The effect of midazolam administration for the prevention of emergence agitation in pediatric patients with extreme fear and non-cooperation undergoing dental treatment under sevoflurane anesthesia, a double-blind, randomized study.

Background: Sevoflurane is generally the preferred anesthetic agent for general anesthesia in pediatric patients, due to its rapid induction and recovery characteristics. However, it has been recognized that a major complication is emergence agitation when awakening from general anesthesia. The aim of this study was to evaluate the occurrence rate of emergence agitation in the operating room and postoperative recovery area following intraoperative administration of midazolam to pediatric patients under general anesthesia. Patients and methods: One hundred and twenty pediatric patients undergoing dental treatment under sevoflurane anesthesia were enrolled in this study. The patients were divided into three groups (n=40 each in the 0.1 mg/kg midazolam, 0.05 mg/kg midazolam, and control with saline groups). Midazolam or saline was injected intravenously approximately 30 minutes before the end of the dental treatment. We used the Richmond Agitation and Sedation Scale (RASS) to assess the level of sedation and drowsiness at emergence phase in the operating room. We also used the Pediatric Anesthesia Emergence Delirium Scale (PAED) to assess the level of agitation and delirium at the full recovery phase from anesthesia in the recovery area. Results: At the emergence phase, the incidence of emergence agitation in the 0.1 mg/kg midazolam group was significantly lower than in the other groups (p=0.0010). At the recovery phase, there was no significant difference among the three groups. The odds ratio between PAED score and RASS score was 4.0 using logistic regression analysis. The odds ratio between PAED score and Disability was 2.5. Conclusion: Administration of a single dose of 0.1 mg/kg midazolam dose significantly decreases the incidence of severe emergence agitation at the emergence after sevoflurane anesthesia, but not at the recovery phase. Furthermore, the evaluation of sedative and agitation condition using RASS score at emergence from anesthesia is useful to predict occurrence of agitation in the recovery phase.

Effects of general anesthesia on postoperative sleep cycles in dentally disabled patients.

AIMS: Although it has been reported that general anesthesia affect the perioperative sleep cycle, no studies have yet evaluated how general anesthesia affects dentally disabled patients. In this study, we investigated the alteration of perioperative sleep cycles in dentally disabled patients receiving dental treatment under general anesthesia. SUBJECTS AND METHODS: The study included 16 patients receiving dental procedures under general anesthesia. Using a sleep monitoring mat, the patients' sleep cycles were measured at home from 5 days before the scheduled surgery date until 5 days after discharge following general anesthesia. The change in all the variables of sleep cycles were analyzed in comparison to the value in preoperative period. Daily differences in these variables were assessed for statistical analysis. RESULTS: The percentage of deep sleep (Stages 3 and 4) decreased significantly on postoperative day 1, and the percentage of light sleep increased. Furthermore, sleep cycles were significantly extended on postoperative day 1. CONCLUSION: The percentage of deep sleep decreased significantly on postoperative day 1 while the percentage of light sleep increased. Sleep cycles were also significantly extended on postoperative day 1. These results reveal that the sleep cycle is somehow affected on the first day following general anesthesia.

Nitrous Oxide Inhalation Sedation Through a Nasal High-Flow System: The Possibility of a New Technique in Dental Sedation.

High-flow nasal cannula (HFNC) systems are increasingly used for patients with both acute and chronic respiratory failure because of the clinical effectiveness and patient comfort associated with their use. Recently, HFNC has been used not only as a respiratory support device, but also as a drug delivery system. HFNC is designed to administer heated and humidified inspiratory oxygen flows (100% relative humidity at 37°C). Therefore, HFNC can provide high flows (up to 60 L/min) without discomfort. Moreover, HFNC improves oxygenation by exerting physiologic effects such as (a) dead-space washout and (b) moderate positive airway pressure. These characteristics and physiologic effects of HFNC may permit administration of high-flow nitrous oxide sedation while ensuring patient comfort and adequate sedative effect.

Effect of nasal high-flow oxygen therapy on the swallowing reflex: an in vivo volunteer study.

OBJECTIVE: The advantages of nasal high-flow oxygen therapy (NHF) include not only allowing talking, but also eating and drinking, during the therapy. However, the effect of NHF on the swallowing reflex remains unclear. In the present study, we aimed to assess the effects of NHF on the swallowing reflex. METHODS: Nine healthy adult Japanese male volunteers with no history of dysphagia or diseases that may cause dysphagia, such as stroke or Parkinson's disease, were evaluated. Participants received one of four levels of NHF intervention (0 (control), 15, 30 and 45 L/min of oxygen) with the NHF system through the nasal cannula. Swallowing was induced by the administration of a bolus injection of 5 mL of distilled water over 3 s through a polyethylene catheter at each level of oxygen flow. The primary end-point was the latency period of the swallowing reflex after bolus injection, which was defined as the time from the start of the bolus injection to the onset of the electromyogram (EMG) burst of the first swallow. RESULTS: Mean latency times of the swallowing reflex with 15 (9.8 ± 2.9 s), 30 (9.0 ± 2.7 s) and 45 (8.5 ± 3.0 s) L/min of NHF were significantly shorter than those under control conditions (11.9 ± 3.7 s; P < 0.05). CONCLUSIONS: Our study demonstrates that NHF may enhance swallowing function with increasing levels of NHF by reducing the latency of the reflex. CLINICAL RELEVANCE: NHF may allow continuation of oral intake without aspiration during oxygen therapy.

A pilot study of upper airway management using a remote-controlled artificial muscle device during propofol anesthesia.

STUDY OBJECTIVE: To test the hypothesis that the jaw closure using a pneumatic actuator device affect airway collapsibility and resistance during propofol anesthesia. DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital. PATIENTS: Six male subjects were included in the present study. INTERVENTION: We used pressure-flow relationships to evaluate critical closing pressure (PCRIT) and upper airway resistance in different conditions of body and head position. Anesthesia was induced and maintained with a propofol infusion, targeting a constant blood concentration of 1.5 to 2.0µg/mL to establish an adequate depth of anesthesia, with patients breathing spontaneously through a nasal mask. An air-inflatable pneumatic actuator was used to achieve jaw closure. Nasal mask pressure was intermittently reduced to evaluate upper airway collapsibility (passive PCRIT) and upstream resistance under 4 different conditions: (1) neutral occlusion at 0-cm head elevation (baseline), (2) jaw closure at 0-cm head elevation, (3) neutral occlusion at 6-cm head elevation, and (4) jaw closure at 6-cm head elevation. PCRIT and upstream resistance under each condition were compared using 1-way analysis of variance. P<.05 was considered significant. MEASUREMENTS: The pressure and inspiratory flow at the subjects' nose mask were recorded. Polysomonographic parameters (electroencephalograms, electrooculograms, submental electromyograms, and plethysmogram) were also recorded. MAIN RESULTS: The combination of 6-cm head elevation with jaw closure using the pneumatic actuator decreased upper airway collapsibility (PCRIT≈-3.0 cm H2O) compared to the baseline position (PCRIT≈-1.2 cm H2O; P=.0003). CONCLUSION: We demonstrated that jaw closure using an air-inflatable pneumatic actuator device can produce substantial decreases in upper airway collapsibility and maintain upper airway patency during propofol anesthesia.

Comparison of the hemodynamic effects of propofol and ketamine as anesthetic induction agents during high-dose remifentanil administration: a single-center retrospective comparative study.

BACKGROUND: We hypothesized that ketamine, when administered as the anesthetic induction agent, may prevent cardiovascular depression during high-dose remifentanil administration, unlike propofol. To test our hypothesis, we retrospectively compared the hemodynamic effects of ketamine, during high-dose remifentanil administration, with those of propofol. METHODS: Thirty-eight patients who underwent oral surgery at the Nagasaki University Hospital between April 2014 and June 2015 were included in this study. Anesthesia was induced by the following procedure: First, high-dose remifentanil (0.3-0.5 µg/kg/min) was administered 2-3 min before anesthesia induction; next, the anesthetic induction agent, either propofol (Group P) or ketamine (Group K), was administered. Mean arterial pressure (MAP) and the heart rate were recorded by the automated anesthesia recording system at four time points: immediately before the administration of high-dose remifentanil (T1); immediately before the administration of propofol or ketamine (T2); 2.5 min (T3), and 5 min (T4) after the administration of the anesthetic induction agent. RESULTS: In Group P, the MAP at T3 (75.7 ± 15.5 mmHg, P = 0.0015) and T4 (68.3 ± 12.5 mmHg, P < 0.001) were significantly lower than those at T1 (94.0 ± 12.4 mmHg). However, the MAP values in the K group were very similar (P = 0.133) at all time points. The heart rates in both Groups P (P = 0.254) and K (P = 0.859) remained unchanged over time. CONCLUSIONS: We showed that ketamine, when administered as the anesthetic induction agent during high-dose remifentanil administration, prevents cardiovascular depression.

Upside-down mask ventilation technique for a patient with a long and narrow mandible.

Mask ventilation, along with tracheal intubation, is one of the most basic skills for managing an airway during anesthesia. Facial anomalies are a common cause of difficult mask ventilation, although numerous other factors have been reported. The long and narrow mandible is a commonly encountered mandibular anomaly. In patients with a long and narrow mandible, the gaps between the corners of the mouth and the lower corners of the mask are likely to prevent an adequate seal and a gas leak may occur. When we administer general anesthesia for these patients, we sometimes try to seal the airway using several sizes and shapes of commercially available face masks. We have found that the management of the airway for patients with certain facial anomalies may be accomplished by attaching a mask upside down.

Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.

BACKGROUND: Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. METHODS AND RESULTS: An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. CONCLUSION: Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

The effects of hormonal status on upper airway patency in normal female subjects during propofol anesthesia.

STUDY OBJECTIVE: To determine the mechanical upper airway properties and compensatory neuromuscular responses to obstruction during propofol anesthesia in the follicular and luteal phases of the menstrual cycle. DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital. SUBJECTS: 12 premenopausal female volunteers for studies of upper airway collapse throughout their menstrual cycle during the follicular phase (6 -10 days) and mid-late luteal phase (20 - 24 days). MEASUREMENTS: The level of propofol anesthesia (1.5 - 2.0 µg/mL) required to suppress arousal responses was determined by Observer's Assessment of Alertness/Sedation scoring (level 2) and confirmed by bispectral index monitoring. Pressure-flow relationships were constructed to evaluate collapsibility (P(CRIT)) and up-stream resistance (R(US)) during acute [Passive; hypotonic electromyography (EMG)] and sustained (Active; elevated EMG) changes in nasal mask pressure. The difference between passive P(CRIT) and active P(CRIT) (ΔP(CRIT A-P)) represented the magnitude of the compensatory response to obstruction. MAIN RESULTS: Passive P(CRIT) was significantly higher in the mid-late luteal phase (-4.7 cm H(2)O) than in the follicular phase (-6.2 cmH(2)O; P < 0.05). Active P(CRIT) significantly decreased compared with passive P(CRIT) in the follicular phase (-10.1 cm H(2)O) and in the mid-late luteal phase (-7.7 cm H(2)O) and (P < 0.05). No significant difference was noted in ΔP(CRIT) between the follicular (3.9 ± 2.9 cm H(2)O) and mid-late luteal phases (3.0 ± 2.6 cm H(2)O). No differences were seen in R(US) between the menstrual phases for either the passive (P = 0.8) or active (P = 0.75) states. CONCLUSIONS: Menstrual phase has an effect on anatomical alterations (mechanical properties) in the hypotonic upper airway during propofol anesthesia.

Successful treatment of acquired hemophilia A, complicated by chronic GVHD, with tocilizumab.

A 65-year-old woman who had suffered from chronic graft-versus-host disease (GVHD) presented with extensive purpura and was diagnosed with acquired hemophilia A. Because she was refractory to corticosteroids and her condition was complicated with diabetes mellitus, glaucoma, and hypoglobulinemia, she was treated with tocilizumab. Tocilizumab treatment increased the activity of factor VIII in a rapid and sustained manner, leading to a reduction of the prednisolone dose. Tocilizumab may thus be an optional treatment modality for acquired hemophilia A.

The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab.

OBJECTIVE: SSc is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although the aetiology remains uncertain, many reports have suggested that IL-6 is involved in SSc pathogenesis. Tocilizumab, an anti-IL-6 receptor antibody, is an anti-arthritis medicine that works through the blockade of IL-6 functions. To examine the effect of tocilizumab on SSc, we administered tocilizumab to two SSc patients. METHODS: Two dcSSc patients were administered tocilizumab at 8 mg/kg once a month for 6 months. One patient had pulmonary fibrosis assessed by CT and spirometry, and the other had chronic renal failure caused by scleroderma renal crisis. Their skin condition was monitored with a Vesmeter and the modified Rodnan total skin score (mRTSS). Skin biopsies were obtained before and after the tocilizumab treatment to investigate the histological changes. RESULTS: After tocilizumab treatment, both patients showed softening of the skin with reductions of 50.7 and 55.7% in the total z-score of Vesmeter hardness and 51.9 and 23.0% in the mRTSS, respectively. Histological examination showed thinning of the collagen fibre bundles in the dermis. The creatinine clearance in the patient with chronic renal failure improved from 38 to 55 ml/min. However, the fibrotic changes in the lung in the other patient remained unchanged. CONCLUSIONS: In the two cases of SSc that we report here, softening of the skin was observed during the treatment with tocilizumab.

Calicheamicin γ1(I) and phenyl tert-butyl nitrone (PBN): observation of a kinetic isotope effect by an ESR study.

ESR study of enediyne calicheamicin gamma(1)(I) with phenyl tert-butyl nitrone (PBN) gave a significant kinetic isotope effect (k(H)/k(D) = 1.8) for the formation of the phenyl radical PBN monoadducts.

Minimal influence of tocilizumab on IFN-gamma synthesis by tuberculosis antigens.

Interferon gamma (IFN-gamma) production is a critical step of antituberculosis (anti-TB) immune response. The purpose of this study was to determine the influences of biologics, including the interleukin (IL)-6 receptor-inhibitor tocilizumab (TCZ), and tumor necrosis factor (TNF) antagonists infliximab (INF) and etanercept (ETA), on Mycobacterium tuberculosis (MTB) antigen-induced IFN-gamma production. MTB antigen (ESAT-6 and CFP-10)-induced IFN-gamma-releasing assay was performed with or without addition of biologics (TCZ, ETA, and INF) using whole blood from patients with active TB. ETA and INF inhibited IFN-gamma production in a dose-dependent manner. In whole blood from TB patients, ESAT-6 stimulated significant production of IFN-gamma (1.30 +/- 1.95 IU/ml), and TCZ did not inhibit IFN-gamma production (1.56 +/- 1.88 IU/ml). IFN-gamma production by ESAT-6 was inhibited by ETA and INF (0.98 +/- 1.74, 0.75 +/- 1.66 IU/ml, respectively). CFP-10 stimulated significant production of IFN-gamma (1.46 +/- 1.60 IU/ml), and TCZ did not inhibit IFN-gamma production (1.51 +/- 1.77 IU/ml). IFN-gamma production by CFP-10 was inhibited by ETA and INF (0.91 +/- 0.99, 0.72 +/- 0.88 IU/ml, respectively). TCD did not inhibit MTB antigen-induced IFN-gamma production. As IFN-gamma production is important in antimycobacterial host defenses, the minimal influence of TCZ on IFN-gamma-releasing assay suggests a low risk of latent TB infection reactivation during tocilizumab therapy.

A case of Mikulicz's disease with Th2-biased cytokine profile: possible feature discriminable from Sjögren's syndrome.

This article concerns a male patient with Mikulicz's disease (MD) accompanied with marked elevation of serum immunoglobulin (Ig)G4 and IgE levels. His peripheral blood mononuclear cells (PBMC) showed markedly enhanced in vitro production of interleukin (IL)-4, IL-5, IL-13, but not interferon gamma (IFN-gamma) compared with patients with Sjögren's syndrome (SS) and healthy donors, suggesting distinct Th2 bias in this MD patient. Besides the prominent infiltration of IgG4-producing plasma cells, the enhanced expression of both CD40 and CD40 ligand (CD40L) were observed in the swollen salivary gland of the MD patient, suggesting enhanced signaling pathways for the induction of IgG4 and IgE switching. Possible differences between MD and SS in light of their underlying pathogenesis are discussed.

Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial fibroblast via interference with the Akt signaling pathway.

Overgrowth of the synovium plays an important role in the pathogenesis of rheumatoid arthritis (RA). Platelet-derived growth factor (PDGF) is one of the most potent mitogenic factors of synovial cells, and imatinib mesylate (imatinib) is a specific inhibitor of the PDGF receptor tyrosine kinase. The aim of this study was to elucidate the anti-rheumatic activity of imatinib. The in vivo effects of imatinib were assessed by evaluating the sequential manifestation of adjuvant-induced arthritis in rats using paw volume and clinical scores. Imatinib was found to inhibit rat adjuvant-induced arthritis, but the inhibitory effects were incomplete. To confirm the mechanism of anti-rheumatic-activity of imatinib, we assessed the in vitro effects of imatinib on the proliferation of RA synovial fibroblast-like cells (RASFs) using a MTT assay. Intracellular signaling of PDGF was evaluated by Western blot analysis. Platelet-derived growth factor was found to induce a significant proliferation of RASFs, while imatinib inhibited PDGF-induced proliferation of RASF. Imatinib also inhibited PDGF-induced phosphorylation of the PDGF receptor and Akt, whereas constitutive activated extracellular signal-regulated kinase was not inhibited by imatinib. In contrast, imatinib did not inhibit transforming growth factor beta- and basic fibroblast growth factor-induced proliferation of RASF. Oral administration of imatinib ameliorated adjuvant-induced arthritis in rats, and it inhibited PDGF-induced RASF proliferation through disruption of the PDGF-R to Akt kinase signaling pathway. Because imatinib cannot inhibit the non-PDGF-dependent proliferation of RASFs, the anti-rheumatic effect of imatinib may be incomplete. The development of inhibitors of RASF proliferation may lead to the successful treatment of RA.

Preventative effect of a flavonoid, enzymatically modified isoquercitrin on ocular symptoms of Japanese cedar pollinosis.

BACKGROUND: Flavonoids are nutrients that exert anti-allergic effects. We investigated the preventative effect of enzymatically modified isoquercitrin (EMIQ), a flavonoid, to relieve the symptoms of Japanese cedar pollinosis. METHODS: In a parallel-group, double-blind placebo-controlled study design, 24 subjects with Japanese cedar pollinosis took 100mg EMIQ or a placebo for 8 weeks, starting 4 weeks prior to the onset of pollen release. Subjective symptoms, ADL scores and the usage of drugs were recorded daily, and the QOL score was obtained every 4 weeks. Blood sampling was performed before and after the study to measure serum levels of IgE and flavonoids. RESULTS: During the entire study period, ocular symptom + medication score for the EMIQ group was significantly lower (p < 0.05) than that of the placebo group. When limited to the period, ocular symptom scores (p < 0.05, weeks 5-6), and ocular congestion scores (p < 0.05, weeks 5-6) for the EMIQ group was significantly lower than that for the placebo group while other scores for the EMIQ group, such as ocular itching scores (p = 0.09, weeks 4-5), lacrimation scores (p = 0.07, weeks 5-6), and ocular congestion scores (p = 0.06, weeks 4-5), all tended to be lower. However no significant differences were found in nasal symptoms between the two groups. Serum concentrations of IgE were not significantly downregulated but the serum concentrations of quercetin and its derivatives were elevated significantly by the intake of EMIQ. CONCLUSIONS: Intake of the quercetin glycoside EMIQ proved to be effective for the relief of ocular symptoms caused by Japanese cedar pollinosis.

Effect of enzymatically modified isoquercitrin, a flavonoid, on symptoms of Japanese cedar pollinosis: a randomized double-blind placebo-controlled trial.

BACKGROUND: Flavonoids exert antiallergic and antioxidant effects. We investigated the efficacy of enzymatically modified isoquercitrin (EMIQ), a flavonoid, to relieve symptoms of pollinosis. METHODS: In a parallel-group, double-blind placebo-controlled study design, 20 subjects with Japanese cedar pollinosis took two capsules daily of 100 mg EMIQ or a placebo for 8 weeks during the pollen season. Subjective symptoms and activities of daily living (ADL) scores were recorded every day, and the quality of life (QOL) score was obtained every 4 weeks. Blood sampling was performed before and after the study to measure serum cytokines, chemokines, IgE, quercetin and oxidized biomarkers. RESULTS: During the entire study period, total ocular score and ocular itching score for the EMIQ group were significantly lower (p < 0.05) than for the placebo group. When limited to the individual periods, total symptom score for the EMIQ group was significantly lower (p < 0.05, week 4-5) than that for the placebo group while other scores for the EMIQ group, such as total nasal score (p = 0.06, week 4-5), nasal obstruction score (p = 0.08, week 4-5), lacrimation score (p = 0.06, week 5-6), ocular congestion score (p = 0.08, week 4-7) and ADL score (p = 0.08, week 4-7), all tended to be lower. The levels of serum cytokines such as interleukin (IL)-4, IL-5, IL-12, IL-13, interferon-gamma, and eotaxin and IgE were not significantly downregulated by the intake of EMIQ but the serum concentrations of oxidized low-density lipoprotein and thymus and activation-regulated chemokine were reduced. CONCLUSION: Intake of the quercetin glycoside EMIQ was safe and influenced ocular symptoms caused by pollinosis.