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1.  IV ATP Potentiates Midazolam Sedation as Assessed by Bispectral Index 
Anesthesia Progress  2014;61(3):95-98.
In this study, by measuring bispectral index (BIS), we tested the hypothesis that intravenous adenosine 5′-triphosphate (ATP) infusion would deepen the level of midazolam-induced sedation. Ten healthy volunteers underwent 2 experiments with at least 2 weeks' interval: immediately after intravenous bolus administration of midazolam (0.04 mg/kg), they received continuous infusion of either ATP infusion (100 μg/kg/min) or placebo (saline) for 40 minutes in a double-blind, randomized, crossover manner. Changes in BIS values and responsiveness to verbal command as well as cardiorespiratory variables were observed throughout the study periods. Administration of midazolam alone reduced BIS value from control: 97 ± 1 to 68 ± 18 at 25 minutes, which was accompanied by significant cardiopulmonary depressant effects, while maintaining responsiveness to verbal command (consciousness) throughout the study period. Coadministration of ATP with midazolam further reduced BIS value to 51 ± 13, associated with complete loss of consciousness without adverse effect on the cardiorespiratory systems. We conclude that the addition of ATP infusion to midazolam significantly enhances midazolam sedation without disturbing cardiorespiratory functions.
PMCID: PMC4156379  PMID: 25191981
Midazolam sedation; ATP; Central adenosine receptors
2.  Prediction Formulas for Individual Opioid Analgesic Requirements Based on Genetic Polymorphism Analyses 
PLoS ONE  2015;10(1):e0116885.
The analgesic efficacy of opioids is well known to vary widely among individuals, and various factors related to individual differences in opioid sensitivity have been identified. However, a prediction model to calculate appropriate opioid analgesic requirements has not yet been established. The present study sought to construct prediction formulas for individual opioid analgesic requirements based on genetic polymorphisms and clinical data from patients who underwent cosmetic orthognathic surgery and validate the utility of the prediction formulas in patients who underwent major open abdominal surgery.
To construct the prediction formulas, we performed multiple linear regression analyses using data from subjects who underwent cosmetic orthognathic surgery. The dependent variable was 24-h postoperative or perioperative fentanyl use, and the independent variables were age, gender, height, weight, pain perception latencies (PPL), and genotype data of five single-nucleotide polymorphisms (SNPs). To examine the utility of the prediction formulas, we performed simple linear regression analyses using subjects who underwent major open abdominal surgery. Actual 24-h postoperative or perioperative analgesic use and the predicted values that were calculated using the multiple regression equations were incorporated as dependent and independent variables, respectively.
Multiple linear regression analyses showed that the four SNPs, PPL, and weight were retained as independent predictors of 24-h postoperative fentanyl use (R2 = 0.145, P = 5.66 × 10-10) and the two SNPs and weight were retained as independent predictors of perioperative fentanyl use (R2 = 0.185, P = 1.99 × 10-15). Simple linear regression analyses showed that the predicted values were retained as an independent predictor of actual 24-h postoperative analgesic use (R2 = 0.033, P = 0.030) and perioperative analgesic use (R2 = 0.100, P = 1.09 × 10-4), respectively.
We constructed prediction formulas, and the possible utility of these prediction formulas was found in another type of surgery.
PMCID: PMC4304713  PMID: 25615449
3.  Functional expression of bradykinin B1 and B2 receptors in neonatal rat trigeminal ganglion neurons 
Bradykinin (BK) and its receptors (B1 and B2 receptors) play important roles in inflammatory nociception. However, the patterns of expression and physiological/pathological functions of B1 and B2 receptors in trigeminal ganglion (TG) neurons remain to be fully elucidated. We investigated the functional expression of BK receptors in rat TG neurons. We observed intense immunoreactivity of B2 receptors in TG neurons, while B1 receptors showed weak immunoreactivity. Expression of the B2 receptor colocalized with immunoreactivities against the pan-neuronal marker, neurofilament H, substance P, isolectin B4, and tropomyosin receptor kinase A antibodies. Both in the presence and absence of extracellular Ca2+ ([Ca2+]o), BK application increased the concentration of intracellular free Ca2+ ([Ca2+]i). The amplitudes of BK-induced [Ca2+]i increase in the absence of [Ca2+]o were significantly smaller than those in the presence of Ca2+. In the absence of [Ca2+]o, BK-induced [Ca2+]i increases were sensitive to B2 receptor antagonists, but not to a B1 receptor antagonist. However, B1 receptor agonist, Lys-[Des-Arg9]BK, transiently increased [Ca2+]i in primary cultured TG neurons, and these increases were sensitive to a B1 receptor antagonist in the presence of [Ca2+]o. These results indicated that B2 receptors were constitutively expressed and their activation induced the mobilization of [Ca2+]i from intracellular stores with partial Ca2+ influx by BK. Although constitutive B1 receptor expression could not be clearly observed immunohistochemically in the TG cryosection, cultured TG neurons functionally expressed B1 receptors, suggesting that both B1 and B2 receptors involve pathological and physiological nociceptive functions.
PMCID: PMC4466439  PMID: 26124706
bradykinin; B1 receptor; B2 receptor; neuropathic pain; pain; trigeminal ganglion neuron; Ca2+ signaling
4.  Factors that Affect Intravenous Patient-Controlled Analgesia for Postoperative Pain Following Orthognathic Surgery for Mandibular Prognathism 
PLoS ONE  2014;9(6):e98548.
The predictors of postoperative pain and analgesic consumption were previously found to include preoperative pain, anxiety, age, type of surgery, and genotype, but remaining unclear was whether intraoperative factors could predict postoperative pain. In the present study, we investigated the time-course of fentanyl consumption using intravenous patient-controlled analgesia records from patients who underwent orthognathic surgery for mandibular prognathism and analyzed the influence of anesthesia methods and surgical methods together with sex on the time course. A significant difference in the time course of fentanyl administration was found (P<0.001). No significant difference in the time course of fentanyl administration was found between males and females (P = 0.653), with no interaction between time course and sex (P = 0.567). No significant difference in the time course of fentanyl administration was found among anesthesia methods, such as fentanyl induction followed by fentanyl maintenance, fentanyl induction followed by remifentanil maintenance, and remifentanil induction followed by remifentanil maintenance (P = 0.512), but an interaction between time course and anesthesia method was observed (P = 0.004). A significant difference in the time course of fentanyl administration was found between surgical methods, such as bilateral mandibular sagittal split ramus osteotomy (BSSRO) and BSSRO combined with Le Fort I osteotomy (bimaxillary; P = 0.008), with no interaction between time course and surgical method (P = 0.535). Total postoperative 24 h consumption associated with the bimaxillary procedure was significantly higher than with BSSRO (P = 0.008). The present results indicate that administration patterns and total 24 h consumption were different among the three groups of anesthesia methods and between the two groups of surgical methods, respectively. Although more research on patient-controlled analgesia patterns and consumption is necessary, the present study will contribute to adequately relieving individual patients from postoperative pain.
PMCID: PMC4043772  PMID: 24893040
5.  Sodium-calcium exchangers in rat trigeminal ganglion neurons 
Molecular Pain  2013;9:22.
Noxious stimulation and nerve injury induce an increase in intracellular Ca2+ concentration ([Ca2+]i) via various receptors or ionic channels. While an increase in [Ca2+]i excites neurons, [Ca2+]i overload elicits cytotoxicity, resulting in cell death. Intracellular Ca2+ is essential for many signal transduction mechanisms, and its level is precisely regulated by the Ca2+ extrusion system in the plasma membrane, which includes the Na+-Ca2+ exchanger (NCX). It has been demonstrated that Ca2+-ATPase is the primary mechanism for removing [Ca2+]i following excitatory activity in trigeminal ganglion (TG) neurons; however, the role of NCXs in this process has yet to be clarified. The goal of this study was to examine the expression/localization of NCXs in TG neurons and to evaluate their functional properties.
NCX isoforms (NCX1, NCX2, and NCX3) were expressed in primary cultured rat TG neurons. All the NCX isoforms were also expressed in A-, peptidergic C-, and non-peptidergic C-neurons, and located not only in the somata, dendrites, axons and perinuclear region, but also in axons innervating the dental pulp. Reverse NCX activity was clearly observed in TG neurons. The inactivation kinetics of voltage-dependent Na+ channels were prolonged by NCX inhibitors when [Ca2+]i in TG neurons was elevated beyond physiological levels.
Our results suggest that NCXs in TG neurons play an important role in regulating Ca2+-homeostasis and somatosensory information processing by functionally coupling with voltage-dependent Na+ channels.
PMCID: PMC3646678  PMID: 23628073
Calcium homeostasis; Sodium-calcium exchangers; Orofacial pain; Trigeminal neuron; Voltage-dependent Na+ channels
6.  Large-Dose Epinephrine Reduces Skeletal Muscle Blood Flow Under General Anesthesia in Rabbits 
Anesthesia Progress  2012;59(3):118-122.
The goal of this study was to investigate the effect of an epinephrine continuous infusion on muscle blood flow in rabbits. Sixteen male Japan White rabbits were randomly allocated to 1 of 2 groups: epinephrine continuous infusion at 0.01 μg/kg/min (Ep-0.01 group, n = 8) and at 0.1 μg/kg/ min (Ep-0.1 group, n = 8). The observed variables were heart rate, femoral artery blood pressure, common carotid artery blood flow (CCBF), masseter muscle blood flow (MBF), and quadriceps muscle blood flow (QBF). In the Ep-0.01 group, CCBF, MBF, and QBF were increased by 14, 22, and 21% from respective control values. In contrast, in the Ep-0.1 group, CCBF, MBF and QBF were decreased by 10, 30, and 27% from respective control values. There were no differences in the percentage change between MBF and QBF during epinephrine continuous infusion. Positive correlations were observed between CCBF and MBF and between CCBF and QBF. In conclusion, skeletal muscle blood flow was increased during the small-dose epinephrine infusion, whereas it was decreased during large-dose infusion.
PMCID: PMC3468289  PMID: 23050751
Epinephrine; Skeletal muscle blood flow; Rabbits
7.  Oral Mucosal Injection of a Local Anesthetic Solution Containing Epinephrine Enhances Muscle Relaxant Effects of Rocuronium 
Anesthesia Progress  2012;59(1):18-21.
The purpose of this study was to examine how submucosal injection of a clinically relevant dose of a lidocaine hydrochloride solution containing epinephrine affects the muscle relaxant effects of rocuronium bromide. Sixteen patients scheduled for orthognathic surgery participated in this study. All patients were induced with fentanyl citrate, a target-controlled infusion of propofol and rocuronium bromide. Anesthesia was maintained by total intravenous anesthesia. After nasotracheal intubation, an infusion of rocuronium bromide was started at 7 µg/kg/min, and the infusion rate was then adjusted to maintain a train of four (TOF) ratio at 10 to 15%. The TOF ratio just prior to oral mucosal injection of a 1% lidocaine hydrochloride solution containing 10 µg/mL epinephrine (LE) was taken as the baseline. TOF ratio was observed for 20 minutes, with 1-minute intervals following the start of injection. Mean epinephrine dose was 85.6 ± 18.6 µg and mean infusion rate of rocuronium bromide was 6.3 ± 1.6 µg/kg/min. TOF ratio began to decrease 2 minutes after the injection of LE, reached the minimum value at 3.1 ± 3.6% 12 minutes after the injection, and then began to recover. We conclude that oral mucosal injection of LE enhances the muscle relaxant effects of rocuronium bromide.
PMCID: PMC3309297  PMID: 22428970
Rocuronium; Lidocaine with epinephrine; Muscle relaxant effects
8.  Pain Management for Nerve Injury following Dental Implant Surgery at Tokyo Dental College Hospital 
By allowing reconstruction of compromised occlusion, dental implants contribute to an improvement in quality of life (QOL) and diet. Injury to a nerve during such treatment, however, can result in a sudden decline in QOL. And once a nerve has been injured, the chances of a full recovery are slim unless the damage is only slight. If such damage causes neuropathic pain severe enough to prevent sleep, the patient's QOL will deteriorate dramatically. While damage to skin tissue or bone invariably heals over time, damage to nerves does not, indicating the need to avoid such injury while performing implant insertion, for example. This means not relying solely on X-ray images, which can be rather unclear, but also using computed tomography to allow preoperative planning and intraoperative execution to be performed as accurately as possible. Moreover, if sensory damage does occur it is essential to avoid breaking the bond of trust between dentist and patient by giving false assurances of recovery. In such cases, appropriate measures must be taken promptly. This paper describes pain management for nerve injury following dental implant surgery at the Orofacial Pain Center of Tokyo Dental College Suidoubashi Hospital.
PMCID: PMC3413988  PMID: 22899928
9.  Diversity of Opioid Requirements for Postoperative Pain Control Following Oral Surgery—Is It Affected by Polymorphism of the μ-Opioid Receptor? 
Anesthesia Progress  2010;57(4):145-149.
We experience individual differences in pain and sensitivity to analgesics clinically. Genetic factors are known to influence individual difference. Polymorphisms in the human OPRM1 gene, which encodes the μ-opioid receptors, may be associated with the clinical effects of opioid analgesics. The purpose of this study was to determine whether any of the 5 common single-nucleotide polymorphisms (SNPs) of the OPRM1 gene could affect the antinociceptive effect of fentanyl. Fentanyl was less effective in subjects with the G allele of the OPRM1 A118G SNP than in those with the A allele, and subjects with the G allele required more fentanyl for adequate postoperative pain control than those with the A allele. In the future, identifying SNPs might give us information to modulate the analgesic dosage of opioid individually for better pain control. Factors underlying individual differences in sensitivity to pain other than genetic factors may include environmental and psychological factors. We therefore examined the effects of preoperative anxiety on the analgesic efficacy of fentanyl in patients undergoing sagittal split mandibular osteotomy (SSMO). From among the patients enrolled in the study, 60 patients (male/female: 18/42, age: 24.6 ± 6.7 years) who gave informed consent were examined for correlations between preoperative trait/state anxiety, as measured by the state-trait anxiety inventory (STAI) on the day before surgery, and postoperative consumption of patient-controlled analgesia (PCA) fentanyl and visual analog scale (VAS) assessment by patients. Levels of trait and state anxieties measured by the STAI were correlated with neither the consumption of PCA fentanyl nor postoperative VAS assessment. These findings suggest that psychological factors are unlikely to affect postoperative pain or the use of analgesics.
PMCID: PMC3006662  PMID: 21174568
Polymorphism; μ-Opioid receptor; Postoperative pain; Patient-controlled analgesia; Preoperative anxiety
10.  Health professional's perceptions of and potential barriers to smoking cessation care: a survey study at a dental school hospital in Japan 
BMC Research Notes  2010;3:329.
Smoking is currently accepted as a well-established risk factor for many oral diseases such as oral cancer and periodontal disease. Provision of smoking cessation care to patients with oral problems is a responsibility of health care professionals, particularly dentists and dental hygienists. This study examined the smoking-related perceptions and practices of dental school hospital-based health professionals in Japan.
A cross-sectional study design was used. The sample was formed from dentists, dental hygienists, physicians and nurses of a dental school hospital in Tokyo, Japan (n = 93, 72%). Participants were asked to complete an 11-item questionnaire assessing demographic variables and smoking history, provision of smoking cessation advice or care, attitudes about smoking cessation, and perceived barrier(s) to smoking cessation care. Eighteen percent of participants reported being current smokers and 15% reported being ex-smokers, with higher smoking rates reported by dentists compared with other health professionals (p = 0.0199). While recognizing the importance of asking patients about their smoking status, actual provision of smoking cessation advice or care by participants was relatively insufficient. Interventions such as 'assess willingness to make a quit attempt' and 'assist in quit attempt' were implemented for less than one-quarter of their patients who smoke. Non-smokers were more likely to acknowledge the need for increased provision in smoking cessation care by oral health professionals. 'Lack of knowledge and training' was identified as a central barrier to smoking cessation care, followed by 'few patients willing to quit'.
A need for further promotion of smoking cessation activities by the health professionals was identified. The findings also suggest that dentists and dental hygienists, while perceiving a role in smoking care, do require training in the provision of smoking cessation care to hospital patients. In order to overcome the potential barriers, it is necessary to provide staff with appropriate training and create an atmosphere supportive of smoking cessation activities.
PMCID: PMC3016266  PMID: 21138553
11.  Negative Pressure Pulmonary Edema After Oral and Maxillofacial Surgery 
Anesthesia Progress  2009;56(2):49-52.
Negative pressure pulmonary edema (NPPE) following upper airway obstruction (UAO) has been reported in several clinical situations. The main cause of NPPE is reported to be increased negative intrathoracic pressure. We present a case of NPPE that occurred after general anesthesia for plate removal after jaw deformity surgery. After completion of the surgery, administration of inhaled anesthetics was stopped and the patient opened his eyes on verbal command. Immediately after extubation, the patient stopped breathing and became cyanotic. Acute UAO following laryngospasm was suspected. Soon after reintubation, pink, frothy fluid came out of the endotracheal tube, and a tentative diagnosis of NPPE was made. Continuous positive airway pressure was applied. In addition, furosemide and dexamethasone were administered. By the next day, the symptoms had almost disappeared.
PMCID: PMC2699692  PMID: 19642719
Negative pressure pulmonary edema; Upper airway obstruction; Continuous positive airway pressure
12.  Lack of Pain Reduction by a Vibrating Local Anesthetic Attachment: A Pilot Study 
Anesthesia Progress  2005;52(2):62-64.
A vibrating dental local anesthesia attachment (Vibraject, LLC, Calif) based on the concept of the gate-control theory has been used in clinical practice. The theoretical advantage of the vibrating needle is that it reduces the injection pain. We evaluated the effectiveness of Vibraject in combination with an electrical injection device. Injections were given into the alveolar mucosa adjacent to the root apex of the maxillary lateral incisor in 10 volunteers. Vibraject was randomly applied to either the left or right side of the injection. No statistically significant decrease in pain scores was found at needle insertion or anesthetic injection. The clinical efficacy of Vibraject remains controversial.
PMCID: PMC2527045  PMID: 16048153
Local anesthesia; Injection; Pain; Vibrating needle

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