九州大学 研究者情報
研究者情報 (研究者の方へ)入力に際してお困りですか?
基本情報 研究活動 教育活動 社会活動 病院臨床活動
徳田 賢太郎(とくだ けんたろう) データ更新日:2020.05.27

助教 /  九州大学病院 集中治療部 九州大学病院 集中治療部


主な研究テーマ
ドキソルビシン誘導性心筋障害に対する、チオ硫酸による心筋保護効果
キーワード:チオ硫酸、心筋保護効果、ドキソルビシン誘導性心不全
2016.04~2019.03.
急性肝不全・劇症肝炎における硫化水素の肝保護作用
キーワード:硫化水素、急性肝不全、肝保護作用
2013.04~2016.03.
敗血症・全身性炎症における硫化水素の病態生理学的意義
キーワード:敗血症、全身性炎症、硫化水素
2009.09~2015.03.
従事しているプロジェクト研究
薬剤性心筋障害に対して、硫化水素代謝物チオ硫酸は心筋保護効果を発揮するか?
2016.04~2019.03, 代表者:徳田賢太郎, 九州大学, 九州大学
生体内ガス状生理活性物質である硫化水素は、その作用の一部を代謝産物であるチオ硫酸を介して発揮することを、私たちは世界に先駆けて報告した。酸化ストレスやアポトーシスといった機序によって発症する薬剤性心筋症に対して、抗酸化作用やアポトーシス抑制作用を有すると推定されるチオ硫酸が治療効果を発揮するかという問題について、米国マサチューセッツ総合病院麻酔科と共同で研究を行っている。.
急性肝不全・劇症肝炎に対する硫化水素の肝保護作用
2013.04~2016.03, 代表者:徳田賢太郎, 九州大学, 九州大学
生体内ガス状生理活性物質である硫化水素が生体機能調節に非常に重要な役割を持っている事が近年明らかとなってきた。私は集中治療医の立場から、重症疾患における硫化水素の病態生理学的意義に興味を持って研究を進めてきた。本プロジェクトでは、致死率が高く集中治療の対象となる急性肝不全・劇症肝炎に対して硫化水素が肝保護作用を発揮するかという問題について、米国マサチューセッツ総合病院麻酔科と共同で研究を行っている。.
全身性炎症反応による心筋障害に対して硫化水素は保護的に働くか?
2012.04~2015.03, 代表者:神田橋忠, 九州大学, 九州大学病院(日本)
生体内ガス状生理活性物質である硫化水素が様々な疾患の病態生理に関与している事が明らかとなってきた。我々は、敗血症を含む全身性炎症反応における硫化水素の病態生理学的意義に興味を持って研究を進めてきた。本プロジェクトではその中でも、全身性炎症反応による心筋障害に対して硫化水素は保護的に働くかという事を解明する事を目的としている。.
研究業績
主要著書
1. 徳田賢太郎, 重症患者における急性肝不全・急性腎傷害・代謝異常
1-1 劇症肝炎
, 中山書店, 2018.02, [URL].
主要原著論文
1. Manabu Kakinohana, Eizo Marutani, Kentaro Tokuda, Kotaro Kida, Shizuko Kosugi, Shingo Kasamatsu, Aurora Magliocca, Kohei Ikeda, Shinichi Kai, Masahiro Sakaguchi, Shuichi Hirai, Ming Xian, Masao Kaneki, Fumito Ichinose, Breathing hydrogen sulfide prevents delayed paraplegia in mice, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2018.12.003, 131, 243-250, 2019.02, [URL], Delayed paraplegia complicates the recovery from spinal cord ischemia or traumatic spinal cord injury. While delayed motor neuron apoptosis is implicated in the pathogenesis, no effective treatment or preventive measures is available for delayed paraplegia. Hydrogen sulfide exerts anti-apoptotic effects. Here, we examined effects of hydrogen sulfide breathing on the recovery from transient spinal cord ischemia. Breathing hydrogen sulfide starting 23 h after reperfusion for 5 h prevented delayed paraplegia after 5 min of spinal cord ischemia. Beneficial effects of hydrogen sulfide were mediated by upregulation of anti-apoptotic Bcl-XL and abolished by nitric oxide synthase 2 deficiency. S-nitrosylation of NFkB p65 subunit, which is induced by nitric oxide derived from nitric oxide synthase 2, facilitated subsequent sulfide-induced persulfidation of p65 and transcription of anti-apoptotic genes. These results uncover the molecular mechanism of the anti-apoptotic effects of sulfide based on the interaction between nitric oxide and sulfide. Exploitation of the anti-apoptotic effects of delayed hydrogen sulfide breathing may provide a new therapeutic approach for delayed paraplegia..
2. Eizo Marutani, Marina Yamada, Tomoaki Ida, Kentaro Tokuda, Kohei Ikeda, Shinichi Kai, Kazuhiro Shirozu, Kei Hayashida, Shizuko Kosugi, Kenjiro Hanaoka, Masao Kaneki, Takaaki Akaike, Fumito Ichinose, Thiosulfate mediates cytoprotective effects of hydrogen sulfide against neuronal ischemia, Journal of the American Heart Association, 10.1161/JAHA.115.002125, 4, 11, 2015.11, [URL], Background-Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. Methods and Results-We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating "carrier" molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. Conclusions-The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury..
3. Kazuhiro Shirozu, Kentaro Tokuda, Eizo Marutani, David Lefer, Rui Wang, Fumito Ichinose, Cystathionine γ-Lyase deficiency protects mice from Galactosamine/lipopolysaccharide-induced acute liver failure, Antioxidants and Redox Signaling, 10.1089/ars.2013.5354, 20, 2, 204-216, 2014.01, [URL], Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-Apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-Apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-Apoptotic mechanisms. Antioxid. Redox Signal. 20, 204-216..
4. Eizo Marutani, Shizuko Kosugi, Kentaro Tokuda, Ashok Khatri, Rebecca Nguyen, Dmitriy N. Atochin, Kotaro Kida, Klaus Van Leyen, Ken Arai, Fumito Ichinose, A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death, Journal of Biological Chemistry, 10.1074/jbc.M112.374124, 287, 38, 32124-32135, 2012.09, [URL], Physiological levels of H2S exert neuroprotective effects, whereas high concentrations of H2S may cause neurotoxicity in part via activation ofNMDAR.To characterize the neuroprotective effects of combination of exogenous H2S and NMDAR antagonism, we synthesized a novel H2S-releasing NMDAR antagonist N-((1r,3R,5S,7r)-3,5- dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzamide (S-memantine) and examined its effects in vitro and in vivo. S-memantine was synthesized by chemically combining a slow releasing H2S donor 4-(3-thioxo-3H-1,2- dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na2S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na2S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H2S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury..
5. Kentaro Tokuda, Kotaro Kida, Eizo Marutani, Ettore Crimi, Masahiko Bougaki, Ashok Khatri, Hideo Kimura, Fumito Ichinose, Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice, Antioxidants and Redox Signaling, 10.1089/ars.2011.4363, 17, 1, 11-21, 2012.07, [URL], Aims: The role of hydrogen sulfide (H2S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H2S breathing on LPS-induced changes in sulfide metabolism, systemic inflammation, and survival in mice. Results: Mice that breathed air alone exhibited decreased plasma sulfide levels and poor survival rate at 72 h after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) activity and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80 ppm of H2S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p<0.05). H2S breathing attenuated LPS-induced increase of plasma ALT activity and NOx levels and lung MPO activity. Inhaled H 2S suppressed LPS-induced upregulation of inflammatory cytokines, while it markedly induced anti-inflammatory interleukin (IL)-10 in the liver. Beneficial effects of H2S inhalation after LPS challenge were associated with restored sulfide levels and markedly increased thiosulfate levels in plasma. Increased thiosulfate levels after LPS challenge were associated with upregulation of rhodanese, but not cystathionine-γ-lyase (CSE), in the liver. Administration of sodium thiosulfate dose-dependently improved survival after LPS challenge in mice. Innovation: By measuring changes in plasma levels of sulfide and sulfide metabolites using an advanced analytical method, this study revealed a critical role of thiosulfate in the protective effects of H2S breathing during endotoxemia. Conclusion: These observations suggest that H2S breathing prevents inflammation and improves survival after LPS challenge by altering sulfide metabolism in mice..
6. Shizuka Minamishima, Kotaro Kida, Kentaro Tokuda, Huifang Wang, Patrick Y. Sips, Shizuko Kosugi, Joseph B. Mandeville, Emmanuel S. Buys, Peter Brouckaert, Philip K. Liu, Christina H. Liu, Kenneth D. Bloch, Fumito Ichinose, Inhaled nitric oxide improves outcomes after successful cardiopulmonary resuscitation in mice, Circulation, 10.1161/CIRCULATIONAHA.111.025395, 124, 15, 1645-1653, 2011.10, [URL], Background-: Sudden cardiac arrest (CA) is a leading cause of death worldwide. Breathing nitric oxide (NO) reduces ischemia/reperfusion injury in animal models and in patients. The objective of this study was to learn whether inhaled NO improves outcomes after CA and cardiopulmonary resuscitation (CPR). Methods and Results-: Adult male mice were subjected to potassium-induced CA for 7.5 minutes whereupon CPR was performed with chest compression and mechanical ventilation. One hour after CPR, mice were extubated and breathed air alone or air supplemented with 40 ppm NO for 23 hours. Mice that were subjected to CA/CPR and breathed air exhibited a poor 10-day survival rate (4 of 13), depressed neurological and left ventricular function, and increased caspase-3 activation and inflammatory cytokine induction in the brain. Magnetic resonance imaging revealed brain regions with marked water diffusion abnormality 24 hours after CA/CPR in mice that breathed air. Breathing air supplemented with NO for 23 hours starting 1 hour after CPR attenuated neurological and left ventricular dysfunction 4 days after CA/CPR and markedly improved 10-day survival rate (11 of 13; P=0.003 versus mice breathing air). The protective effects of inhaled NO on the outcome after CA/CPR were associated with reduced water diffusion abnormality, caspase-3 activation, and cytokine induction in the brain and increased serum nitrate/nitrite levels. Deficiency of the α1 subunit of soluble guanylate cyclase, a primary target of NO, abrogated the ability of inhaled NO to improve outcomes after CA/CPR. Conclusions-: These results suggest that NO inhalation after CA and successful CPR improves outcome via soluble guanylate cyclase-dependent mechanisms..
7. Kotaro Kida, Marina Yamada, Kentaro Tokuda, Eizo Marutani, Manabu Kakinohana, Masao Kaneki, Fumito Ichinose, Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson's disease, Antioxidants and Redox Signaling, 10.1089/ars.2010.3671, 15, 2, 343-352, 2011.07, [URL], Parkinson's disease is one of the major neurodegenerative disorders. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause Parkinson's disease-like symptoms and biochemical changes in humans and animals. Hydrogen sulfide (H2S) has been shown to protect neurons. The goal of this study was to examine the effects of inhaled H2S in a mouse model of Parkinson's disease induced by MPTP. Male C57BL/6J mice received MPTP at 80mg/kg and breathed air with or without 40 ppm H2S for 8h/day for 7 days. Administration of MPTP induced movement disorder and decreased tyrosine hydroxylase (TH)-containing neurons in the substantia nigra and striatum in mice that breathed air. Inhalation of H2S prevented the MPTP-induced movement disorder and the degeneration of TH-containing neurons. Inhaled H 2S also prevented apoptosis of the TH-containing neurons and gliosis in nigrostriatal region after administration of MPTP. The neuroprotective effect of inhaled H2S after MPTP administration was associated with upregulation of genes encoding antioxidant proteins, including heme oxygenase-1 and glutamate-cysteine ligase. These observations suggest that inhaled H 2S prevents neurodegeneration in a mouse model of Parkinson's disease induced by MPTP, potentially via upregulation of antioxidant defense mechanisms and inhibition of inflammation and apoptosis in the brain..
8. Kentaro Tokuda, Yoshimasa Motoyama, Yoichiro Kai, Yoshiro Sakaguchi, Sumio Hoka, Anesthetic management for a patient with significant orthostatic hypotension probably due to pure autonomic failure, Japanese Journal of Anesthesiology, 58, 8, 1010-1013, 2009.08, A 73-year-old man with severe orthostatic hypotension was scheduled for open cholecystectomy. His blood pressure was 126/80 mmHg in the supine position and 50/30 mmHg in the upright posture. Preoperative autonomic function tests suggested that postsynaptic fibers of the sympathetic nervous system were impaired, and the disorder was probably due to pure autonomic failure. Anesthesia was induced with thiamylal and vecuronium, and maintained with sevoflurane (3%) and fentanyl (100 μg). Epidural anesthesia was used in the latter half of the operation. Meticulous use of vasoactive drugs such as dopamine and phenylephrine as well as adequate maintenance of systemic blood volume by infusion of a crystalloid solution enabled his hemodynamic condition to become stable during anesthesia..
9. Kentaro Tokuda, T. Inamura, T. Uesaka, H. Kenai, A. Karashima, T. Matsushima, M. Fukui, Surgery for acoustic neurinoma treated by gamma-knife radiosurgery
A case report, Neurological Surgery, 29, 8, 761-765, 2001.08, A 52-year-old woman had a history of left hearing loss for 5 years. An acoustic neurinoma with 3.2 cm in diameter was diagnosed and treated with gamma-knife radiosurgery (19 Gy of marginal dose) 1 year and 4 months ago. She developed headache, nausea, and visual disturbance 1 month prior to admission. Slight left facial palsy appeared after radiosurgery. Magnetic resonance imaging demonstrated the tumor with central necrosis in the left cerebellopontine angle cistern, increasing in size to 3.5 cm in diameter, and hydrocephalus. Tumor removal was performed incompletely, because of the fibrous appearance of the tumor and severe adherence with the surrounding cerebellar tissue. Facial palsy did not worsen after surgery. Since the hydrocephalus was not resolved, a right ventriculo-peritoneal shunt was inserted. The clinical course in this case suggests that tumor removal followed by radiosurgery was an approximately effective treatment for large acoustic neurinoma..
主要総説, 論評, 解説, 書評, 報告書等
1. 徳田 賢太郎, 市瀬 史, <特集>毒ガス?いいえ、治療薬です:硫化水素, 臨床麻酔:真興交易(株)医書出版部, 2015.06, 硫化水素は、「卵の腐った臭い」と形容される特異な臭いを持つ毒ガスとして知られている。近年、硫化水素が我々の細胞内で微量ながら産生されている事、さらにガス状生理活性物質として様々な生体機能の調節に関与している事が明らかとなってきた。また硫化水素には多彩な臓器保護効果があるという報告が相次ぎ、その作用機序の解明が進められている。さらには様々な病態・疾患に対して硫化水素および硫化水素供与体を投与する事で治療効果を得ようとする試みが、基礎実験および臨床試験レベルで進行中である。本稿では、この20年間で大きく変遷した硫化水素研究の歴史、および臓器保護効果を期待した臨床応用へ試みについて概説する。.
2. 徳田 賢太郎, 硫化水素の臨床への応用, LiSA, 2012.12, 近年注目を浴びているガス状メディエーターの一つである硫化水素の臨床応用の可能性について探る.
3. 徳田賢太郎, 心不全患者の麻酔, A-net, 2009.09.
主要学会発表等
1. 徳田 賢太郎, 生体ガスと臓器保護, 日本麻酔科学会第66回学術集会, 2019.06,  生体ガスとは、生命活動に伴って体内で産生されるガス分子、と定義することができる。そのうち、一酸化窒素(NO)、一酸化炭素(CO)、および硫化水素(H2S)に関しては、それぞれのガス分子産生酵素が細胞内に存在し、生体内で恒常的に産生されていることが現在では知られている。これらのガス分子は、自然環境中に豊富に存在する毒ガスとして古くから認識されており、生体が比較的高濃度のこれらのガスに暴露された時にどのような影響があるか、という毒物学の観点から研究が行われてきた。
しかし1980年代になって、これらのガス分子の研究に転機が訪れた。血管内皮細胞から血管弛緩因子が生成されて血管機能を調節していること、そして実はその血管弛緩因子の正体がNOであることがその頃明らかにされた。さらにはNO合成酵素欠損マウスの樹立といった実験系の確立によりNOの多彩な生理作用の報告が相次ぎ、NO研究が一気に加速した。生体内でのごく微量のNOが生理活性を有するという知見は、1998年のノーベル医学・生理学賞に結実した。NO研究の発展に歩調を合わせるかのように、COおよびH2Sの研究に関しても毒ガスという範疇を離れ、これらのガス分子が生体内でごくわずかに存在していることの意義が生理学・薬理学の研究対象となり、その生体作用が次々と明らかになった。
その結果今世紀初めには、これら3種類の生体ガス分子は、生体内の様々な組織・臓器において多彩な作用を発揮する、内因性ガス状シグナル伝達物質(ガスメディエーター)として並び称されるようになった。その後現在に至るまで、これらのガス分子が、少なくとも基礎研究のレベルでは細胞・臓器保護効果を有することが相次いで報告されており、その臨床応用へ向けた研究が進められている。
本セミナーでは、これら3種類の生体ガス分子の生物学的特徴について概説し、現在研究の進むそれぞれの臓器保護効果について紹介する。.
2. Kentaro Tokuda, Emergency intubation with/without neuromuscular blocking agents outside of the operating room., Korean Association for Respiratory Care, 2018.07, Tracheal intubation outside of the operating room (OR), i.e. intensive care unit, emergency department, general wards, etc., is more problematic than that performed in the OR. A number of researchers have reported that the incidence of difficult intubation and the rate of complications associated with tracheal intubation is higher in cases of non-OR intubation than in elective surgical patients. There are several reasons as to why airway management in critically ill patients can be challenging. First, the patients are in a life-threatening condition that requires emergency intubation. Because their physiological reserve is highly impaired, they can rapidly progress to severe hypoxemia during intubation procedure or to profound hypotension or even cardiac arrest due to the administration of sedatives prior to intubation. Second, the preparation time to intubation is limited, preventing critical care physicians from evaluating the airway of the patients adequately, and the patients might be at risk of aspiration due to insufficient fasting time. Third, the availability of airway devices as well as staff skilled in airway management is limited outside of the OR.
One of the most contested issues associated with airway management in critical care is whether or not neuromuscular blocking agents (NMBA) should be used for emergent tracheal intubation in critically ill patients. It has been claimed that maintaining spontaneous respiration during emergency intubation is the best way to prevent the airway management from deteriorating in such patients. However, recent evidence has shown that the use of NMBA during emergency intubation facilitates the intubation procedure, improves the success rate of the first intubation attempt, and decreases the rate of procedure-related complications. Regardless of the effects of NMBA, the presence of skilled personnel is crucial for a successful procedure, and an airway evaluation predicting the difficulty of intubation prior to the procedure is useful when it can be performed. As with the procedure in the OR, emergency tracheal intubation outside the OR should not be performed until the airway is precisely evaluated so that we can decide whether or not to administer NMBA.
In this lecture, I will focus on the potential risks as well as the advantages associated with the use of NMBA during emergency intubation of critically ill patients.
.
3. 徳田 賢太郎, ProsCons(呼吸):院内手術室外の気道確保:筋弛緩薬は投与すべきか?(CONSの立場から)., 日本麻酔科学会第64回学術集会, 2017.06, ICU、救急外来、一般病棟といった、手術室外における気管挿管は、手術室内での予定された気管挿管と比べて明らかに不利な条件下で行う必要があり、そのため合併症も多いと報告されている(1,2)。手術室外という厳しい環境下で安全に気管挿管を行うために、筋弛緩薬の投与は必要なのであろうか?
手術室外での気管挿管に筋弛緩薬を用いることで、合併症の頻度は低下し(3)、また一回の挿管操作で成功する確率も高まる(4)、との報告がある。その一方で、症例ごとに筋弛緩薬使用の是非を検討すべきとも指摘されており(5)、手術室内での場合と同じく、挿管操作を行う前にきちんと気道評価を行った上で初めて、筋弛緩薬の使用を考慮すべきであろう(2)。つまり、筋弛緩薬を投与すべきではないと思われる患者を適切に認識し、そのような患者に対しては筋弛緩薬非投与下に気管挿管を行う必要がある、と考える。
筋弛緩薬の臨床における目覚ましい進歩の一つは、ロクロニウム投与後のスガマデクスによる緊急リバースであろう。JSA気道管理ガイドラインにもあるように、マスク換気を容易にするために筋弛緩薬の投与が選択肢になりうるが、スガマデクスという保険ができたことで我々は安心して筋弛緩薬の投与が行えるようになったのである。しかし、果たして手術室外でスガマデクスが入手可能な医療機関はどれだけあるであろうか。
また、2016年だけでも3件の筋弛緩薬紛失事件が公表されており(茨城、岡山、沖縄)、各医療機関における筋弛緩薬の管理方法は今後一層厳しくなることが予想される。その結果、緊急気管挿管を行う際に筋弛緩薬の準備が間に合わない、特に一般病棟においては使用不可能な状態になることが危惧される。
以上のような観点から、手術室外での気道確保に際して、筋弛緩薬は全例では投与すべきではない、あるいは使用できない、という立場で話を進める。
(1) Anaesthesia 2011; 66(Suppl 2): 81
(2) Br J Anaesth 2011; 106: 632
(3) Crit Care Med 2012; 40: 1808
.
4. 徳田 賢太郎, 牧 盾, 賀耒 典之, 水口 壮一, 深田 光敬, 赤星 朋比古, 外 須美夫, 前原 喜彦, The Presepsin Level on ICU Admission Is a Marker of the Severity of ICU Patients. , 46th Critical Care Congress (Society of Critical Care Medicine), 2017.01.
5. Kentaro Tokuda, Improvement of postoperative analgesia by transversus abdominis plane block in patients with living donor hepatectomy, The 33rd Congress of the Scandinavian Society of Anaesthesiology and Intensive Care, 2015.06.
6. Kentaro Tokuda, Ken Yamaura, Midoriko Higashi, Sumio Hoka, The effect of cardiopulmonary bypass on the accuracy of non-invasive hemoglobin measurement by pulse co-oximetry, American society of Anesthesiologists 2014 Annual Meeting, 2014.10.
7. Kentaro Tokuda, Fumito Ichinose, Hepatoprotective effects of hydrogen sulphide against acute liver failure, European Society of Intensive Care Medicine 2014 Annual Meeting, 2014.09.
8. Kentaro Tokuda, Fumito Ichinose, Inhaled Hydrogen Sulfide Protects Mice against Acute Liver Failure, 14th Asian Australasian Congress of Anaesthesiologists, 2014.02, AIM: Acute liver failure is caused by massive hepatocyte apoptosis that is resistant to conventional medical therapies. Consequently, liver transplantation is required in many cases. An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis. In this model, LPS stimulates macrophages to release TNFα, which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure. Hydrogen sulfide (H2S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties. Previously, we reported that H2S attenuates liver dysfunction arising from LPS-induced systemic inflammation. It has been also reported that H2S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver. However, whether H2S exerts hepatoprotective effects against fulminant hepatitis, in which both inflammatory responses and apoptosis play pivotal roles, remains unknown.
METHODS: Mice were challenged with saline or combination of Gal and LPS and thereafter randomized to breathe either air alone or air supplemented with H2S for 6h.
RESULTS: Mice that breathed air after Gal/LPS challenge showed poor survival rate (13%) and marked increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma. In contrast, H2S inhalation for 6h after challenge markedly improved survival (60%, p < 0.05) and suppressed Gal/LPS-induced elevation of ALT and AST levels in plasma. Inhaled H2S suppressed TNFα in plasma at 1h after Gal/LPS challenge. Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H2S breathing inhibited activation of caspase 3, 8, and 9. Gal/LPS challenge did not increase gene expression of anti-inflammatory IL-10, whereas H2S inhalation after Gal/LPS challenge significantly increased IL-10 gene expression.
CONCLUSION: These results suggest that H2S protects mice from acute liver failure at least in part by inhibition of caspase activation and by augmentation of anti-inflammatory IL-10 expression in the liver. .
9. 徳田 賢太郎, 白水 和宏, 市瀬 史, マウス急性肝不全モデルにおいて、硫化水素吸入療法は肝保護効果を発揮する, 第40回日本集中治療医学会学術集会, 2013.03.
10. Kentaro Tokuda, Fumito Ichinose, Hydrogen Sulfide Protects Hepatocytes against Acute Liver Failure , Annual Meeting of American Society of Anesthesiologists 2012, 2012.10, Introduction: Acute liver failure is a fatal syndrome attributed to massive hepatocyte apoptosis that is resistant to conventional medical therapies. Consequently, liver transplantation is required in many cases. An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis. In this model, LPS stimulates macrophages to release TNFα, which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure. Hydrogen sulfide (H2S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties. Previously, we reported that H2S attenuates liver dysfunction arising from LPS-induced systemic inflammation. It has also been reported that H2S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver. However, whether H2S exerts hepatoprotective effects against acute liver failure, in which both inflammatory responses and apoptosis have pivotal roles, remains unknown. Here, we examined the impact of H2S on acute liver failure in mice induced by Gal and LPS or TNFα.
Methods: Mice were challenged with saline or combination of Gal (700 mg/kg) and LPS (10 µg/kg) intraperitoneally and thereafter randomized to breathe either air alone or air supplemented with H2S (80 ppm) for 6h.
Results: Mice that breathed air after Gal/LPS challenge showed poor survival rate and marked increase of alanine/aspartate aminotransferase (ALT/AST) in plasma. In contrast, H2S inhalation for 6h after challenge markedly improved survival (Fig. 1) and suppressed Gal/LPS-induced elevation of ALT and AST levels in plasma. Inhaled H2S suppressed TNFα in plasma at 1h after Gal/LPS challenge. Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H2S breathing inhibited activation of caspase 3, 8, and 9, suggesting inhaled H2S after Gal/LPS challenge suppressed both extrinsic and intrinsic pathways of caspase-dependent apoptosis in the liver (Fig. 2). Gal/LPS challenge increased phosphorylated STAT3 transcription factor. H2S inhalation after Gal/LPS challenge further augmented phosphorylation of STAT3 compared to air alone. The protective effects of H2S inhalation after Gal/LPS challenge were associated with upregulation of gene expression of anti-inflammatory IL-10, which stimulates STAT3 phosphorylation, in the liver. These results suggest that inhaled H2S contributes to survival of mice in acute liver failure at least in part through activation of IL-10/STAT3 pathway. To determine whether or not H2S protects hepatocytes directly, in vitro experiments using primary murine hepatocytes were conducted. GYY4137, an H2S donor, improved cell survival after stimulation with Gal/TNFα, suggesting H2S protects hepatocytes directly against lethal hepatic failure.
Conclusions: These results suggest that H2S protects mice from acute liver failure via direct hepatoprotective effects. These protective effects appear to be mediated at least in part by inhibition of caspase activation and by augmentation of IL-10/STAT3 signaling pathway in the liver. .
11. Kentaro Tokuda, Fumito Ichinose, Inhaled Hydrogen Sulfide Protects Mice against Gal/LPS-induced Acute Liver Failure
, Second International Conference on H2S Biology and Medicine, 2012.09, Introduction
Acute liver failure is a fatal syndrome attributed to massive hepatocyte apoptosis that is resistant to conventional medical therapies. Consequently, liver transplantation is required in many cases. An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis. In this model, LPS stimulates macrophages to release TNFα, which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure. Hydrogen sulfide (H2S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties. Previously, we reported that H2S attenuates liver dysfunction arising from LPS-induced systemic inflammation. It has also been reported that H2S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver. However, whether H2S exerts hepatoprotective effects against acute liver failure, in which both inflammatory responses and apoptosis play pivotal roles, remains unknown. Here, we examined the impact of inhaled H2S on acute liver failure in mice induced by Gal and LPS.
Methods
Mice were challenged with saline or combination of Gal (700 mg/kg) and LPS (10 μg/kg) intraperitoneally and thereafter randomized to breathe either air alone or air supplemented with H2S (80 ppm) for 6h.Results
Mice that breathed air after Gal/LPS challenge showed poor survival rate (13%) and marked increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma. In contrast, H2S inhalation for 6h after challenge markedly improved survival (60%, p < 0.05) and suppressed Gal/LPS-induced elevation of ALT and AST levels in plasma. Inhaled H2S suppressed TNFα in plasma at 1h after Gal/LPS challenge. Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H2S breathing inhibited activation of caspase 3, 8, and 9, suggesting inhaled H2S after Gal/LPS challenge suppressed both extrinsic and intrinsic pathways of caspase-dependent apoptosis in the liver. Gal/LPS challenge increased phosphorylated STAT3 transcription factor. H2S inhalation after Gal/LPS challenge further augmented phosphorylation of STAT3 compared to air alone. The protective effects of H2S inhalation after Gal/LPS challenge were associated with upregulation of gene expression of anti-inflammatory IL-10, which stimulates STAT3 phosphorylation, in the liver. These results suggest that inhaled H2S contributes to survival of mice in acute liver failure at least in part through activation of IL-10/STAT3 pathway.Conclusions
These results suggest that H2S protects mice from acute liver failure at least in part by inhibition of caspase activation and by augmentation of IL-10/STAT3 signaling pathway in the liver. .
12. Kentaro Tokuda, Eizo Marutani, Kotaro Kida, Fumito Ichinose,
Inhaled Hydrogen Sulfide Prevents Endotoxin-induced Systemic Inflammation and Improves Survival by Altering Sulfide Metabolism in Mice, International Anesthesia Research Society Annual Meeting 2012, 2012.05, Introduction: Hydrogen sulfide (H2S) is a colorless gas with a characteristic rotten-egg odor found in various natural and industrial sources. In mammalian tissues, H2S is also produced endogenously, acting as a gaseous-signaling molecule. Although it has become increasingly clear that H2S can exert a host of biological effects on various targets, the role of H2S in inflammation remains controversial. We examined impact of H2S-breathing on lipopolysaccharide[LPS]-induced changes in sulfide metabolism, systemic inflammation, and survival in mice.
Methods: After obtaining IRB approval, all animal experiments were performed. Mice were administered with LPS (10 mg/kg) or saline intraperitoneally (IP) followed by breathing air or H2S (80 ppm) mixed in air for 6h. Tissue and blood were harvested at 6h or 24h after LPS challenge. To examine the effects of thiosulfate, a major metabolite of H2S, sodium thiosulfate (STS, 1 or 2 g/kg) was administered IP immediately after LPS challenge in separate groups of mice. Data were analyzed by one-way ANOVA. Kaplan-Meier survival analysis was performed using Log-rank test.
Results: Mice that breathed air alone exhibited poor survival rate and decreased plasma sulfide levels after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80ppm of H2S for 6h after LPS challenge markedly improved survival rate and attenuated LPS-induced increase of plasma ALT and NOx levels and lung MPO activity. Inhaled H2S suppressed LPS-induced upregulation of inflammatory cytokines in the liver and the lung. Beneficial effects of H2S inhalation after LPS challenge were associated with restored sulfide levels and remarkably increased thiosulfate levels in plasma. Increased thiosulfate levels in mice that breathed H2S after LPS challenge were associated with upregulation of rhodanese, an enzyme responsible for H2S metabolism, but not cystathionine γ-lyase, a H2S-producing enzyme, in the liver. Administration of STS dose-dependently improved survival after LPS challenge in mice.
Discussion: Our results revealed that plasma sulfide levels were decreased by LPS challenge whereas H2S breathing after LPS challenge restored sulfide levels and remarkably increased thiosulfate concentrations. We further demonstrated that administration of thiosulfate per se markedly improved survival after LPS challenge. These observations suggest that H2S breathing attenuates inflammation and improves survival after LPS challenge in part by altering sulfide metabolism in mice.
.
13. Kentaro Tokuda, Anti-inflammatory effects of inhaled hydrogen sulfide, Combined laboratory meeting of the Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, 2010.12.
14. Kentaro Tokuda, Kotaro Kida, Fumito Ichinose, Inhaled Hydrogen Sulfide Attenuates Liver Injury in Septic Mice via NF-κB and STAT3 Signaling Pathways, American Society of Anesthesiologists 2011 Annual Meeting, 2011.10, Background: Hydrogen sulfide (H2S) is a colorless gas with a characteristic rotten-egg odor found in various natural and industrial sources. H2S has been suggested to have anti-inflammatory as well as pro-inflammatory effects. However, the role of H2S in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. A number of studies using H2S donors or inhibitors of H2S-producing enzymes have been conducted, and numerous conflicting data regarding the roles of H2S during endotoxemia have been reported. We have previously reported inhaled H2S improves survival during endotoxemia and prevents LPS-induced systemic inflammation in mice: H2S suppressed up-regulation of gene expression levels of inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 in the liver after LPS administration. Here, we examined molecular mechanisms responsible for the organ protective effects of H2S inhalation during endotoxemia.
Methods/Results: Male mice (C57BL/6J, 8-10 weeks old) were administered with LPS (10 mg/kg) or saline intraperitoneally followed by breathing air or H2S (80 parts per million) mixed in air for 6 hours in custom-made chambers. Liver tissue and blood were harvested at 1 or 6 h and at 24 h after LPS administration, respectively. Plasma alanine aminotransferase (ALT) levels increased at 24 hours after LPS administration, whereas inhaled H2S for 6 hours attenuated LPS-induced elevation of ALT levels (LPS+air 137±38 vs LPS+ H2S 75±7 unit/L, P<0.05). While phosphorylation of inhibitor kappa B (IκB) in the liver was increased at 1 hour after LPS injections, H2S breathing attenuated phosphorylation of IkB induced by LPS challenge. This result suggests H2S breathing during endotoxemia decreased activation of nuclear factor kappa B (NF-κB)-dependent signaling pathway, resulting in suppressing inflammatory cytokines such as TNFα. Gene expression levels of IL-10, a representative anti-inflammatory cytokine, were not affected by LPS administration, whereas H2S inhalation after LPS challenge markedly increased gene expression levels of IL-10 (P<0.05). IL-10 is known to interact with signal transducer and activator of transcription 3 (STAT3), leading to anti-inflammation. While LPS challenge increased phosphorylated STAT3 in the nucleus in mice that breathed air, H2S breathing after LPS administration further augmented the nuclear translocation of phosphorylated STAT3 in the livers (P<0.05, Figure 2B). Taken together, H2S breathing after LPS administration augments STAT3/IL-10 signaling pathway, resulting in anti-inflammatory effects.
Conclusions: These results suggest that H2S inhalation exerts hepatoprotective effects during endotoxemia. These protective effects of H2S inhalation appear to be mediated at least in part by suppression of the NF-κB signaling pathway and by augmentation of the STAT3 signaling pathway..
15. Tokuda K, Hayamizu K, Sumie M, Hirai T, Irita K., Non-linear regression curve model for desaturation in pulse oximetry during breath-holding in healthy volunteers., Euroanaesthesia 2008, 2008.06.
16. Tokuda K, Hayamizu K, Ogawa K, Hirai T, Irita K., A Comparison of Finger, Ear and Forehead SpO2 on Detecting Oxygen Desaturation in Healthy Volunteers, American Society of Anesthesiologists, 2007.10, [URL].
特許出願・取得
特許出願件数  1件
特許登録件数  0件
学会活動
所属学会名
日本集中治療医学会
日本麻酔科学会
欧州集中治療医学会
米国集中治療医学会
米国麻酔科学会
日本呼吸療法医学会
日本心臓血管麻酔学会
学協会役員等への就任
2020.03~2022.02, 日本集中治療医学会, 評議員.
2018.07~2020.12, 日本集中治療医学会, 集中治療室における安全管理指針作成ワーキンググループ メンバー.
2018.05~2019.05, 日本麻酔科学会, 第66回学術集会実行委員会 第2・呼吸WG サテライトメンバー.
2018.02~2021.12, 日本集中治療医学会, 薬事・規格・安全対策委員会委員.
学会大会・会議・シンポジウム等における役割
2019.09.14~2019.09.14, 九州麻酔科学会第57回大会, 座長.
2019.06.13~2019.06.13, 第43回 呼吸管理セミナー, 座長(Chairmanship).
2018.09.08~2018.09.08, 九州麻酔科学会第56回大会, 座長.
2017.12.08~2017.12.08, 若手医師のためのDIC治療研究会, 座長(Chairmanship).
2017.10.05~2017.10.05, 第38回 呼吸管理セミナー, 座長(Chairmanship).
2017.05.19~2017.05.19, 若手医師のための敗血症セミナー, 座長(Chairmanship).
2017.05.13~2017.05.13, 日本集中治療医学会第1回九州支部学術集会, 座長(Chairmanship).
2016.10.20~2016.10.20, 第35回 呼吸管理セミナー, 座長(Chairmanship).
2008.12.06~2008.12.06, 第1回九州周術期超音波研究会, 座長(Chairmanship).
学術論文等の審査
年度 外国語雑誌査読論文数 日本語雑誌査読論文数 国際会議録査読論文数 国内会議録査読論文数 合計
2020年度      
2019年度     19  23 
2018年度     12  13 
2017年度      
2016年度      
2015年度      
2014年度      
その他の研究活動
海外渡航状況, 海外での教育研究歴
Massachusetts General Hospital, UnitedStatesofAmerica, 2012.10~2012.10.
Massachusetts General Hospital, UnitedStatesofAmerica, 2013.04~2013.04.
Dr. Fumito Ichinose Laboratory, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, UnitedStatesofAmerica, 2009.09~2012.03.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2016年度~2018年度, 基盤研究(C), 代表, 薬剤性心筋障害に対して、硫化水素代謝物チオ硫酸は心筋保護効果を発揮するか?.
2013年度~2016年度, 基盤研究(C), 代表, 急性肝不全・劇症肝炎に対する硫化水素の肝保護作用.
2012年度~2014年度, 基盤研究(C), 分担, 全身性炎症反応による心筋障害に対して硫化水素は保護的に働くか?.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。
 
 
九州大学知的財産本部「九州大学Seeds集」