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藤本 大地医学部附属国際がん医療・研究センター助教
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■ 論文- BACKGROUND: Recent research has suggested that general anesthetics may affect the immune system, but it is unclear how they affect the mitochondria of neutrophils. The effects of general anesthetics on neutrophil-like differentiated HL60 cells mitochondrial function and their production of reactive oxygen species (ROS) were examined in this study. METHODS: HL60 cells were differentiated into neutrophil-like cells by treating them with 1 μM all-trans-retinoic acid for 4 days. The differentiated HL60 cells were exposed to propofol (4 μg ml-1), midazolam (0.5 μg ml-1), or sevoflurane (3 %) for 1 h or 5 h. Following the exposure to the anesthetics, we analyzed the production of ROS, bactericidal effects, cell viability, and apoptosis of the neutrophil-like differentiated HL60 cells. We also investigated the effects of these anesthetics on mitochondrial morphology and function of the neutrophil-like differentiated HL60 cells. RESULTS: Administration of propofol or midazolam activated neutrophil-like differentiated HL60 cells mitochondrial respiration and increased ATP production (P < 0.05). However, there was no significant change in production of ROS or cell death. Exposure to sevoflurane activated mitochondrial respiration, ATP production (P < 0.05) and ROS production (P < 0.05). Additionally, exposure to sevoflurane led to a significant increase in phagocytosis. Filamentous mitochondria appeared after treatment with propofol, midazolam, and sevoflurane, while fragmented and filamentous mitochondria were seen in untreated neutrophil-like differentiated HL60 cells. CONCLUSION: We investigated the effects of three anesthetics on the mitochondrial and bactericidal functions of differentiated HL60 cells. Our results indicate that sevoflurane activates mitochondrial function in differentiated HL60 cells, promotes the production of reactive oxygen species, and enhances bactericidal activity.2025年12月, Biochemistry and biophysics reports, 44, 102272 - 102272, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: Patients undergoing surgery are prone to postoperative hyponatremia, which can lead to delirium. However, the optimal sodium concentration for postoperative maintenance fluids in adult patients is still unclear. Therefore, this study examined the incidence of hyponatremia and delirium in postoperative patients. METHODS: This was a single-center, non-blinded, randomized trial. The inclusion criteria for this study were age 20 years or older and elective head and neck cancer or esophageal cancer surgery between April 2018 and June 2023. Patients were randomly assigned to one of three groups based on the sodium concentration in the intravenous fluids administered after surgery: the 140 mmol/L sodium (Na140) group, the 77 mmol/L sodium (Na77) group, and the 35 mmol/L sodium (Na35) group. RESULTS: A total of 105 patients had complete data at the end of the study: Na140 group (n = 35), Na77 group (n = 32), and Na35 group (n = 38). The incidence of postoperative hyponatremia was 22.9% (8/35) in the Na140 group, significantly lower than in the Na77 group [56.3% (18/32)] and the Na35 group [60.5% (23/38)] (both p < 0.01). The incidence of postoperative delirium was 20.0% (7/35) in the Na140 group, 31.3% (10/32) in the Na77 group, and 23.7% (9/38) in the Na35 group. No significant difference was observed among the groups (p = 0.56). CONCLUSION: The use of postoperative fluids with a sodium concentration of 140 mmol/L significantly reduced the incidence of hyponatremia. There was no significant difference in the incidence of postoperative delirium.2025年11月, Journal of anesthesia, 英語, 国内誌研究論文（学術雑誌）
- Background and objective Dobutamine, a β1-adrenergic agonist, is frequently used to enhance myocardial contractility in patients with critical illness. However, it also increases tachyarrhythmia and myocardial oxygen consumption. Landiolol, an ultra-short-acting and highly β1-selective β-blocker, is used to manage tachycardia in patients with critical illness; however, the combination of a β-agonist and β-blocker seems contradictory at first glance. Previous studies have examined this combination in healthy subjects; however, its effects on patients with critical illness have not been fully elucidated. Hence, this study aimed to address that gap in the literature. Methods This single-center, retrospective, observational study included adult ICU patients who received combination therapy with dobutamine and landiolol between January 1, 2014, and December 31, 2023. Patients who received combination therapy for less than 24 hours or who required extracorporeal circulatory support were excluded. Continuous hemodynamic data were extracted from electronic medical records. Primary outcomes were changes in heart rate (HR) and mean arterial pressure (MAP) after initiation of landiolol administration. Secondary outcomes were achievement of HR <110 bpm, incidence of hypotension (MAP <65 mmHg), change in lactate levels, and rhythm conversion in patients with atrial fibrillation (AF). Linear mixed-effects models were used to evaluate changes in HR and MAP after the initiation of landiolol treatment. Results A total of 72 patients were included in the final analysis. Landiolol treatment was significantly associated with a significant decrease in HR (β = -2.61, p < 0.001) without a significant decrease in MAP. Landiolol treatment also significantly decreased lactate levels (p = 0.029). In patients with atrial fibrillation (n = 53), 79.2 % converted to sinus rhythm or paced rhythm after the initiation of landiolol treatment. Conclusions Landiolol effectively reduced HR without reducing MAP in critically ill patients with dobutamine-induced tachycardia. Furthermore, landiolol may promote rhythm control and improve metabolic parameters such as lactate levels.2025年09月, Cureus, 17(9) (9), e92273, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: Postoperative delirium (POD) is a frequent complication after surgery, especially in elderly patients undergoing head and neck cancer surgery with free flap reconstruction. This study aimed to assess the associations between intraoperative hypotension (IOH), its duration, and occurrence of POD. METHODS: This retrospective study included 239 patients aged 65 years or older who underwent head and neck cancer surgery with free flap reconstruction. IOH was defined at seven mean arterial pressure (MAP) thresholds, ranging from 55 to 85 mmHg, in 5 mmHg increments. The duration of each IOH was compared between patients with or without POD before and after initiation of microsurgery. Multivariate analysis was conducted to assess the independent association of each IOH duration with the risk of POD. RESULTS: POD occurred in 43 (18.0%) of the 239 patients. Before the initiation of microsurgery, the cumulative duration of hypotension below MAP thresholds of < 70 to 80 mmHg was significantly longer in patients with POD. After the initiation of microsurgery, the cumulative duration of hypotension below MAP thresholds of < 55 to 85 mmHg was also significantly longer in patients with POD. In multivariate analysis, the cumulative duration of hypotension below MAP thresholds of 70, 75, and 80 mmHg before and after the initiation of microsurgery was independently associated with POD (p < 0.05 at each threshold). CONCLUSION: Prolonged IOH, particularly below MAP thresholds of 70, 75, and 80 mmHg, was significantly associated with POD in elderly patients undergoing head and neck cancer surgery with free flap reconstruction.2025年07月, Journal of anesthesia, 英語, 国内誌研究論文（学術雑誌）
- PURPOSE: Elderly patients with proximal femoral fractures are known to be a high-risk group for postoperative delirium (POD). The aim of this study was to determine the association of the benzodiazepine drug remimazolam with POD in elderly patients with proximal femoral fractures. METHODS: In this single-center retrospective observational study, we included patients aged 65 years or older who underwent general anesthesia for proximal femoral fractures. We collected data for the incidence of POD within 3 days after surgery. We also obtained data for complications, preoperative blood examinations, maintenance anesthetic and intraoperative vital data. The occurrence of POD in patients who received remimazolam for general anesthesia (remimazolam group) was compared to that in patients who received general anesthesia with other anesthetic agents (other group). We finally conducted a multivariate analysis to assess the independent association of remimazolam with the risk of POD. RESULTS: A total of 230 patients, including 54 patients who received remimazolam for maintenance anesthesia, were included in this study. The incidence of POD in the patients was 26.1%. The incidence of delirium within 3 days after surgery was significantly lower in the remimazolam group than in the other group (14.8% vs. 29.5%, p = 0.03). The multivariate analysis showed that the use of remimazolam independently reduced the occurrence of POD (adjusted odds ratio = 0.42, p = 0.04). CONCLUSION: This retrospective observational study showed that the use of remimazolam is independently associated with a reduced incidence of POD. Remimazolam may be considered as an option to reduce POD in elderly patients with proximal femoral fractures.2024年03月, Journal of anesthesia, 英語, 国内誌研究論文（学術雑誌）
- The neuromuscular blocking potency of rocuronium varies with respiratory pH changes, increasing at lower pH and decreasing at higher pH; thus, hyperventilation-induced respiratory alkalosis is expected to decrease the potency of rocuronium. We report a case of anesthetic management of modified electroconvulsive therapy (m-ECT) for a patient monitored with electromyography-based neuromuscular monitoring during two patterns of ventilation to elucidate their relationship and propose the possible mechanisms underlying the effects by computational simulations. Case presentation: The patient was a 25-year-old man with schizophrenia. In m-ECT, hyperventilation may be used to produce longer seizures. We compared the neuromuscular monitoring data recorded during hyperventilation and during normal ventilation while receiving the same dose of rocuronium. Despite receiving the same dose of rocuronium, the time required for the first twitch to decrease to 80% of the control value was delayed in hyperventilation compared to normal ventilation. Conclusions: This case report and computational simulation suggest that respiratory alkalosis might delay the action of rocuronium. It is necessary to consider the delayed action of rocuronium when hyperventilation is performed.2023年08月, Journal of clinical monitoring and computing, 37(4) (4), 1115 - 1118, 英語, 国際誌研究論文（学術雑誌）
- OBJECTIVES: To study the timing, threshold, and duration of intraoperative hypotension (IOH) associated with the risk of postoperative delirium (POD). DESIGN: A single-center retrospective observational study. SETTING: University teaching hospital. PARTICIPANTS: A total of 503 adult patients who underwent cardiac valvular surgery that required cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS: The authors predefined the following 4 periods: (1) during surgery, (2) pre-CPB, (3) during CPB, and (4) post-CPB, and 8 thresholds of mean arterial pressure for IOH according to every 5 mmHg between 50 mmHg and 85 mmHg. The authors calculated the cumulative duration below the 8 thresholds in each period. The primary outcome was delirium defined as a score of ≥4 for at least one Intensive Care Delirium Screening Checklist assessment during 48 h after the surgery. Among 503 patients, POD occurred in 95 patients (18.9%). There was no significant association of POD with all of the thresholds of IOH in the periods of pre-CPB, during CPB, and during surgery. However, in the post-CPB period, the patients with POD had a significantly longer cumulative duration of IOH according to all of the thresholds of mean arterial pressure. In multivariate analyses, 4 IOH thresholds in the post-CPB period were associated independently with POD: <60 mmHg (odds ratio [OR] =1.84 [95% CI 1.10-3.10]), <65 mmHg (OR = 1.72 [1.01-2.92]), <70 mmHg (OR = 1.83 [1.03-3.26]), and <75 mmHg (OR = 1.94 [1.02-3.69]). CONCLUSIONS: A longer cumulative duration of IOH with the threshold between <60 and <75 mmHg that occurred after CPB was independently associated with the risk of POD.2022年11月, Journal of cardiothoracic and vascular anesthesia, 36(11) (11), 4062 - 4069, 英語, 国際誌研究論文（学術雑誌）
- Elsevier Inc., 2021年12月, Perioperative Care and Operating Room Management, 25, 英語研究論文（学術雑誌）
- Continuous Mandibular Nerve Block for Intractable Mandibular Pain Due to Antiresorptive Agent-Related Osteonecrosis of the Jaw: A Case Report.Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) causes severe pain that cannot be controlled well by common analgesic drugs. This is a first case report of intractable mandibular pain due to ARONJ that was eliminated by a continuous mandibular nerve block. A 72-year-old woman with osteoporosis had been administered bisphosphonate. One year after extraction of her tooth, she was diagnosed as having ARONJ. Jaw pain was so severe that she was unable to open her mouth and eat. We performed a continuous mandibular nerve block through an indwelling catheter with levobupivacaine for pain management. After the procedure, her rest pain was markedly improved, and the pain induced by opening her mouth disappeared. We conclude that a continuous mandibular nerve block may be helpful in the management of ARONJ.2020年11月, The Kobe journal of medical sciences, 66(3) (3), E90-E93, 英語, 国内誌研究論文（学術雑誌）
- BACKGROUND: The risk of surgical site infection has been reported to be higher in patients with poorly controlled diabetes. Since chronic hyperglycemia impairs neutrophil functions, preoperative glycemic control may restore neutrophil function. However, long-term insulin therapy may lead to a delay in surgery, which may be a problem, especially in cancer surgery. It is therefore unfortunate that there have been few studies in which the optimal duration of perioperative glycemic control for diabetes with chronic hyperglycemia was investigated. Therefore, we investigated the effects of preoperative long-term insulin therapy and short-term insulin therapy on perioperative neutrophil functions in diabetic mice with chronic hyperglycemia. METHODS: Five-week-old male C57BL/6 J mice were divided into four groups (No insulin (Diabetes Mellitus: DM), Short-term insulin (DM), Long-term insulin (DM), and Non-diabetic groups). Diabetes was established by administrating repeated low-dose streptozotocin. The Short-term insulin (DM) group received insulin therapy for 6 h before the operation and the Long-term insulin (DM) group received insulin therapy for 5 days before the operation. The No insulin (DM) group and the Non-diabetic group did not receive insulin therapy. At 14 weeks of age, abdominal surgery with intestinal manipulation was performed in all four groups. We carried out a phagocytosis assay with fluorescent microspheres and a reactive oxygen species (ROS) production assay with DCFH-DA (2',7'-dichlorodihydrofluorescein diacetate) before and 24 h after the operation using FACSVerse™ with BD FACSuite™ software. RESULTS: Blood glucose was lowered by insulin therapy in the Short-term insulin (DM) and Long-term insulin (DM) groups before the operation. Neutrophilic phagocytosis activities before and after the operation were significantly restored in the Long-term insulin (DM) group compared with those in the No insulin (DM) group (before: p = 0.0008, after: p = 0.0005). However, they were not significantly restored in the Short-term insulin (DM) group. Neutrophilic ROS production activities before and after the operation were not restored in either the Short-term insulin (DM) group or Long-term insulin (DM) group. CONCLUSIONS: Preoperative and postoperative phagocytosis activities are restored by insulin therapy for 5 days before the operation but not by insulin therapy for 6 h before the operation.2020年09月, BMC endocrine disorders, 20(1) (1), 146 - 146, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: Patients undergoing gynecological surgery are considered to be a high-risk cohort for postoperative nausea and vomiting (PONV). The purpose of this study was to assess the association of intraoperative end-tidal carbon dioxide (EtCO2) with risk of PONV in patients underwent gynecological open surgery. METHODS: In this single-center retrospective observational study, we included patients aged 20-60 years who underwent elective gynecological open surgery. We obtained data for the incidence of PONV within 24 h after operation. We collected EtCO2 every minute during the operation, and determined the lowest value of EtCO2. We compared the lowest EtCO2 between patients with and without PONV. Multivariate logistic regression analysis was performed to assess the independent association of EtCO2 with the risk of PONV. RESULTS: A total of 146 patients were included in the current study. There were 81 patients with PONV within 24 h after the operation. The median lowest value of EtCO2 in patients with PONV was significantly lower than that in patients without PONV (31 vs 33 mmHg, p = 0.02). In the multivariate logistic regression model, we found that lowest EtCO2 ≤ 31 mmHg was independently associated with increase in the risk of PONV (adjusted odds ratio = 3.37, p = 0.02). CONCLUSION: In this retrospective observational study, low intraoperative EtCO2 was shown to be independently associated with increased risk of PONV. However, this result may be skewed by uncollected information including previous PONV, motion sickness or other unknown bias, so future studies should be conducted to refute or confirm our findings.2020年04月, Journal of anesthesia, 34(2) (2), 195 - 201, 英語, 国内誌研究論文（学術雑誌）
- 2020年04月, Journal of anesthesia, 34(2) (2), 316 - 316, 英語, 国内誌
- PURPOSE: The purpose of this study was to compare the incidences of hyponatremia in adult postoperative critically ill patients receiving isotonic and hypotonic maintenance fluids. METHODS: In this single-center retrospective before/after observational study, we included patients who had undergone an elective operation for esophageal cancer or for head and neck cancer and who received postoperative intensive care for >48 h from August 2014 to July 2016. In those patients, sodium-poor solution (35 mmol/L of sodium; Na35) had been administered as maintenance fluid until July 2015. From August 2015, the protocol for postoperative maintenance fluid was revised to the use of isotonic fluid (140 mmol/L of sodium; Na140). The primary outcome was the incidence of hyponatremia (<135 mmol/L) until the morning of postoperative day (POD) 2. RESULTS: We included 179 patients (Na35: 87 patients, Na140: 92 patients) in the current study. The mean volume of fluid received from ICU admission to POD 2 was not significantly different between the two groups (3291 vs 3337 mL, p = 0.84). The incidence of postoperative hyponatremia was 16.3% (15/92) in the Na140 cohort, which was significantly lower than that of 52.9% (46/87) in the Na35 group (odds ratio = 0.17, 95% confidence interval 0.09-0.35, p < 0.001]. The incidences of hypernatremia, defined as serum sodium concentration >145 mmol/L, were not significantly different between the two groups. CONCLUSION: In this study, the use of intravenous maintenance fluid with 35 mmol/L of sodium was significantly associated with an increased risk of hyponatremia compared to that with 140 mmol/L of sodium in adult postoperative critically ill patients.2017年10月, Journal of anesthesia, 31(5) (5), 657 - 663, 英語, 国内誌研究論文（学術雑誌）
- [Vital Sign Changes and the Requirement of Analgesics after Discontinuation of Dexmedetomidine in Patients after Esophageal Cancer Surgery.]BACKGROUND: There is few study to examine the vital sign changes and the requirement of analgesics after discontinuation of dexmedetomidine in postopera- tive patients. METHODS: This is a retrospective observational study conducted in 74 patients after esophageal cancer sur- gery. We recorded vital signs including blood pressure, heart rate and respiratory rate one hour before discon- tinuation of dexmedetomidine, and at 1, 2, 4, 6 hours after its discontinuation. We also recorded the use of opioid and analgesic within 6 hours after discontinua- tion. RESULTS: Mean blood pressure, pulse rate, and respi- ratory rate significantly increased after DEX discon- tinuation. Compared with the data before discontinua- tion, the mean blood pressure increased by 13.3 mmHg, heart rate increased by 7.5 beats - min- and respira- tory rate increased by 3.0 times - min-' in average at 6 hours after discontinuation. There were 28 patients (38%) who required the additional analgesics within 6 hours after discontinuation. CONCLUSIONS: After discontinuation of dexmedetomi- dine, significant changes of vital signs, especially in mean blood pressure, were observed in post-esopha- gectomy patients. About 38% of them required addi- tional analgesics within 6 hours after dexmedetomidine discontinuation.2016年09月, Masui. The Japanese journal of anesthesiology, 65(8) (8), 795 - 800, 日本語, 国内誌研究論文（学術雑誌）
- 2024年, 日本麻酔科学会学術集会(Web), 71st全身麻酔薬が好中球培養細胞のミトコンドリア代謝と活性酸素産生に与える影響
- 2024年, 日本集中治療医学会学術集会(Web), 51stトラファイン挿入時に生じた気管損傷部の観察にラリンジアルマスクが有用であった1例
- 2017年, 日本ペインクリニック学会誌, 24(4) (4)持続下顎神経ブロックで管理した難治性下顎部痛の1例
- 日本学術振興会, 科学研究費助成事業 若手研究, 若手研究, 神戸大学, 2021年04月01日 - 2024年03月31日術後の低活動型せん妄に対するカフェインの治療薬としての有効性の検討本研究では、カフェインの低活動型せん妄抑制効果を検討・解明することが目的である。まず、マウスのせん妄を診断するために、行動実験と脳波測定の検討を行なっている。行動実験に関しては、解析ソフトであるDeepLabCutを用いたオープンフィールドテストを検討している。現在のところDeepLabCutをコンピューターへのインストールに成功し、オープンフィールド実験中のマウス動画を解析できるようになっている。また、その他の行動実験として、buried food testやYメイズテストを検討している。脳波測定に関しては、鎮静中のマウスに対して、頭蓋骨を露出させ、頭部固定用の固定具を直接頭蓋骨に固定を行っている。後日、全身麻酔下のマウスに対して、歯科用ドリルで頭蓋骨に穴をあけ、脳表面に3つ電極をおき、脳波を測定できるようになった。まだ手技にばらつきがあるためか、脳挫傷を引き起こすことがある。現在は鎮静中の脳波測定を行なっているが、今後は覚醒時・活動時の脳波を測定する。今年度上半期中に手術によるせん妄誘発を行い、行動実験・脳波測定を行い、せん妄の病型分類を行なってみる予定である。 本研究では上述の動物実験の他に、ヒトに対する無作為化研究を平行して行う予定である。現在、その計画を練っている段階である。今後、当院の倫理委員会に提出し、研究の許可を得る予定である。
- 日本学術振興会, 科学研究費助成事業 若手研究, 若手研究, 神戸大学, 2018年04月01日 - 2021年03月31日慢性高血糖の糖尿病モデルにおける至適な術前血糖管理の開発慢性高血糖マウスに対して、長期間インスリンコントロールを行うと、術前及び術後のマウス好中球の貪食能の改善を認めた。一方で、活性酸素産生能に関しては、コントラバーシャルな結果が得られ、一定した結果を得られていないのが現状である。本研究で行う予定であった、殺菌能の評価、及び、遊走能の検討を行った。殺菌能検査では、得られたマウス血液に、黄色ブドウ球菌を添加し、一定時間インキュベートして、その血液をベアードパーカー寒天培地に塗布し、24時間後の菌量を測定したが、非糖尿病のコントロール群でも一定の結果を得ることができなかった。そのため、この方法については一定の結果が得られるようにさらに検討中である。また、遊走能の測定は、アガロースプレート法及びボイデンチャンバー室法で行ったが、これも非糖尿病のコントロール群の結果が一定しておらず、これも方法の検討中のままである。一方で、マウス好中球の貪食能の改善のメカニズムを調べるために、インスリン投与量と血糖変化からインスリン効果値(Insulin sensitivity factor;ISF)を測定した。その結果、インスリン効果値の改善とともに、好中球貪食能の改善が怒っている可能性を得た。 また、昨年度はストレプトゾトシンを使用した1型糖尿病に相当するマウスで実験を行ったが、今年度はdb/dbマウスと言うレプチン遺伝子異常の先天性2型糖尿病マウスを用いているところである。7週齢では有意に高血糖であったが、HbA1cには有意差は認められなかったが、9週齢ではHbA1cの有為な上昇を認め、13-15週齢まで飼育することで、十分に慢性高血糖と言えると考えられる。今後、このマウスを用いて研究する予定である。
- 日本学術振興会, 科学研究費助成事業 挑戦的萌芽研究, 挑戦的萌芽研究, 神戸大学, 2016年04月01日 - 2018年03月31日既存のMEMSセンサを用い、原理実証試作機を開発した。気管モデルを用いた実験の結果、以下の２点が明らかとなった。すなわち、① 3つのセンサの出力を均一になるようにデバイス先端を屈曲させることで、風上に先端を誘導することができる、② 気道と食道の分岐部ではセンサすべての出力が上昇しその後下降するため、万が一食道挿管が行われた際もセンサの出力が大幅に下がることからすぐに食道挿管と判別することが可能である、であった。①は提案手法のアイディアが実現できることを裏付ける結果であり、②は本デバイスにより気管挿管が安全に行うことができることを示す結果となった。