A multi-centre, double-blind, randomized, placebo-controlled trial to evaluate the effectiveness and safety of ramelteon for the prevention of postoperative delirium in elderly cancer patients: a study protocol for JORTC-PON2/J-SUPPORT2103/NCCH2103.

Postoperative delirium is an important issue in cancer patients, affecting surgical outcomes and the quality of life. Ramelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors. Clinical trials and observational studies in Japan, including in surgical cancer patients, have shown efficacy of ramelteon in delirium prevention, with no serious safety concerns. However, clinical trials from the USA have reported conflicting results. A Japanese phase II study investigated the efficacy and safety of ramelteon for delirium prevention following gastrectomy in patients aged ≥75 years, with findings suggesting the feasibility of a phase III trial. The aim of this multi-centre, double-blind, randomized placebo-controlled phase III trial is to evaluate the effectiveness and safety of oral ramelteon for postoperative delirium prevention in cancer patients aged ≥65 years as advanced medical care. The trial protocol is described here.

Prevention of delirium with agitation by yokukansan in older adults after cancer surgery.

OBJECTIVE: Preventing postoperative delirium with agitation is vital in the older population. We examined the preventive effect of yokukansan on postoperative delirium with agitation in older adult patients undergoing highly invasive cancer resection. METHODS: We performed a secondary per-protocol analysis of 149 patients' data from a previous clinical trial. Patients underwent scheduled yokukansan or placebo intervention 4-8 days presurgery and delirium assessment postoperatively. Delirium with agitation in patients aged ≥75 years was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the Japanese version of the Delirium Rating Scale-Revised-98. We assessed odds ratios for yokukansan (TJ-54) compared with placebo for the manifestation of postoperative delirium with agitation across patients of all ages (n = 149) and those aged ≥65 years (n = 82) and ≥ 75 years (n = 21) using logistic regression. RESULTS: Delirium with agitation manifested in 3/14 and 5/7 patients in the TJ-54 and placebo groups, respectively, among those aged ≥75 years. The odds ratio for yokukansan vs. placebo was 0.11 (95% confidence interval: 0.01-0.87). An age and TJ-54 interaction effect was detected in patients with delirium with agitation. No intergroup differences were observed in patients aged ≥65 years or across all ages for delirium with agitation. CONCLUSIONS: This is the first study investigating the preventive effect of yokukansan on postoperative delirium with agitation in older adults. Yokukansan may alleviate workforce burdens in older adults caused by postoperative delirium with agitation following highly invasive cancer resection.

Uniform infection screening allowed safe head and neck surgery during the coronavirus disease 2019 pandemic in Japan.

BACKGROUND: The purpose of this study was to determine whether a uniform infection screening protocol could be used to safely perform head and neck cancer surgery during the coronavirus disease 2019 pandemic and clarify how surgical treatment changed compared with the pre-pandemic period. MATERIALS AND METHODS: During the unprecedented coronavirus disease 2019 pandemic in Tokyo, we continued providing head and neck cancer care, guided by our own uniform screening protocol. In this study, medical records of 208 patients with head and neck malignancy, who underwent surgical treatment at our hospital during the first and second wave of pandemic for each 2-month period (first wave: 30 March 2020-30 May 2020, second wave: 14 July 2020-14 September 2020) and the 2-month pre-pandemic period (30 October 2019-30 December 2020), were analysed. RESULTS: A total of 133 patients were admitted for surgical treatment and all, except six patients with emergency tracheostomy, were screened according to the protocol. As a result, all 127 patients received surgical treatment as planned, and all 1247 medical staff members involved in the surgeries were uninfected by severe acute respiratory syndrome coronavirus 2. During the first wave of pandemic, 20% reduction of head and neck surgery was requited; however, restrictions of surgery were not necessary during the second wave. Surgical procedure, length of hospitalization, postoperative complications and number of medical staff were unchanged compared with pre-pandemic period. CONCLUSION: Our data indicate that continuation of head and neck anticancer surgical treatment in an epidemic area during the coronavirus disease 2019 pandemic were safe and feasible, if adequate and strict preventive measures are vigorously and successfully carried out.

[Successful treatment of very severe late-onset sinusoidal obstruction syndrome with recombinant human soluble thrombomodulin, steroids, and control of intra-abdominal pressure].

We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).

Possible biased analgesic of hydromorphone through the G protein-over ß-arrestin-mediated pathway: cAMP, CellKey™, and receptor internalization analyses.

Morphine, fentanyl, and oxycodone are widely used as analgesics, and recently hydromorphone has been approved in Japan. Although all of these are selective for µ-opioid receptors (MORs) and have similar structures, their analgesic potencies and adverse effects (AEs) are diverse. Recent molecular analyses of MOR signaling revealed that the G protein-mediated signaling pathway causes analgesic effects and the ß-arrestin-mediated signaling pathway is responsible for AEs. We used several cell-based analyses that selectively measure cellular responses activated by either G protein- or ß-arrestin-mediated pathways. GloSensor™ cAMP, CellKey™, and receptor internalization assays were performed with four different types of cells stably expressing differentially labelled MOR. EC50 values measured by cAMP and CellKey™ assays had potencies in the order fentanyl ≤ hydromorphone < morphine ≤ oxycodone, all also exhibiting full agonist responses. However, in the internalization assay, only fentanyl elicited a full agonist response. Hydromorphone had the strongest potency next to fentanyl; however, contribution of the ß-arrestin-mediated pathway was small, suggesting that its effect could be biased toward the G protein-mediated pathway. Based on these properties, hydromorphone could be chosen as an effective analgesic.

Preoperative Anxiety as a Predictor of Delirium in Cancer Patients: A Prospective Observational Cohort Study.

BACKGROUND: Postoperative delirium is a common and important complication in cancer patients. We need to identify patients at high risk of postoperative delirium such that it can be prevented preoperatively or in early postoperative phase. The aim of this study was to investigate whether preoperative anxiety predicted onset of postoperative delirium in cancer patients, not only in order to identify high-risk groups but also to help develop new preventive approaches. METHODS: This was a prospective observational cohort study of cancer patients undergoing tumor resections. Postoperative delirium was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Preoperative anxiety was evaluated with the Hospital Anxiety and Depression Scale-Anxiety (HADS-A), and we defined HADS-A > 7 as clinical anxiety. We conducted multivariate logistic regression to determine which factors were predictors of delirium. RESULTS: The final analysis included 91 patients, 29 of whom met the criteria for postoperative delirium. In multivariable logistic regression, age (5-year increments; odds ratio (OR) = 1.565, 95% confidence interval (CI) = 1.057-2.317, p = 0.025) and HADS-A > 7 (OR = 4.370, 95% CI = 1.051-18.178, p = 0.043) predicted delirium onset. These variables explained 74.2% of the variance. CONCLUSIONS: Preoperative anxiety strongly predicted postoperative delirium in cancer patients. Our findings suggest that preoperative anxiety may be a new target for prevention of postoperative delirium. Trial registration number This study was registered at UMIN000018980.

Current Ventilator and Oxygen Management during General Anesthesia: A Multicenter, Cross-sectional Observational Study.

BACKGROUND: Intraoperative oxygen management is poorly understood. It was hypothesized that potentially preventable hyperoxemia and substantial oxygen exposure would be common during general anesthesia. METHODS: A multicenter, cross-sectional study was conducted to describe current ventilator management, particularly oxygen management, during general anesthesia in Japan. All adult patients (16 yr old or older) who received general anesthesia over 5 consecutive days in 2015 at 43 participating hospitals were identified. Ventilator settings and vital signs were collected 1 h after the induction of general anesthesia. We determined the prevalence of potentially preventable hyperoxemia (oxygen saturation measured by pulse oximetry of more than 98%, despite fractional inspired oxygen tension of more than 0.21) and the risk factors for potentially substantial oxygen exposure (fractional inspired oxygen tension of more than 0.5, despite oxygen saturation measured by pulse oximetry of more than 92%). RESULTS: A total of 1,786 patients were found eligible, and 1,498 completed the study. Fractional inspired oxygen tension was between 0.31 and 0.6 in 1,385 patients (92%), whereas it was less than or equal to 0.3 in very few patients (1%). Most patients (83%) were exposed to potentially preventable hyperoxemia, and 32% had potentially substantial oxygen exposure. In multivariable analysis, old age, emergency surgery, and one-lung ventilation were independently associated with increased potentially substantial oxygen exposure, whereas use of volume control ventilation and high positive end-expiratory pressure levels were associated with decreased potentially substantial oxygen exposure. One-lung ventilation was particularly a strong risk factor for potentially substantial oxygen exposure (adjusted odds ratio, 13.35; 95% CI, 7.24 to 24.60). CONCLUSIONS: Potentially preventable hyperoxemia and substantial oxygen exposure are common during general anesthesia, especially during one-lung ventilation. Future research should explore the safety and feasibility of a more conservative approach for intraoperative oxygen therapy.

[Anaphylactoid Reactions Suspected to Be Caused by Neostigmine in Pediatric Patients under General Anesthesia].

Anaphylactoid reaction is a rapid systemic allergic reaction to many kinds of allergen. The peak age of onset is in the forties and there are not many reports on anaphylactoid reactions in pediatric patients. We report two cases of pediatric patients who underwent surgical treatment on retinoblastoma and developed anaphylactoid reaction probably caused by neostigmine. General anesthesia was induced with fentanyl, sevoflurane, dinitrogen monoxide, and rocronium. The procedure was uneventfully completed. Just after the administration of neostigmine to reverse rocronium, the patients showed red flare on the face and chest, and wheezes were heard, but the vital signs were relatively stable. The rapid onset from the administration of neostigmine to the allergic reaction accompanied by skin and respiratory manifestations strongly suggested the anaphylactoid reaction to neostigmine.

Safety and effectiveness of propofol-based monitored anesthesia care without intubation during endoscopic submucosal dissection for early gastric and esophageal cancers.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) becomes more difficult with an increased risk of complications if patient sedation is insufficient. We assessed the safety and effectiveness of propofol-based monitored anesthesia care (MAC) without intubation during ESD for early esophageal cancer (EEC) or early gastric cancer (EGC) in the endoscopy room. METHODS: We investigated 1013 consecutive patients with 1126 lesions who underwent ESD for EGC/EEC with either MAC or regular sedation by endoscopists (control group) between July 2010 and March 2013. Patient characteristics, endoscopic findings, technical results, body movement, oxygen saturation (SpO2 ), and drug dosages were then examined. RESULTS: MAC was carried out in 137 EGC (16%) and 82 EEC patients (57%), whereas regular sedation was used in 731 EGC (84%) and 63 EEC patients (43%). MAC was conducted in 21% of all ESD procedures. In the MAC and control groups, body movement requiring a third person for control occurred in 30 (22%) and 533 (72%) cases during gastric ESD (P < 0.0001) and in 36 (44%) and 53 (84%) cases during esophageal ESD (P < 0.0001), respectively. The median minimum SpO2 was significantly lower in the MAC group than in the control group during both gastric and esophageal ESD (96% vs 98%, P < 0.0001; 96% vs 98%, P < 0.0004, respectively). MAC did not cause any adverse effects requiring prolongation of hospitalization. CONCLUSIONS: Propofol-based MAC without intubation provided a safer treatment environment by significantly reduced body movement and was very effective for difficult cases requiring longer procedure times or more powerful sedation.

[Examination of the Untoward Removal of the Epidural Catheter Due to Differences in Its Fixation Methods].

BACKGROUND: Epidural anesthesia is a useful tool for postoperative pain control. However, inappropriate fixing of the catheter not only hinders the analgesic effect, but could lead to serious accidents as a result of the untoward removal of the epidural catheter. METHODS: In our hospital, in order to reduce the removal of catheter, we introduced a new method of fixing by Steri-StripTM from fiscal 2011. RESULTS: We compared 2337 cases of epidural use for general anesthesia in one fiscal year of 2010. In fiscal year 2011, 2500 examples were examined backward. CONCLUSIONS: The group using the Steri-Strip, was able to significantly reduce the untoward removal (P = 0.002).

[Intraoperative body temperature changes and short-term outcomes of open and minimally invasive esophagectomy].

BACKGROUND: Esophagectomy is a highly invasive procedure, and recently the use of minimally invasive esophagectomy (MIE) via thoracoscopy and laparoscopy increased, since this technique possibly enhances the recovery and outcomes of the patient compared with open esophagectomy (OE). However there is little data about intraoperative changes in body temperature during OE and MIE. METHODS: We retrospectively investigated the intraoperative body temperature and the postoperative short-term outcomes of patients undergoing OE (n = 33) or MIE (n = 24). The rectal temperature was recorded at 5 time points (at the start of the surgery, 1, 3, and 5 h after the start of the surgery, and at the end of the surgery). RESULTS: The average body temperature at the start was similar between the OE and MIE groups (36.5 +/- 0.4 vs. 36.6 +/- 0.5 degrees C, P = 0.497). Throughout the surgery, the temperature of the OE group increased to 37.1 +/- 0.6 degrees C, but the temperature in the MIE group decreased to 36.1 +/- 0.8 degrees C. There was no significant difference in 30-day mortality and short-term complications between the two groups. CONCLUSIONS: Our study showed that the intraoperative temperature during MIE tended to decrease compared with OE, but the short-term outcomes were comparable.

Safety of propofol sedation administered by interventional radiologists for radiofrequency ablation in patients with hepatocellular carcinoma.

PURPOSE: To evaluate the safety of propofol sedation administered by interventional radiologists during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Propofol sedation was administered by interventional radiologists in 72 patients (85 procedures, 93 tumors) during RFA for HCC between August 2018 and December 2020. Interventional radiologists equipped with adequate knowledge and skills in sedation and respiratory management were responsible for sedation. Sedation was carefully assessed based on vital signs, including end-tidal carbon dioxide, consciousness status, and bispectral index. The primary endpoint was the incidence of sedation-related complications, which were evaluated separately as respiratory and cardiovascular complications. Secondary endpoints were technical success rate, ablation-related complications, and local tumor control rate. Technical success was defined as completion of ablation in the planned area. Complications were evaluated using the Clavien-Dindo classification. Sedation-related complications, technical success rate, and ablation-related complications were evaluated on a procedure basis, and local tumor control was evaluated on a tumor basis. RESULTS: Respiratory and cardiovascular complications were observed in eight (8/85, 9.4%) and two (2/85, 2.4%) patients, respectively. Four patients required the jaw thrust maneuver due to glossoptosis, whereas a decrease in oxygen saturation to < 90% was recorded in the other four patients. However, these were temporary, and none required manual ventilation or endotracheal intubation. Bradycardia (< 50 bpm) was detected in two patients; one recovered immediately without treatment, whereas the other rapidly improved after atropine sulfate administration. No severe hypotension (< 80 mmHg) was observed. The technical success rate was 100% (85/85). Grade 3 ablation-related complications were identified in three patients (3/85, 3.5%). The local tumor control rate was 95.7% (89/93). CONCLUSION: Propofol sedation can be safely administered by interventional radiologists during RFA for HCC. Although it requires special safety considerations, it may be a sedation option during hepatic RFA.

[Anticholinesterases; peripheral and central effects].

Anticholinesterase, such as neostigmine, was used to be a standard drug at the end of surgery for reversal of nondepolarizing neuromuscular block. Neostigmine decreases the metabolism of acetylcholine (ACh) at the neuromuscular junction and allows its concentration to increase and overcome the effect of the muscle relaxant. But this approach is ineffective against profound block. Rapid reversal from deep block is not possible and giving a reversal agent early will not speed up the recovery time. Anticholinesterases have actions both at the nicotinic and the muscarinic receptors, and even when accompanied by an antimuscarinic agent, they produce undesirable autonomic responses. Some anticholinesterase, like donepezil, exhibits high specificity for centrally active acetylcholinesterase and raise ACh levels in the brain. The deficiency in cholinergic neurotransmission in Alzheimer's disease (AD) has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. In addition to donepezil, two other cholinesterase inhibitors have recently been approved for the treatment of AD patients. The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. Donepezil can also reverse opioid-induced respiratory depression.

[Spinal paralysis by extradural hematoma following catheter removal].

A 63-year-man with lung cancer underwent right upper lobectomy under general anesthesia combined with thoracic epidural anesthesia. The surgical course was uneventfully completed. On the second postoperative day, he developed complete paralysis below T4 level 1 hour after removal of the epidural catheter. The magnetic resonance imaging (MRI) showed extradural hematoma compressing the spinal cord from T4 to T6 segments. Surgical removal of hematoma was scheduled. However, his neurological condition improved rapidly within a couple of hours, and the surgery was not carried out. The time course of recovery from complete paralysis suggests that extradural hematoma diffused into the extradural space, resulting in a decrease in the epidural pressure.

Protective effect of propofol compared with sevoflurane on liver function after hepatectomy with Pringle maneuver: A randomized clinical trial.

While the Pringle maneuver reduces intraoperative blood loss in hepatectomies, this technique can also be hepatotoxic. Hepatectomies require general anesthesia with propofol or volatile anesthetics like sevoflurane, agents known to offer multi-organ protection. However, their clinical effect after liver resection is unclear. We aimed to assess the effect of the two anesthetics on post-hepatectomy liver damage via measuring liver function tests. Fifty-six patients who underwent elective hepatectomies with the Pringle maneuver due to metastatic hepatic masses were preoperatively randomized to be anesthetized by sevoflurane or propofol. The primary and secondary outcomes were the postoperative peak levels of aspartate transaminase (AST) and alanine transaminase (ALT), respectively. Patients anesthetized by propofol exhibited significantly lower transaminases than those given sevoflurane (AST, p = 0.005; ALT, p = 0.006). The former agent significantly affected postoperative transaminases (AST hazard ratio -192.2, 95% confidence interval [-332.1 to -52.4], p = 0.00; ALT hazard ratio -140.2, 95% confidence interval [-240.0 to -40.7], p = 0.007). In conclusion, propofol had a greater hepatoprotective effect than sevoflurane as assessed by postoperative transaminases after hepatectomy with Pringle maneuver for metastatic liver tumors.

Multicenter study verifying a method of noninvasive continuous cardiac output measurement using pulse wave transit time: a comparison with intermittent bolus thermodilution cardiac output.

BACKGROUND: Many technologies have been developed for minimally invasive monitoring of cardiac output. Estimated continuous cardiac output (esCCO) measurement using pulse wave transit time is one noninvasive method. Because it does not require any additional sensors other than those for conducting 3 basic forms of monitoring (electrocardiogram, pulse oximeter wave, and noninvasive (or invasive) arterial blood pressure measurement), esCCO measurement is potentially useful in routine clinical circulatory monitoring for any patient including low-risk patients. We evaluated the efficacy of noninvasive esCCO using pulse wave transit time in this multicenter study. METHODS: We compared esCCO and intermittent bolus thermodilution cardiac output (TDCO) in 213 patients, 139 intensive care units (ICUs), and 74 operating rooms (ORs), at 7 participating institutions. We performed electrocardiogram, pulse oximetry, TDCO, and arterial blood pressure measurements in patients in ICUs and ORs; a single calibration was performed to measure esCCO continuously. TDCO measurement was performed once daily for ICU patients and every hour for OR patients, and just before the removal of the pulmonary arterial catheter from patients in both the ICU and OR. We evaluated esCCO against TDCO with correlation analysis and Bland and Altman analysis and also assessed the change of bias over time. Furthermore, we inspected the impact of change in systemic vascular resistance (SVR) on change in bias because abnormal SVR was assumed to be a factor contributing to the change of the bias. RESULTS: From among 588 esCCO and TDCO datasets (excluding calibration points), 587 datasets were analyzed for 213 patients. The analysis results show a correlation coefficient of 0.79 (P < 0.0001, 95% confidence limits of 0.756-0.819), a bias (mean difference between esCCO and TDCO) of 0.13 L/min (95% confidence interval of bias 0.04-0.22 L/min), and a precision (1 SD) of 1.15 L/min (95% prediction interval was -2.13 to 2.39 L/min). There were no significant differences among 3 defined time intervals over 48 hours after calibration (repeated-measures analysis of variance P = 0.781) in the ICU. The influence of SVR on esCCO analysis showed a correlation coefficient between SVR and an error of 0.37 (P < 0.0001, 95% confidence interval 0.298-0.438). CONCLUSION: The efficacy of noninvasive esCCO technology was compared with TDCO in 213 cases. Five hundred eighty-seven datasets comparing esCCO and TDCO showed close correlation and small bias and precision, which were comparable to current arterial waveform analysis technologies.

The ability of a new continuous cardiac output monitor to measure trends in cardiac output following implementation of a patient information calibration and an automated exclusion algorithm.

A new non-invasive continuous cardiac output (esCCO) monitoring system solely utilizing a routine cardiovascular monitor was developed, even though a reference cardiac output (CO) is consistently required. Subsequently, a non-invasive patient information CO calibration together with a new automated exclusion algorithm was implemented in the esCCO system. We evaluated the accuracy and trending ability of the new esCCO system. Either operative or postoperative data of a multicenter study in Japan for evaluation of the accuracy of the original version of esCCO system were used to develop the new esCCO system. A total of 207 patients, mostly cardiac surgical patients, were enrolled in the study. Data were manually reviewed to formulate a new automated exclusion algorithm with enhanced accuracy. Then, a new esCCO system based on a patient information calibration together with the automated exclusion algorithm was developed. CO measured with a new esCCO system was compared with the corresponding intermittent bolus thermodilution CO (ICO) utilizing statistical methods including polar plots analysis. A total of 465 sets of CO data obtained using the new esCCO system were evaluated. The difference in the CO value between the new esCCO and ICO was 0.34 ± 1.50 (SD) L/min (95 % confidence limits of -2.60 to 3.28 L/min). The percentage error was 69.6 %. Polar plots analysis showed that the mean polar angle was -1.6° and radial limits of agreement were ±53.3°. This study demonstrates that the patient information calibration is clinically useful as ICO, but trending ability of the new esCCO system is not clinically acceptable as judged by percentage error and polar plots analysis, even though it's trending ability is comparable with currently available arterial waveform analysis methods.

[Comparison of continuous cardiac output measurement methods: non-invasive estimated CCO using pulse wave transit time and CCO using thermodilution].

BACKGROUND: esCCO (estimated continuous cardiac output, Nihon Kohden, esCCO) is a new cardiac output measurement system which uses pulse wave transit time to calculate cardiac output continuously and non-invasively. One of the most commonly used methods to monitor cardiac output is continuous cardiac output CCO (Edwards Lifesciences) which has an accuracy equivalent to that of thermodilution method. METHODS: We compared esCCO to CCO in 67 operating room patients and 128 intensive care unit patients. CCO and esCCO were measured simultaneously in patients with a pulmonary artery catheter inserted after admission to the operating room or intensive care unit. RESULTS: CCO and esCCO showed a high correlation with a correlation coefficient of 0.84 in 496 total data points, and 95% limits of agreement between these two methods were -2.49 to 2.35 l x min(-1). CONCLUSIONS: This result suggests that esCCO could be used to measure cardiac output accurately and non-invasively in different cases.

Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine.

The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of µ-opioid receptors (MORs). We measured changes in MOR activity and intracellular signaling induced by repeated fentanyl and morphine administration and investigated the effects of ketamine on these changes with human embryonic kidney 293 cells expressing MOR using the CellKey™, cADDis cyclic adenosine monophosphate, and PathHunter® ß-arrestin recruitment assays. Repeated administration of fentanyl or morphine suppressed the second MOR responses. Administration of ketamine before a second application of opioids within clinical concentrations improved acute desensitization and enhanced ß-arrestin recruitment elicited by fentanyl but not by morphine. The effects of ketamine on fentanyl were suppressed by co-treatment with an inhibitor of G-protein-coupled receptor kinase (GRK). Ketamine may potentially reduce fentanyl tolerance but not that of morphine through modulation of GRK-mediated pathways, possibly changing the conformational changes of ß-arrestin to MOR.

Combination of asleep and awake craniotomy as a novel strategy for resection in patients with butterfly glioblastoma: Two case reports.

Background: Several studies have reported that gross total resection contributes to improved prognosis in patients with butterfly glioblastoma (bGBM). However, it sometimes damages the corpus callosum and cingulate gyrus, leading to severe neurological complications. Case Description: We report two cases of bGBM that was safely and maximally resected using brief and exact awake mapping after general anesthesia. Two patients had butterfly tumors in both the frontal lobes and the genu of the corpus callosum. Tumor resection was first performed on the nondominant side under general anesthesia to shorten the resection time and maintain patient concentration during awake surgery. After that, awake surgery was performed for the lesions in the dominant frontal lobe and genu of the corpus callosum. Tumor resection was performed through minimal cortical incisions in both frontal lobes. Postoperative magnetic resonance imaging showed gross total resection, and the patients had no chronic neurological sequelae, such as akinetic mutism and abulia. Conclusion: bGBM could be safely and maximally resected by a combination of asleep and brief awake resection, which enabled patients to maintain their attention to the task without fatigue, somnolence, or decreased attention. The bilateral approach from a small corticotomy can avoid extensive damage to the cingulate gyrus.