Amiodarone Provides Long-Lasting Local Anesthesia and Analgesia in Open-State Mouse Nociceptors.

Local anesthetics with long-lasting effects and selectivity for nociceptors have been sought over the past decades. In this study, we investigated whether amiodarone, a multiple channel blocker, provides long-lasting local anesthesia and whether adding a TRPV1 channel activator selectively prolongs sensory anesthetic effects without prolonging motor blockade. Additionally, we examined whether amiodarone provides long-lasting analgesic effects against inflammatory pain without TRPV1 channel activator co-administration. In the sciatic nerve block model, 32 adult C57BL/6J mice received either bupivacaine, amiodarone with or without capsaicin (a TRPV1 agonist), or vehicle via peri-sciatic nerve injection. Sensory and motor blockade were assessed either by pinprick and toe spread tests, respectively. In another set of 16 mice, inflammatory pain was induced in the hind paw by zymosan injection, followed by administration of either amiodarone or vehicle. Mechanical and thermal sensitivity and paw thickness were assessed using the von Frey and Hargreaves tests, respectively. The possible cardiovascular and neurological side effects of local amiodarone injection were assessed in another set of 12 mice. In the sciatic nerve block model, amiodarone produced robust anesthesia, and the co-administration of TRPV1 agonist capsaicin prolonged the duration of sensory blockade, but not that of motor blockade [complete sensory block duration: 195.0 ± 9.8 min vs. 28.8 ± 1.3 min, F (2, 21) = 317.6, p < 0.01, complete motor block duration: 27.5 ± 1.6 min vs. 21.3 ± 2.3 min, F (2, 22) = 11.1, p = 0.0695]. In the zymosan-induced inflammatory pain model, low-dose amiodarone was effective in reversing the mechanical and thermal hypersensitivity not requiring capsaicin co-administration [50% withdrawal threshold at 8 h (g): 0.85 ± 0.09 vs. 0.25 ± 0.08, p < 0.01, withdrawal latency at 4 h (s) 8.5 ± 0.5 vs. 5.7 ± 1.4, p < 0.05]. Low-dose amiodarone did not affect zymosan-induced paw inflammation. Local amiodarone did not cause cardiovascular or central nervous system side effects. Amiodarone may have the potential to be a long-acting and nociceptor-selective local anesthetic and analgesic method acting over open-state large-pore channels.

Severe hypoglycemia reduces the shivering threshold in rabbits.

BACKGROUND: We previously reported that each 100 mg dL- 1 reduction in blood glucose over the range from ≈90 to > 300 mg dL- 1 decreases the shivering threshold (triggering core temperature) in rabbits by 1 °C. However, the effects of lower blood glucose concentrations has yet to be evaluated. We thus evaluated the relationship between the shivering threshold and blood glucose concentration over the mild-to-severe hypoglycemic range. METHODS: Thirty-nine rabbits were lightly anaesthetized with isoflurane and randomly assigned to one of the three groups: 1) severe hypoglycemia, insulin and dextrose infusions titrated to achieve blood glucose concentration at 45-75 mg dL- 1; 2) mild hypoglycemia, insulin and dextrose infusions titrated to achieve blood glucose concentration at 75-100 mg dL- 1; and 3) saline infusion. Cooling by colonic perfusion of water at 10 °C was continued until shivering occurred or esophageal core temperatures reached to 34 °C. RESULTS: The shivering threshold in the severe hypoglycemic rabbits was 35.7 ± 1.1 °C (mean ± SD); the thresholds in the mild hypoglycemic rabbits was 37.0 ± 0.7 °C; and the threshold in the control rabbits was 37.9 ± 1.0 °C. The shivering threshold increased linearly with blood glucose concentration: shivering threshold (°C) = 0.032 ∙ [blood glucose concentration (mg dL- 1)] + 34.1, R2 = 0.45. The shivering threshold thus decreased by approximately 1 °C for each 31 mg dL- 1 decrease in blood glucose concentration. CONCLUSIONS: There was a linear relationship between blood glucose and the shivering threshold over the range from severe hypoglycemia to normoglycemia. Blood glucose perturbations in the hypoglycemic range reduced the shivering threshold about three times as much as previously reported for the hyperglycemic range.

Analgesic effects of amiodarone in mouse models of pain.

Purpose: Although amiodarone is classified as a Vaughan-Williams class Ⅲ antiarrhythmic drug, it has inhibitory effects on voltage-gated sodium and calcium channels and on ß-adrenergic receptors. Given these pharmacological profiles, amiodarone may have analgesic properties. Most patients who are prescribed amiodarone possess multiple cardiovascular risk factors. Despite the fact that pain plays a crucial role as a clinical indicator of cardiovascular events, the effects of amiodarone on pain have not been investigated. The aim of the current study was to investigate the analgesic effects of amiodarone by using mouse models of pain in an effort to elucidate underlying mechanisms. Methods: Adult male C57B6 mice received single bolus intraperitoneal injections of amiodarone at doses of 25, 50, 100, and 200 mg/kg, while the mice in the control group received only normal saline. The analgesic effects of amiodarone were evaluated using the acetic acid-induced writhing test, formalin test, and tail withdrawal test. In addition, the potassium channel opener NS1643, voltage-gated sodium channel opener veratrine, calcium channel opener BAYK8644, and selective ß-adrenergic agonist isoproterenol were used to uncover the underlying mechanism. Results: During the acetic acid-induced writhing test, formalin test, and tail withdrawal test, amiodarone induced analgesic responses in a dose-dependent manner. The analgesic effects of amiodarone were abolished by veratrine but not by NS1643, BAYK8644, or isoproterenol. Conclusion: Amiodarone induced analgesic responses in a dose-dependent manner, likely by blocking voltage-gated sodium channels. These results indicate that clinical doses of amiodarone can affect nociception and may mask or attenuate pain induced by acute cardiovascular events.

The Effects of Blood Glucose Concentration on the Shivering Threshold in Rabbits.

BACKGROUND: Hyperglycemia is common in critically ill and surgical patients, as are core temperature disturbances. The effect of hyperglycemia on thermoregulatory defenses remains unknown. We determined the effect of blood glucose concentration on the shivering threshold in rabbits. METHODS: Twenty-seven rabbits lightly anesthetized with isoflurane were randomly assigned to infusions of (1) saline, (2) insulin titrated to produce blood glucose concentrations 60 to 100 mg/dL, or (3) 50% dextrose titrated to produce blood glucose concentrations 200 to 300 mg/dL. Core temperature was reduced at a rate of 2 to 3°C/h by perfusing water at 10°C through a plastic tube positioned in the colon. Cooling continued until shivering was observed by an investigator blinded to treatment or until esophageal (core) temperature reached 34°C. Core temperatures at the onset of shivering defined the threshold. All analyses were conducted using SAS version 9.3 (SAS Institute Inc., Cary, NC). RESULTS: Rabbits given saline shivered at 37.2 ± 0.5°C (mean ± SD). Rabbits given insulin shivered at 36.3 ± 1.1°C. Rabbits given dextrose shivered at 38.0 ± 0.6°C. The shivering threshold increased as a function of blood glucose concentration: shivering threshold (°C) = 0.009 [blood glucose concentration (mg/dL)] + 35.6, r = 0.53. The shivering threshold thus increased approximately 1°C for each 100 mg/dL increase in blood glucose concentration. CONCLUSIONS: Hyperglycemia increases the threshold for shivering, whereas hypoglycemia lowers the threshold on rabbits.

The usefulness of an earphone-type infrared tympanic thermometer during cardiac surgery with cardiopulmonary bypass: clinical report.

We evaluated the usefulness of a novel earphone-type infrared tympanic thermometer (IRT) during cardiac surgery with cardiopulmonary bypass. Tympanic membrane temperature (T(Tym)) was monitored using the IRT inserted into the right ear canal of 12 adult patients (ASA III) who had been scheduled for elective cardiac surgery with cardiopulmonary bypass under general anesthesia. Rectum (T(Rec)) and nasopharyngeal temperatures (T(Naso)) were also monitored, and all temperatures were recorded at 5-min intervals during cardiopulmonary bypass. Operating room temperature was kept at 20°-27°C; a conductive warming/cooling system was used to control the patient's body temperature. Of 265 measurements obtained, body temperature range was 31.6°-37.6°C. No complications were related to site of insertion of the monitoring probe. Significant correlations were seen between T(Tym) and T(Naso) (r = 0.971, P < 0.001), and T(Tym) and T(Rec) (r = 0.759, P < 0.001). A Bland-Altman plot showed that average temperature of T (Tym) was 0.06°C above T(Naso) (±0.66°C, 2 SD) and 0.12°C below T(Rec) (±1.78°C, 2 SD). We conclude that an earphone-type IRT is noninvasive and hygienic and could continuously evaluate selective cerebral temperature during cardiopulmonary bypass in adults.

[Spinal anesthesia for a inguinal hernia repair in a small child with laryngeal stenosis].

We experienced spinal anesthesia for inguinal hernia repair in combination with general anesthesia in a 4-year-old child with functional laryngeal stenosis and tendency of laryngeal edema. His airway was managed without endotracheal tube or laryngeal mask airway because these devices could worsen the upper airway stenosis. Spinal anesthesia offered reliable and potent analgesia leading to safe anesthetic management under spontaneous breathing. Although spinal anesthesia in combination with general anesthesia is not common in pediatric patients, it is effective and safe to apply for a case requiring more reliable and potent analgesia with understanding anatomical and physiological characteristics in children.