Yumiko Tomoyasu

The influence of oral VPA on the required dose of propofol for sedation during dental treatment in patients with mental retardation: A prospective observer-blinded cohort study

In sedation of dental patients with moderate or severe mental retardation, it is difficult to identify the optimum sedation level and to maintain it appropriately. Moreover, many patients have concomitant epilepsy and are medicated with oral antiepileptic drugs (AEDs), which influence the drug‐metabolizing enzymes. In particular, valproate (VPA) has been demonstrated to inhibit propofol metabolism in vitro. Therefore, the objective of the present study was to investigate the clinical influence of oral VPA on the required dose of propofol for sedation, with use of a prospective cohort study design. We studied 45 patients with moderate or severe mental retardation who underwent dental treatment under sedation. Propofol was infused, and sedation was maintained at the same level in all patients using a bispectral index (BIS) monitor. After the completion of treatment for the scheduled patients, patients were divided into those with oral VPA treatment (VPA group: 20 patients) and without any oral antiepileptic treatment (control group: 25 patients). The propofol dose required for sedation and times to the recovery of the eyelash reflex and spontaneous eye opening were evaluated. The median required propofol doses in the VPA and control groups were 4.15 (range 1.97–5.88) and 5.67 (2.92–7.17) mg/kg/h, respectively. We observed a statistically significant difference between the two patient groups with respect to median VPA dose (p < 0.01). However, no statistically significant differences were noted in the time until eyelash reflex recovery or spontaneous eye opening between the two groups. The results suggest that oral VPA reduces the dose of propofol required for sedation during dental treatment in patients with moderate or severe mental retardation.

Locally injected dexmedetomidine induces vasoconstriction via peripheral α-2A adrenoceptor subtype in guinea pigs

Background and Objectives Recent research shows that locally injected dexmedetomidine enhances the local anesthetic potency of lidocaine via the &agr;-2A adrenoceptor subtype in guinea pigs. However, little is known about the effect of locally injected dexmedetomidine on the peripheral vascular response. This study aimed to evaluate the effect of locally injected dexmedetomidine on the peripheral vascular response, measuring skin blood flow in the injected area in guinea pigs. Methods Dexmedetomidine was intracutaneously injected at a volume of 0.1 mL into the backs of guinea pigs, and further injected combined with yohimbine, a selective antagonist of &agr;-2 adrenoceptors, or prazosin, a selective antagonist of &agr;-1 adrenoceptors and an antagonist of both &agr;-2B and &agr;-2C adrenoceptor subtypes. Skin blood flow was measured until 60 minutes after injection using a laser-Doppler flowmeter. Furthermore, systemic arterial blood pressure and pulse of the guinea pigs were monitored via a catheter inserted into the carotid artery throughout every experiment. Results Dexmedetomidine at a concentration of 1 &mgr;M significantly decreased the skin blood flow in a dose-dependent manner with no changes in the mean blood pressure and pulse. Yohimbine completely antagonized the effect of dexmedetomidine, but prazosin did not. Conclusions The results reveal that locally injected dexmedetomidine at a concentration of 1 &mgr;M induced peripheral vasoconstriction without a systemic cardiovascular response via the peripheral &agr;-2A adrenoceptor subtype.

Effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans: a crossover double-blind study.

PURPOSE Recently, attention has been paid to dexmedetomidine, a selective α-2 adrenoceptor agonist, as a possible additive for local anesthesia. However, the effect of locally injected dexmedetomidine on the anesthetic action in humans has not fully been clarified. Thus, the purpose of the present study was to evaluate the effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans. MATERIALS AND METHODS Twenty healthy volunteers were included in the present crossover double-blinded study. Lidocaine solution or lidocaine plus dexmedetomidine solution was submucosally injected into the alveolar mucosa in a crossover and double-blinded manner. The local anesthetic effect of the solutions was evaluated by measuring the current perception threshold (CPT) in the oral mucosa for 120 minutes after injection. Furthermore, the sedation level, blood pressure, and heart rate of the volunteers were evaluated. For statistical analysis, the Wilcoxon signed rank test and 2-way repeated measures analysis of variation were used. RESULTS The CPT was increased with the 2 solutions and peaked 10 minutes after injection. CPT values 10 and 20 minutes after injection of lidocaine plus dexmedetomidine solution were considerably higher than those with lidocaine solution. The duration of an important increase in the CPT after injection with lidocaine plus dexmedetomidine solution was longer than that with lidocaine. Furthermore, the area under the time curve of CPT was considerably higher with lidocaine plus dexmedetomidine solution than with lidocaine solution. No volunteer showed a change in sedation level, blood pressure, or heart rate after injection with either test solution throughout the experiment. CONCLUSION The present study showed that a combination of dexmedetomidine plus lidocaine considerably enhances the local anesthetic potency of lidocaine without any major influences on the cardiovascular system when locally injected into the oral mucosa.

Liposome-encapsulated midazolam for oral administration.

The oral administration of midazolam has often been used for sedation in pediatric patients. However, oral administration of an intravenous formulation of midazolam is difficult for younger pediatric patients because of its bitter taste. Liposomes have been developed as vesicles encapsulating various kinds of drugs to serve as a medical drug-delivery system. Thus, the aim of the present study was to produce pH-sensitive liposomes encapsulating midazolam and to evaluate its pharmacokinetics on rabbits. Liposome-encapsulated midazolam was produced from hydrogenated L-α-phosphatidylcholine, cholesterol, dipalmitoylphosphatidic acid, and midazolam. The capacity of liposomes to encapsulate midazolam (encapsulation efficiency), stability of encapsulation, and release efficiency were evaluated in vitro. Further, the produced liposome-encapsulated midazolam solution was orally administered to rabbits in vivo. As a result, midazolam was encapsulated by liposomes with a high encapsulation efficiency and was stably encapsulated in a physiological medium. Further, the produced liposomes rapidly and effectively released midazolam in an acidic medium in vitro. When the liposome-encapsulated midazolam solution was orally administered to rabbits, the time to achieve the maximum plasma concentration of midazolam after administration was slightly longer, but both the maximum plasma concentration and area under the concentration-time curve were higher than those receiving midazolam solution. In conclusion, we produced pH-sensitive liposome-encapsulated midazolam, which remained stable in a physiological medium and showed efficient release in an acidic environment. The results suggest that it is possible to clinically use liposome-encapsulated midazolam for oral administration as a useful drug-delivery vehicle.

Midazolam is associated with delay in recovery and agitation after ambulatory general anesthesia for dental treatment in patients with disabilities: a retrospective cohort study.

PURPOSE Some patients with intellectual disabilities (IDs) who undergo total intravenous anesthesia (TIVA) have complications associated with the anesthesia such as prolonged recovery. The purposes of this study were to estimate the frequency of TIVA complications among patients with IDs and to identify factors associated with TIVA complications. MATERIALS AND METHODS This study was designed as a retrospective cohort study. Study samples were selected from the clinical records of patients with IDs who underwent ambulatory general anesthesia in a special dental clinic at the Okayama University Hospital, Okayama, Japan. Predictor variables were patient background, anesthesia-related variables, and dental treatment. Outcome variables were delayed recovery and the complication of agitation. Factors affecting delayed recovery and complications were examined with multivariable analysis. RESULTS We enrolled 106 cases (81 male and 25 female patients) in this study. The mean age was 23.9 years. Serious complications were not observed in any cases. The amount of intravenous midazolam was an independent determinant of delayed recovery. Oral midazolam contributed to delayed recovery, although it is very useful for induction in patients with a high level of fear. Oral midazolam and a younger age were independent predictors of agitation. CONCLUSIONS Intravenous midazolam may not have an advantage in ambulatory general anesthesia. Oral midazolam contributes to delayed recovery and is an independent predictor of agitation.

Allergic reactions to local anesthetics in dental patients: analysis of intracutaneous and challenge tests.

Some dental patients have histories of adverse reactions to local anesthesia. The aim of the present study was to investigate the frequency of allergy to local anesthetics of dental patients who had histories of adverse reactions to local anesthesia based on the results of allergy tests in our institute over a period of 5 years. We investigated the past medical records of dental patients retrospectively, and twenty patients were studied. Three of the 20 showed a positive or false-positive reaction in the intracutaneous test, and one patient showed a false-positive reaction in the challenge test. Our results suggest that the frequency of allergy to local anesthetics is low even if patients have histories of adverse reactions to local anesthesia. However, allergy tests of local anesthetics should be performed in patients in whom it is uncertain whether they are allergic.

Low Bone Mass Is a Risk Factor in Periodontal Disease-Related Tooth Loss in Patients with Intellectual Disability

Teeth are fundamental to maintaining good quality of life, but are often lost prematurely in individuals with intellectual disability. Furthermore, since bone mass decreases in menopausal women, women with intellectual disability have an augmented risk of losing their teeth. However, the relationship between periodontal disease-related tooth loss and bone mass has never been studied specifically in patients with intellectual disability. This study evaluated this relationship in a retrospective cohort study. Participants were female dental patients aged between 20 and 50 years and with an intellectual disability, who were treated in the Special Needs Dentistry unit of the Okayama University Hospital from January 2009 to March 2010. Logistic regression analysis was used to analyze which factors affect periodontal disease-related tooth loss. Information relating to 12 predictor variables, including age and bone mass level, was derived from medical records. The 27 subjects had a total of 704 teeth at the time of initial examination, but 20 teeth (2.8%) had been lost owing to periodontal disease by the time bone mass measurements were recorded. Results of the multinomial logistic regression analysis indicated a significant odds ratio for three items: number of missing teeth at the time of initial examination, bone mass, and living environment. This result suggests that low bone mass is an independent risk factor in tooth loss secondary to periodontal disease in patients with intellectual disability. Dentists should thus take account of this heightened risk of tooth loss when caring for post-menopausal women with intellectual disability.

Female Patients Require a Higher Propofol Infusion Rate for Sedation.

Sedation may minimize physiologic and behavioral stress responses. In our facility, the infusion rate of propofol is adjusted according to the bispectral index (BIS) in all cases of implant-related surgery; multivariate analysis of retrospective data enabled us to extract independent factors that affect the dose of propofol in sedation that are considered useful indicators for achieving adequate sedation. The study population comprised all patients undergoing implant-related surgery under intravenous sedation in Okayama University Hospital from April 2009 to March 2013. The infusion rate of propofol was adjusted to maintain the BIS value at 70-80. The outcome was the average infusion rate of propofol, and potential predictor variables were age, sex, body weight, treatment time, and amount of midazolam. Independent variables that affected the average infusion rate of propofol were extracted with multiple regression analysis. One hundred twenty-five subjects were enrolled. In the multiple regression analysis, female sex was shown to be significantly associated with a higher average infusion rate of propofol. Females may require a higher infusion rate of propofol than males to achieve adequate sedation while undergoing implant-related surgery.

Combination of midazolam and a cyclooxygenase-2 inhibitor inhibits lipopolysaccharide-induced interleukin-6 production in human peripheral blood mononuclear cells

Context: Interleukin-6 (IL-6) plays an important role in immune and inflammatory responses. Midazolam has been reported to modulate IL-6 response. Cyclooxygenase (COX) inhibitors, which are used together with midazolam in some patients undergoing surgery, also modulate it. We hypothesized that their combination results in eliciting the synergistical effect on the IL-6 response. Objective: The aim of the present study was to evaluate the effect of the combination of midazolam and a COX inhibitor on IL-6 production. Materials and methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and incubated with lipopolysaccharide (LPS), midazolam, and/or COX inhibitors, including indomethacin, SC-560, a COX-1 selective inhibitor, and NS-398, a COX-2 selective inhibitor. The supernatant concentrations of IL-6 and prostaglandins (PGs), including PGE2, PGF2α, PGD2, and 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) were measured. Results: Midazolam had no effect on IL-6 production in the cells incubated for 12 h, and any COX inhibitors also had no effect. However, the combination of midazolam and NS-398 significantly inhibited it. Midazolam raised the concentration of 15dPGJ2 in the supernatant of the cells, but not the concentration of other PGs. Disscussion and conclusion: The results in the present study demonstrated that the combination of midazolam and a COX-2 inhibitor inhibited LPS-induced IL-6 production in human PBMCs even if each drug separately did not have any effect on it. The finding suggests that their combination is effective against excessive IL-6 production such as severe inflammatory response and that the effect of midazolam on IL-6 production is possibly elicited via 15dPGJ2.

Effects of midazolam and phenobarbital on brain oxidative reactions induced by pentylenetetrazole in a convulsion model

Context: Brain oxidative reactions are involved in epilepsy as well as neurodegenerative diseases. In animal convulsion models, some anticonvulsants have been found to suppress oxidative reactions associated with convulsions. However, the effect of anticonvulsants on brain oxidative reactions has not fully been clarified. Objective: Midazolam and phenobarbital are often used as an intravenous anesthetic, and are known to have anticonvulsive effect, but antioxidative effect of these drugs has rarely been studied. Thus, the purpose of this study was to evaluate the effects of these drugs on the degree of convulsions and brain oxidative reactions in an animal convulsion model. Materials and methods: In order to evaluate brain oxidative reactions, we measured malondialdehyde (MDA) level and heme oxygenase (HO)-1 mRNA expression level in the brain of mice in a convulsion model generated by a single injection of pentylenetetrazole (PTZ). We evaluated the effects of midazolam and phenobarbital on the degree of PTZ-induced convulsions and on the changes in brain MDA level and HO-1 mRNA expression level. Results: After PTZ injection, severe convulsions were observed in all mice. MDA level was increased in the whole brain, while HO-1 mRNA expression level was increased only in the hippocampus. Both midazolam and phenobarbital prevented the convulsions and suppressed the increase in both MDA level and HO-1 mRNA expression level in the brain. Conclusion: In this study, both midazolam and phenobarbital suppressed PTZ-induced MDA and HO-1 reactions in the brain, suggesting that these drugs inhibit brain oxidative reactions in a convulsion model.