Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism.

Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogens sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Administration of metronidazole or a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.

The Japanese Epidemiologic Study for Perioperative Anaphylaxis, a prospective nationwide study: allergen exposure, epidemiology, and diagnosis of anaphylaxis during general anaesthesia.

BACKGROUND: Diagnosis of perioperative anaphylaxis is often challenging. This study describes the utility of a newly developed tool for identifying patients with a high possibility of anaphylaxis, and aimed to investigate the frequency of anaphylaxis with each drug during the perioperative period in Japan. METHODS: This study included patients with anaphylaxis of Grade 2 or higher severity during general anaesthesia at 42 facilities across Japan in 2019 and 2020. We developed and adopted a unique objective evaluation tool yielding a composite score for diagnosing anaphylaxis, which includes the results of skin tests and basophil activation tests, and clinical scores for perioperative anaphylaxis. The number of cases using each drug and the total number of anaphylaxis cases were investigated to calculate the frequency of anaphylaxis. RESULTS: General anaesthesia was performed in 218 936 cases, which included 55 patients with suspected perioperative anaphylaxis. The developed composite score diagnosed 43 of them with a high probability of anaphylaxis. The causative agent was identified in 32 cases. Plasma histamine levels showed high diagnostic accuracy for anaphylaxis. The top causative agents were rocuronium (10 cases in 210 852 patients, 0.005%), sugammadex (7 cases in 150 629 patients, 0.005%), and cefazolin (7 cases in 106 005 patients, 0.007%). CONCLUSIONS: We developed a composite tool to diagnose anaphylaxis, and found that the combination of tryptase levels, skin testing, and basophil activation testing results and clinical score improved the certainty of anaphylaxis diagnosis. The incidence of perioperative anaphylaxis in our study was 1 in about 5000 general anaesthesia cases. CLINICAL TRIAL REGISTRATION: UMIN000035350.

Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia.

BACKGROUND: Delayed paraplegia is a devastating complication of thoracoabdominal aortic surgery. Hydrogen sulfide (H2S) was reported to be protective in a mouse model of spinal cord ischemia and the beneficial effect of H2S has been attributed to polysulfides. The objective of this study was to investigate the effects of polysulfides on delayed paraplegia after spinal cord ischemia. METHODS AND RESULTS: Spinal cord ischemia was induced in male and female C57BL/6J mice by clamping the aortic arch and the left subclavian artery. Glutathione trisulfide (GSSSG), glutathione (GSH), glutathione disulfide (GSSG), or vehicle alone was administered intranasally at 0, 8, 23, and 32 h after surgery. All mice treated with vehicle alone developed paraplegia within 48 h after surgery. GSSSG, but not GSH or GSSG, prevented paraplegia in 8 of 11 male mice (73%) and 6 of 8 female mice (75%). Intranasal administration of 34S-labeled GSSSG rapidly increased 34S-labeled sulfane sulfur species in the lumbar spinal cord. In mice treated with intranasal GSSSG, there were increased sulfane sulfur levels, and decreased neurodegeneration, microglia activation, and caspase-3 activation in the lumbar spinal cord. In vitro studies using murine primary cortical neurons showed that GSSSG increased intracellular levels of sulfane sulfur. GSSSG, but not GSH or GSSG, dose-dependently improved cell viability after oxygen and glucose deprivation/reoxygenation (OGD/R). Pantethine trisulfide (PTN-SSS) also increased intracellular sulfane sulfur and improved cell viability after OGD/R. Intranasal administration of PTN-SSS, but not pantethine, prevented paraplegia in 6 of 9 male mice (66%). CONCLUSIONS: Intranasal administration of polysulfides rescued mice from delayed paraplegia after transient spinal cord ischemia. The neuroprotective effects of GSSSG were associated with increased levels of polysulfides and sulfane sulfur in the lumbar spinal cord. Targeted delivery of sulfane sulfur by polysulfides may prove to be a novel approach to the treatment of neurodegenerative diseases.

Oral Administration of Glutathione Trisulfide Increases Reactive Sulfur Levels in Dorsal Root Ganglion and Ameliorates Paclitaxel-Induced Peripheral Neuropathy in Mice.

Peripheral neuropathy is a dose-limiting side effect of chemotherapy with paclitaxel. Paclitaxel-induced peripheral neuropathy (PIPN) is typically characterized by a predominantly sensory neuropathy presenting with allodynia, hyperalgesia and spontaneous pain. Oxidative mitochondrial damage in peripheral sensory neurons is implicated in the pathogenesis of PIPN. Reactive sulfur species, including persulfides (RSSH) and polysulfides (RSnH), are strong nucleophilic and electrophilic compounds that exert antioxidant effects and protect mitochondria. Here, we examined the potential neuroprotective effects of glutathione trisulfide (GSSSG) in a mouse model of PIPN. Intraperitoneal administration of paclitaxel at 4 mg/kg/day for 4 days induced mechanical allodynia and thermal hyperalgesia in mice. Oral administration of GSSSG at 50 mg/kg/day for 28 days ameliorated mechanical allodynia, but not thermal hyperalgesia. Two hours after oral administration, 34S-labeled GSSSG was detected in lumber dorsal root ganglia (DRG) and in the lumber spinal cord. In mice treated with paclitaxel, GSSSG upregulated expression of genes encoding antioxidant proteins in lumber DRG, prevented loss of unmyelinated axons and inhibited degeneration of mitochondria in the sciatic nerve. In cultured primary neurons from cortex and DRG, GSSSG mitigated paclitaxel-induced superoxide production, loss of axonal mitochondria, and axonal degeneration. These results indicate that oral administration of GSSSG mitigates PIPN by preventing axonal degeneration and mitochondria damage in peripheral sensory nerves. The findings suggest that administration of GSSSG may be an approach to the treatment or prevention of PIPN and other peripheral neuropathies.

Impact of the First Wave of COVID-19 on the Number of General Anesthesia Cases in 34 Tertiary Hospitals in Japan: A Multicenter Retrospective Study.

Since the first case of coronavirus disease 2019 (COVID-19) was reported in Japan in January 2020, the COVID-19 pandemic has brought about a significant change in people's lives. Although the COVID-19 pandemic is expected to have had an impact on the work of anesthesiologists, the specific impact has been largely unreported. We hypothesized that the number of general anesthesia (GA) cases has decreased due to the COVID-19 pandemic. To test this hypothesis, we conducted a retrospective survey at 34 facilities in Japan as a part of the Japanese Epidemiologic Study for Perioperative Anaphylaxis. The results showed that the number of GA cases had significantly decreased, particularly in May 2020, under the government's declaration of a state of emergency. The decline in GA caseload had not fully recovered by July 2020. Furthermore, there were regional differences in the decline in the number of GA cases. The impact of the COVID-19 pandemic on the work of anesthesiologists was greater in prefectures where there were more COVID-19 patients and where the state of emergency was declared earlier. Our study suggested a region-dependent decrease in the number of GA cases due to the COVID-19 pandemic.

Anesthesia for Cesarean Section and Postpartum Cardiovascular Events in Congenital Heart Disease: A Retrospective Cohort Study.

OBJECTIVE: To clarify the association between anesthetic technique and maternal and neonatal outcomes in parturients with congenital heart disease (CHD). DESIGN: Retrospective, observational cohort study. SETTING: An academic hospital. PARTICIPANTS: A total of 263 consecutive parturients with CHD who underwent cesarean section from 1994 to 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors compared postpartum cardiovascular events (composite of heart failure, pulmonary hypertension, arrhythmia, and thromboembolic complications) and neonatal outcomes (intubation and Apgar score <7 at one or five minutes) by anesthetic technique. Among 263 cesarean sections, general anesthesia was performed in 47 (17.9%) parturients and neuraxial anesthesia in 214 (81.3%) parturients. Cardiovascular events were more common in the general anesthesia group (n = 7; 14.9%) than in the neuraxial anesthesia group (n = 17; 7.9%). Generalized linear mixed models assuming a binomial distribution (ie, mixed-effects logistic regression), with a random intercept for each modified World Health Organization classification for maternal cardiovascular risk, revealed that general anesthesia was not significantly associated with cardiovascular events (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.30-3.29). In addition, general anesthesia was associated with composite neonatal outcomes (Apgar score <7 at one or five minutes or need for neonatal intubation; OR, 13.3; 95% CI, 5.52-32.0). CONCLUSION: Anesthetic technique is not significantly associated with postpartum composite cardiovascular events. General anesthesia is significantly associated with increased need for neonatal intubation and lower Apgar scores.

Effect of left ventricular assist device implantation on right ventricular function: Assessment based on right ventricular pressure-volume curves.

Right ventricular (RV) failure is significantly associated with morbidity and mortality after left ventricular assist device (LVAD) implantation. However, it remains unclear whether LVAD implantation could worsen RV function. Therefore, we aimed to investigate the effect of LVAD implantation on RV function by comparing RV energetics derived from the RV pressure-volume curve between before and after LVAD implantation. This exploratory observational study was performed between September 2016 and January 2018 at a national center in Japan. Twenty-two patients who underwent LVAD implantation were included in the analysis. We measured RV energetics parameters: RV stroke work index (RVSWI), which was calculated by integrating the area within the RV pressure-volume curve; RV minute work index (RVMWI), which was calculated as RVSWI × heart rate; and right ventriculo-arterial coupling, which was estimated as RV stroke volume/RV end-systolic volume. We compared RV energetics between before and after LVAD implantation. Although RVSWI was similar [424.4 mm Hg · mL/m2 (269.5-510.3) vs. 379.9 mm Hg · mL/m2 (313.1-608.8), P = 0.485], RVMWI was significantly higher after LVAD implantation [29 834.1 mm Hg · mL/m2 /min (18 272.2-36 357.1) vs. 38 544.8 mm Hg · mL/m2 /min (29 016.0-57 282.8), P = 0.001], corresponding to a significantly higher cardiac index [2.0 L/min/m2 (1.4-2.2) vs. 3.7 L/min/m2 (3.3-4.1), P < 0.001] to match LVAD flow. Right ventriculo-arterial coupling was significantly higher after LVAD implantation [0.360 (0.224-0.506) vs. 0.480 (0.343-0.669), P = 0.025], suggesting that the efficiency of RV performance improved. In conclusion, higher RVMWI with higher cardiac index to match LVAD flow and improved efficiency of RV performance indicate that LVAD implantation might not worsen RV function.

Sizing of mitral annuloplasty rings using real-time three-dimensional transesophageal echocardiography and the difference between patients with and without recurrent mitral regurgitation: retrospective cohort study.

BACKGROUND: Previous studies showed that the mitral inter-commissural (IC) distance differed by a few millimeters between the systolic and diastolic cardiac cycles. However, sizing of the mitral annuloplasty ring with a ring sizer, which should be performed in the systole, is performed in diastole during hyperkalemic cardioplegic arrest. The aim of this study was to investigate whether three-dimensional transesophageal echocardiography (3D-TEE) measurements of the mitral valve in end-systole are effective to determine the size of the annuloplasty ring. METHODS: This study retrospectively reviewed 92 patients who underwent mitral annuloplasty for degenerative. The IC distance and anterior leaflet height of the A2 segment of the mitral valve were measured by 3D-TEE at the end-systole. The annuloplasty ring size was measured by the surgeons using specific ring sizers. We compared the IC distance measured by 3D-TEE with the implanted annuloplasty size. We also investigated differences in IC distance, A2 height, and ratio of A2 height to IC distance in patients with and without recurrent mild to moderate MR for 36 months. RESULTS: There was a significant correlation between the IC distance by 3D-TEE and the implanted ring size (R2 = 0.7023, p < 0.001). Eight cases had mild or greater recurrent MR. There was a significant difference in the ratio of A2 height to IC distance between patients with and without recurrent MR (p = 0.006). A2 height was greater in patients with recurrent MR, but this difference was not significant (p = 0.059). CONCLUSIONS: Our results demonstrated a larger ratio of A2 height to IC distance in patients with recurrent MR. 3D-TEE could be useful for the ring sizing.

Comparison of Right Ventricular Function Between Patients With and Without Pulmonary Hypertension Owing to Left-Sided Heart Disease: Assessment Based on Right Ventricular Pressure-Volume Curves.

OBJECTIVES: Right ventricular (RV) failure with pulmonary hypertension (PH) is frequently encountered in patients with advanced left-sided heart disease (LHD). However, RV energetics in patients with postcapillary PH because of LHD has not been well studied. The authors investigated intraoperative RV energetics in patients with PH due to LHD based on pressure-volume curves with three-dimensional transesophageal echocardiography and pulmonary artery catheterization. DESIGN: Exploratory study. SETTING: National center. PARTICIPANTS: Thirty-three patients who underwent cardiac surgery for LHD were enrolled. Ten patients had PH (mean pulmonary artery pressure ≥ 25 mmHg). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: RV stroke work index (RVSWI) was calculated by integrating the area bounded by the pressure-volume curve. RV minute work index (RVMWI) was calculated as RVSWI × heart rate. Right ventriculo-arterial coupling was estimated as stroke volume divided by end-systolic volume (SV/ESV). The authors compared RV energetics between patients with and without PH because of LHD. RVSWI and RVMWI were significantly higher in patients with PH (690.7 mmHg·mL/m2 [601.6-737.1] v 440.9 mmHg·mL/m2 [330.8-585.3], p = 0.015, and 60,068 mmHg·mL/m2/min [35,547-68,741] v 26,351 mmHg·mL/m2/min [17,316-32,517], p = 0.011, respectively), although cardiac index was nearly identical. SV/ESV was significantly lower in patients with PH (0.520 [0.305-0.810] v 0.820 (0.650-1.090), p = 0.007). CONCLUSIONS: Although cardiac index was similar, RVSWI and RVMWI were significantly higher and SV/ESV was significantly lower in patients with PH because of LHD, suggesting that patients with postcapillary PH have inefficient RV performance.

Measurement of the Aortic Annulus Area and Diameter by Three-Dimensional Transesophageal Echocardiography in Transcatheter Aortic Valve Replacement.

OBJECTIVES: Sizing of the aortic valve is crucial for transcatheter aortic valve replacement (TAVR). Multidetector computed tomography (MDCT) is used for sizing. Recently, three-dimensional transesophageal echocardiography (3DTEE) has enabled accurate measurement of the aortic annulus area and diameter in cases that are difficult to measure. The authors compared measurements of aortic annulus areas and diameters acquired by MDCT and 3DTEE. DESIGN: Retrospective observational study. SETTING: Single national center. PARTICIPANTS: Sixty-eight patients who underwent TAVR replacement between September 2015 and March 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors extracted and compared preoperative measurements of the aortic annulus area, as well as the long- and short-axis diameter, measured by MDCT and 3DTEE. There was no significant difference in the aortic annulus area (409 ± 74 v 414 ± 70 mm2, p = 0.15) or short-axis diameter (20.4 ± 2.0 v 20.6 ± 1.9 mm, p = 0.103) between 3DTEE and MDCT, but the long-axis diameter differed significantly (25.0 ± 2.4 v 25.8 ± 2.0 mm, p < 0.001), respectively. Prosthesis sizes based on 3DTEE and MDCT were the same, except in 3 patients who could not stay still during MDCT measurement; in those cases, prosthesis sizes based on 3DTEE were adopted. CONCLUSIONS: Measurements of the aortic annulus area and diameter in TAVR were similar between 3DTEE and MDCT. Patients who have difficulty remaining still during MDCT measurement because of dementia should have their prostheses sized based on 3DTEE measurements.

Reappearance of Motor-Evoked Potentials During the Rewarming Phase After Deep Hypothermic Circulatory Arrest.

OBJECTIVE: Although motor-evoked potentials (MEPs) disappear in deep hypothermic circulatory arrest (DHCA), MEPs have been used to confirm whether motor function is intact after DHCA. It is crucial to know the timing, body temperature, and MEP amplitude at MEP reappearance to detect spinal cord ischemia after DHCA. However, data on these parameters are sparse. The authors investigated the characteristics of MEPs at reappearance after DHCA. DESIGN: A retrospective observational study. SETTING: Single national center. PARTICIPANTS: Sixty-one patients who underwent descending aortic replacement and thoracoabdominal aortic replacement with DHCA between January 2013 and December 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors extracted the following data: time to MEP reappearance after the end of lower extremity circulatory arrest, bladder temperature (BT) and nasopharyngeal temperature (NPT) when MEPs recovered, and %amplitude of MEPs relative to control values at MEP reappearance. The median time to MEP reappearance was approximately 70 minutes. BT at MEP reappearance ranged from 34.3°C to 34.6°C and NPT ranged from 36.2°C to 36.4°C. At MEP reappearance, %amplitude less than 50% of the control value was observed in more than 50% of patients. Time to MEP reappearance had a significant positive association with rewarming time (p < 0.01) and BT (p = 0.03). CONCLUSIONS: There was a wide variation in MEP amplitude at reappearance during the rewarming phase. BT was approximately 34°C when MEPs in the leg recovered. The time to MEP reappearance is influenced significantly by rewarming time and BT.

[Anesthetic Management of a Patient with Multiple System Atrophy--A Case Report].

There are only a few reports on anesthetic management for olivopontocerebellar atrophy (OPCA), a type of multiple system atrophy (MSA). We experienced anesthetic management for a surgical repair of cervical spondylotic myelopathy (CSM), a complication of OPCA. We used minimal doses of anesthetics, considering the specific perioperative complications of OPCA patients, such as hypotension, respiratory failure and prolonged effect of muscle relaxants. We were able to perform general anesthesia as safely as in patients without OPCA.