural sympathetic block with 1% mepivacaine for patients compared with right stellate ganglion block, in terms of cardiac repolarization.

Effects of Neostigmine and Sugammadex for Reversal of Neuromuscular Blockade on QT Dispersion Under Propofol Anesthesia: A Randomized Controlled Trial.

INTRODUCTION: Reversal of non-depolarizing neuromuscular blocking agent neostigmine is associated with QT prolongation under general anesthesia. To clarify the effects of neostigmine and sugammadex on hemodynamic status, the QT interval and QT dispersion after reversal of neuromuscular blockade were evaluated with a 12-lead electrocardiogram. To exclude QT prolongation due to sevoflurane, the present study was performed under propofol anesthesia. METHODS: After receiving approval from the ethics committee of Dokkyo Medical University Hospital, 40 patients with American Society of Anesthesiologists physical status I or II were randomly allocated to group N (n = 20) or group S (n = 20). Group N was administered neostigmine (40 µg/kg) and atropine (20 µg/kg), while Group S was administered sugammadex (4 mg/kg) for reversal of neuromuscular blockade after surgery. The changes in RR interval, QT interval (QT), corrected QT interval (QTc), QT dispersion (QTD), and corrected QT dispersion (QTcD) before and after administration of reversal agents were recorded using computerized measurements. Statistical analysis was performed using two-way analysis of variance. RESULTS: The RR interval significantly decreased after reversal of the neuromuscular blockade in group N, compared with group S (p < 0.05). Compared with group S, the QT decreased, whereas QTc and QTcD increased, in group N (p < 0.05). Sugammadex was not found to alter QT, QTc, QTD, or QTcD throughout the study. CONCLUSION: In the present study, a mixture of neostigmine and atropine, but not sugammadex, increased QTc and QTcD under propofol anesthesia. Thus, neostigmine may cause electrocardiogram abnormalities that could precede the development of fatal arrhythmias.

Allopregnanolone suppresses mechanical allodynia and internalization of neurokinin-1 receptors at the spinal dorsal horn in a rat postoperative pain model.

BACKGROUND: To identify a new strategy for postoperative pain management, we investigated the analgesic effects of allopregnanolone (Allo) in an incisional pain model, and also assessed its effects on the activities of the primary afferent fibers at the dorsal horn. METHODS: In experiment 1, 45 rats were assigned to Control, Allo small-dose (0.16 mg/kg), and Allo large-dose (1.6 mg/kg) groups (n = 15 in each). The weight bearing and mechanical withdrawal thresholds of the hind limb were measured before and at 2, 24, 48, and 168 h after Brennan's surgery. In experiment 2, 16 rats were assigned to Control and Allo (0.16 mg/kg) groups (n = 8 in each). The degree of spontaneous pain was measured using the grimace scale after the surgery. Activities of the primary afferent fibers in the spinal cord (L6) were evaluated using immunohistochemical staining. RESULTS: In experiment 1, the withdrawal threshold of the Allo small-dose group was significantly higher than that of the Control group at 2 h after surgery. Intergroup differences in weight bearing were not significant. In experiment 2, intergroup differences in the grimace scale scores were not significant. Substance P release in the Allo (0.16 mg/kg) group was significantly lower than that in the Control group. CONCLUSIONS: Systemic administration of Allo inhibited mechanical allodynia and activities of the primary afferent fibers at the dorsal horn in a rat postoperative pain model. Allo was proposed as a candidate for postoperative pain management.

Effects of intrathecal SNC80, a delta receptor ligand, on nociceptive threshold and dorsal horn substance p release.

Delta-opioid receptors (DOR) are present in the superficial dorsal horn and are believed to regulate the release of small afferent transmitters as evidenced by the effects of spinally delivered delta-opioid preferring peptides. Here we examined the effects of intrathecal SNC80 [(+)-4-[α(R)-α-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-(methoxybenzyl)-N,N-diethylbenzamide], a selective nonpeptidic DOR agonist, in three preclinical pain models, acute thermal escape, intraplantar carrageenan-tactile allodynia, and intraplantar formalin flinches, and on the evoked release of substance P (SP) from small primary afferents. Rats with chronic intrathecal catheters received intrathecal vehicle or SNC80 (100 or 200 µg). Intrathecal SNC80 did not change acute thermal latencies or carrageenan-induced thermal hyperalgesia. However, SNC80 attenuated carrageenan-induced tactile allodynia and significantly reduced both phase 1 and phase 2 formalin-induced paw flinches, as assessed by an automatic flinch counting device. These effects were abolished by naltrindole (3 mg/kg i.p.), a selective DOR antagonist, but not CTOP (10 µg i.t.), a selective MOR antagonist. Furthermore, intrathecal SNC80 (200 µg) blocked formalin-induced substance P release otherwise evoked in the ispilateral superficial dorsal horn as measured by NK1 receptor internalization. In conclusion, intrathecal SNC80 alleviated pain hypersensitivity after peripheral inflammation in a fashion paralleling its ability to block peptide transmitter release from small peptidergic afferents, which by its pharmacology appears to represent an effect mediated by a spinal DOR.

Effects of general anesthetics on substance P release and c-Fos expression in the spinal dorsal horn.

BACKGROUND: The authors examined in vivo the effects of general anesthetics on evoked substance P release (primary afferent excitability) and c-Fos expression (neuronal activation) in superficial dorsal horn. METHODS: Rats received saline, propofol (100 mg/kg), pentobarbital (50 mg/kg), isoflurane (2 minimum alveolar concentration), nitrous oxide (66%), or fentanyl (30 µg/kg). During anesthesia, rats received intraplantar 5% formalin (50 µl) to left hind paw. Ten minutes later, rats underwent transcardial perfusion with 4% paraformaldehyde. Substance P release from small primary afferents was assessed by incidence of neurokinin 1 receptor internalization in the superficial dorsal horn. In separate studies, rats were sacrificed after 2 h and c-Fos expression measured. RESULTS: Intraplantar formalin-induced robust neurokinin 1 receptor internalization in ipsilateral dorsal horn (ipsilateral: 54 ± 6% [mean ± SEM], contralateral: 12 ± 2%; P < 0.05; n = 4). Fentanyl, but not propofol, pentobarbital, isoflurane, nor nitrous oxide alone inhibited neurokinin 1 receptor internalization. However, 2 minimum alveolar concentration isoflurane + nitrous oxide reduced neurokinin 1 receptor internalization (27 ± 3%; P < 0.05; n = 5). All agents reduced c-Fos expression (control: 34 ± 4, fentanyl: 8 ± 2, isoflurane: 12 ± 3, nitrous oxide: 11 ± 2, isoflurane + nitrous oxide: 12 ± 1, pentobarbital: 11 ± 2, propofol: 13 ± 3; P < 0.05; n = 3). CONCLUSION: General anesthetics at anesthetic concentrations block spinal neuron activation through a mechanism that is independent of an effect on small primary afferent peptide release. The effect of fentanyl alone and the synergistic effect of isoflurane and nitrous oxide on substance P release suggest a correlative rationale for the therapeutic use of these anesthetic protocols by blocking nociceptive afferent transmitter release and preventing the initiation of cascade, which is immediately postsynaptic to the primary afferent.

Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors.

Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA(3) and HXB(3)). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB(3) at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB(3) evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.

Regulation of spinal substance p release by intrathecal calcium channel blockade.

BACKGROUND: The authors investigated the role of different voltage-sensitive calcium channels expressed at presynaptic afferent terminals in substance P release and on nociceptive behavior evoked by intraplantar formalin by examining the effects of intrathecally delivered N- (ziconotide), T- (mibefradil), and L-type voltage-sensitive calcium channel blockers (diltiazem and verapamil). METHODS: Rats received intrathecal pretreatment with saline or doses of morphine, ziconotide, mibefradil, diltiazem, or verapamil. The effect of these injections upon flinching evoked by intraplantar formalin (5%, 50 µl) was quantified. To assess substance P release, the incidence of neurokinin-1 receptor internalization in the ipsilateral and contralateral lamina I was determined in immunofluorescent-stained tissues. RESULTS: Intrathecal morphine (20 µg), ziconotide (0.3, 0.6, and 1 µg), mibefradil (100 µg, but not 50 µg), diltiazem (500 µg, but not 300 µg), and verapamil (200 µg, but not 50 and 100 µg) reduced paw flinching in phase 2 compared with vehicle control (P < 0.05), with no effect on phase 1. Ziconotide (0.3, 0.6, and 1 µg) and morphine (20 µg) significantly inhibited neurokinin-1 receptor internalization (P < 0.05), but mibefradil, diltiazem, and verapamil at the highest doses had no effect. CONCLUSION: These results emphasize the role in vivo of N-type but not T- and L-type voltage-sensitive calcium channel blockers in mediating the stimulus-evoked substance P release from small primary afferents and suggest that T- and L-type voltage-sensitive calcium channel blockers exert antihyperalgesic effects by an action on other populations of afferents or mechanisms involving postsynaptic excitability.

The effects of intrathecal and systemic gabapentin on spinal substance P release.

BACKGROUND: Gabapentin binds at the extracellular α2δ1 subunit of voltage- sensitive calcium channels. Some voltage-sensitive calcium channels regulate substance P release from small primary afferents. We sought to determine in vivo whether spinal and systemic gabapentin at antihyperalgesic doses will attenuate substance P release. METHODS: Rats prepared with chronic intrathecal (IT) catheters received IT vehicle or gabapentin 10 minutes before intraplantar formalin (5%, 50 µL) injection. For systemic studies, vehicle or gabapentin was delivered intraperitoneally (IP) 15 minutes before formalin injection. In separate groups of rats, to assess the effect of IT or IP gabapentin upon formalin-evoked substance P release, animals received similar treatment for assessment of flinching, but underwent transcardial perfusion with 4% paraformaldehyde 10 minutes after the formalin injection. Substance P release was determined by the incidence of neurokinin 1 receptor (NK1r) internalization in the ipsilateral and contralateral superficial dorsal horn in immunofluorescent stained tissues. RESULTS: Unilateral intraplantar formalin evoked biphasic hindpaw flinching. IT gabapentin (100 and 200 µg) and IP gabapentin (100 and 200 mg/kg) resulted in a dose-dependent reduction in phase 2, but not phase 1, flinching in comparison with vehicle-treated rats. Intraplanatar formalin resulted in NK1r internalization in the ipsilateral, but not contralateral, superficial dorsal horn. IT gabapentin (200 µg, but not 100 µg) and IP gabapentin (200 mg/kg, but not 100 mg/kg) significantly reduced ipsilateral NK1r internalization in comparison with vehicle-treated control. Importantly, internalization evoked by IT substance P was not blocked by IT gabapentin. CONCLUSION: Systemic and spinal gabapentin have an acute inhibitory effect on the release of substance P from small primary afferents and a concurrent effect upon the initiation of facilitated pain states.

Presynaptic large-conductance calcium-activated potassium channels control synaptic transmission in the superficial dorsal horn of the mouse.

Large-conductance calcium-activated potassium channels (BK channels) have been suggested to play a substantial role in synaptic transmission in the spinal cord dorsal horn. In the present experiments, we attempted to clarify the physiological significance of BK channels in the modulation of synaptic transmission in the superficial dorsal horn where nociceptive information is processed. Spontaneously occurring excitatory postsynaptic currents (sEPSCs) were recorded from the neurons located in the superficial dorsal horn of a mouse spinal cord slice, and the effects of iberiotoxin, a BK channel blocker, on sEPSCs were analyzed. The frequency of sEPSCs was significantly higher in the peripheral nerve-ligated neuropathic mice than in the sham-operated control mice, but the amplitude of sEPSCs was equivalent between the two groups. Iberiotoxin increased the frequency of sEPSCs in the control mice to the same level as that in the neuropathic mice without affecting the amplitude of sEPSCs. In contrast, iberiotoxin did not show any significant effects on the sEPSCs in the neuropathic mice. These findings suggest that the BK channels that are located in presynaptic terminals control synaptic transmission in the superficial dorsal horn, and that functional downregulation of BK channels accompanies the neuropathic pain induced by peripheral nerve injury. This downregulation was confirmed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of the BK channel alpha subunit. Taken together, our present results indicate that BK channels play crucial roles in the synaptic transmission of nociceptive information in the superficial dorsal horn.

[Customized oxygen tube for intubated patients with spontaneous respiration].

Recently, a customized oxygen tube is available. The circumference of a newly designed oxygen tube is larger than the original tube. In addition, new features are attached at the four sides of the connecter. As a result, a customized oxygen tube is safer than the previous original oxygen tube with minimum increase of weight. The customized oxygen tube is useful for reducing the misconnecting trouble of the tracheal tube and oxygen tube.

NMDA receptor 2B subunit-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-injured neuropathic mice.

Previous research has shown that peripheral inflammation and peripheral nerve injury alter the properties of NMDA receptors in the spinal dorsal horn. However, there is no direct evidence that demonstrates the influence of peripheral nerve injury on NMDA receptor-mediated synaptic transmission in the spinal dorsal horn. Using whole cell tight-seal methods, NMDA receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) were recorded from superficial dorsal horn neurons in adult mouse spinal cord slices. Peripheral nerve injury-induced changes in the pharmacological and electrophysiological properties of synaptic NMDA receptors were studied. The ratio of the amplitude of NMDA EPSCs to that of non-NMDA EPSCs was larger in nerve-ligated neuropathic mice than in sham-operated control mice. The decay phase of the NMDA EPSCs was slower in nerve-ligated neuropathic mice. The NR2B subunit-specific NMDA receptor antagonist ifenprodil (10 microM) reduced the amplitude of the NMDA EPSCs and shortened their decay phase. The sensitivity of NMDA EPSCs to ifenprodil was significantly larger in nerve-ligated neuropathic mice than in sham-operated control mice. Single-cell RT-PCR analysis performed on superficial dorsal horn neurons showed that the incidence of NR2A mRNA-expressing neurons was reduced in nerve-ligated neuropathic mice. This result, together with the electrophysiological findings, suggests that the subunit composition of the subsynaptic NMDA receptors in the superficial dorsal horn was altered by peripheral nerve injury. Pharmacological and electrophysiological changes observed in the present experiments might be the underlying causes of the hyperalgesia and allodynia induced by peripheral nerve injury and inflammation.

[Anesthetic management for cesarean section in a patient with corrected transposition of great arteries].

A 20-year-old woman with corrected transposition of great arteries (height 163 cm, weight 69 kg) was scheduled for elective cesarean section at 36 weeks of gestation. Since her mitral insufficiency had deteriorated during pregnancy, she developed dyspnea and lower cardiac function. We decided to perform general anesthesia for her cesarean section. Under the continuous monitoring of arterial blood pressure, anesthesia induction was performed with thiamylal 150 mg, vecuronium 8 mg and fentanyl 0.2 mg, and maintained with oxygen-air-isoflurane (1-1.5%). A Swan-Ganz catheter was inserted for evaluation of her cardiac function. No cardiac events were observed during surgery. The postoperative course was uneventful, and the patient was discharged from the hospital on the 10th postoperative day. Swan-Ganz catheter was useful for the evaluation of cardiac function and for anesthetic management.