Sphigosine-1-phosphate receptor 1 promotes neointimal hyperplasia in a mouse model of carotid artery injury.

Vascular remodeling, resulting from proliferation and migration of vascular smooth muscle cells (VSMCs), is a major cause of atherosclerosis and restenosis. The lysophospholipid mediator sphingosine-1-phosphate (S1P) regulates proliferation and migration of VSMCs via S1P-specific G protein-coupled receptors, including S1P receptor 1 (S1PR1) to S1PR3. However, the role of S1PR1 in vascular remodeling is not well understood. Therefore, in this study, we aimed to investigate the effect of S1PR1 on neointimal hyperplasia in a carotid artery ligation mouse model using transgenic C57Bl/6 mice that overexpressed S1PR1 (Tg-S1PR1) under the control of α-smooth muscle actin promoter. We found that S1PR1 expression in carotid artery was upregulated after carotid artery ligation in non-transgenic (nTg) mice. Tg-S1PR1 mice showed enhanced ligation-induced neointimal hyperplasia with increased neointimal cell proliferation, compared with control nTg mice. VSMCs isolated from Tg-S1PR1 mice showed enhanced proliferation and migration in response to S1P stimulation. VSMCs from Tg-S1PR1 mice showed greater expression of interleukin-6 (IL-6) compared with nTg mouse-derived VSMCs, and administration of IL-6-neutralizing antibody into Tg-S1PR1 mice suppressed neointimal hyperplasia. These results suggest that S1P-S1PR1 signaling plays an important role in neointimal hyperplasia after vascular injury via IL-6 production.

Impact of Bedside Tracheostomy on Procalcitonin Kinetics in Critically Ill Patients.

BACKGROUND: Critically ill patients are particularly vulnerable to invasive procedures and complications; however, tracheostomy is frequently performed in the intensive care unit (ICU). We analyzed the effects of tracheostomy on procalcitonin (PCT) kinetics and investigated whether PCT could reliably predict septic complications after tracheostomy. METHODS: We retrospectively identified 134 patients who underwent bedside tracheostomy during their ICU stay at a Japanese university hospital from October 2010 to December 2015. We extracted PCT data from the day of the procedure (day 0) to postoperative day 2 and defined alert PCT as a PCT level ≥0.5 ng/mL, which had not decreased from the previous day. We divided patients into the following groups: nonevent, aseptic complication, and septic complication. RESULTS: Twelve (9.2%) patients developed acute aseptic complications, and 12 (9.2%) patients developed septic complications. In the nonevent group, the PCT value decreased continuously in the initial PCT ≥ 0.5 ng/mL subgroup (P < .001, P <.001 for trend). In contrast, significant changes were not observed in the initial PCT < 0.5 ng/mL subgroup. Significant differences and an upward trend in alert PCT incidence rate existed between the groups (P < .001, P < .001 for trend): nonevent group, 5.5%; aseptic complication group, 41.7%; and septic complication group, 66.7%. In a multivariate linear regression model, septic complications were independently associated with PCT change at postoperative days 1 and 2 (adjusted ß = 3.58, P < .001; adjusted ß = 9.84, P < .001, respectively). Procalcitonin predicted septic complications more accurately than C-reactive protein, with the area under the receiver operating characteristic curves of 0.8 versus 0.63 (P = .058) and 0.91 versus 0.69 (P = .036) at postoperative days 1 and 2, respectively. CONCLUSION: Our results demonstrated that PCT was not elevated after uncomplicated surgical tracheostomy in critically ill patients.

Successful treatment of exertional heat stroke using continuous plasma diafiltration.

We report a case of severe exertional heat stroke with multiple organ failure successfully treated with continuous plasma diafiltration (CPDF). PDF effectively removed proinflammatory cytokines, and simultaneously, supported liver function. Furthermore, CPDF therapy showed beneficial effects on multiple organ functions. These features suggest that it is a primary treatment option for exertional heat stroke with multiple organ failure. J. Clin. Apheresis 31:490-492, 2016. © 2015 Wiley Periodicals, Inc.

Efficacy of continuous plasma diafiltration therapy in critical patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a critical illness with high mortality. Plasma diafiltration (PDF) is a blood purification therapy that is useful for ALF patients, but it is difficult to use when those patients have multiple organ failure or unstable hemodynamics. In these patients, symptoms are also likely to exacerbate immediately after PDF therapy. We developed continuous PDF (CPDF) as a new concept in PDF therapy, and assessed its efficacy and safety in ALF patients. METHODS: Ten ALF patients (gender: M/F 6/4, Age: 47 ± 14) were employed CPDF therapy. The primary outcomes were altered liver function, measured by the model for end-stage liver disease (MELD) score, and total bilirubin and prothrombin time international normalized ratios (PT-INR), 5 days after CPDF therapy. Secondary outcomes included sequential organ failure assessment (SOFA) scores, 5 days after CPDF therapy, and the survival rate 14 days after this therapy. RESULTS: The MELD score (34.5-28.0; P = 0.005), total bilirubin (10.9-7.25 mg/dL; P = 0.048), PT-INR (1.89-1.31; P = 0.084), and SOFA score (10.0-7.5; P < 0.039) were improved 5 days after CPDF therapy. Nine patients were alive, and one patient died because of acute pancreatitis, complicated by ALF. There were no major adverse events related to this therapy under hemodynamic stability. CONCLUSION: In the present study, CPDF therapy safely supported liver function and generally improved the condition of critically ill patients with ALF.

Attitudes toward automated external defibrillator use in Japan in 2011.

PURPOSE: Early use of an automated external defibrillator (AED) improves the chances of successful resuscitation and survival. We have surveyed Japanese individuals on their attitude towards using an AED if they witnessed a cardiac arrest and compared the results with those of our previous study in 2006. METHODS: Participants were asked to complete questionnaires regarding their familiarity with the AED concept and their willingness to use AEDs. RESULTS: A total of 2,527 high school students, teachers, medical nurses, and medical students completed the questionnaire; the characteristics of these individuals were not statistically different from those of the participants of our previous study. In total, 47 % of the high school students, 89 % of the teachers, 93 % of the nurses, and all of the medical students responded that they were familiar with the concept and use of AEDs. The percentages of high school students, teachers, and nurses indicating a familiarity with AEDs were significantly higher in the current study than in the 2006 study. In total, 73 % of the high school students, 87 % of the teachers, 98 % of the nurses, and all of the medical students surveyed in the current study claimed they would definitely use AEDs if required; these values were also significantly higher than those obtained in 2006. CONCLUSIONS: The number of Japanese individuals who are familiar with the concept of AEDs and who are also willing to use these devices was considerably higher in the current study than in the 2006 study. However, more Japanese individuals should be made aware of AEDs and become familiar with their use.

Aortoesophageal fistula with hemorrhagic shock successfully treated with resuscitative endovascular balloon occlusion of the aorta.

BACKGROUND: Aortoesophageal fistula (AEF) is a rare cause of upper gastrointestinal hemorrhage. Despite diagnostic and therapeutic advances, the mortality rate in AEF patients remains high because of its fulminant course, even with maximal intensive care. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a resuscitation technique to control life-threatening bleeding. It has become an important modality in the management of life-threatening, traumatic or non-traumatic, arterial bleeding. However, it's use in hemorrhagic shock caused by cancer has rarely been reported. CASE PRESENTATION: A 51-year-old woman with a history of esophageal cancer presented to our emergency department with hematemesis. Computed tomography was performed because of a strong suspicion of hemorrhagic shock. With a diagnosis of AEF due to esophageal cancer, emergency thoracic endovascular aortic repair was performed while the bleeding was controlled using REBOA. Staged elective esophageal reconstruction was successfully performed. CONCLUSIONS: Hemostasis is crucial in patients who present with suspected hemorrhagic shock attributable to AEF. The timely implementation of REBOA has shown promise and potential effectiveness in such cases.

Impact of the COVID-19 pandemic on prehospital characteristics and outcomes of out-of-hospital cardiac arrest among the elderly in Japan: A nationwide study.

Aim: To assess the impact of the 2020 coronavirus disease (COVID-19) pandemic on the prehospital characteristics and outcomes of out-of-hospital cardiac arrest (OHCA) in the elderly. Methods: In this population-based nationwide observational study in Japan, 563,100 emergency medical service-unwitnessed OHCAs in elderly (≥65 years) patients involving any prehospital resuscitation efforts were analysed (144,756, 140,741, 140,610, and 136,993 cases in 2020, 2019, 2018, and 2017, respectively). The epidemiology, characteristics, and outcomes associated with OHCAs in elderly patients were compared between 3 years pre-pandemic (2017-2019) and the pandemic year (2020). The primary outcome was neurologically favourable one-month survival. The secondary outcomes were the rate of bystander cardiopulmonary resuscitation (CPR), defibrillation by a bystander, dispatcher-assisted (DA)-CPR attempts, and one-month survival. Results: During the pandemic year, the rates of neurologically favourable 1-month survival (crude odds ratio, 95% confidence interval: 1.19, 1.14-1.25), bystander CPR (1.04, 1.03-1.06), and DA-CPR attempts (1.10, 1.08-1.11) increased, whereas the incidence of public access defibrillation (0.88, 0.83-0.93) decreased. Subgroup analyses based on interaction tests showed that the increased rate of neurologically favourable survival during the pandemic year was enhanced in OHCA at care facilities (1.51, 1.36-1.68) and diminished or abolished on state-of-emergency days (0.90, 0.74-1.09), in the mainly affected prefectures (1.08, 1.01-1.15), and in cases with shockable initial rhythms (1.03, 0.96-1.12). Conclusions: The COVID-19 pandemic increased the bystander CPR rate in association with enhanced DA-CPR attempts and improved the outcomes of elderly patients with OHCAs.

Augmented single-unit muscle sympathetic nerve activity in heart failure with chronic atrial fibrillation.

Atrial fibrillation (AF) is a common complication in heart failure (HF) patients. However, it remains unclear whether irregular ventricular response patterns induced by AF increase sympathetic nerve activity. We measured resting multi- and single-unit muscle sympathetic nerve activity (MSNA) in 21 age-matched HF patients with chronic AF (n = 11) rhythm or sinus rhythm (SR, n = 10). The multi-unit MSNA, which was expressed as total activity, was similar between HF + AF patients and HF + SR patients. However, the single-unit MSNA in HF + AF patients was significantly greater than that in HF + SR patients (62 ± 9 spikes min(-1) vs. 42 ± 4 spikes min(-1), P < 0.05). Moreover, the incidence of multiple firing of single-unit MSNA within a given burst was augmented in HF + AF patients as compared with HF + SR patients (48 ± 8% vs. 26 ± 3%, P < 0.01). A significant negative relationship was observed between the reduced diastolic pressure induced by a prolonged cardiac interval in AF subjects and single-unit MSNA frequency within one cardiac interval in each HF + AF subject. The firing characteristics of single-unit MSNA were different between HF patients with AF and HF patients with SR; particularly, those with a prolonged long RR interval showed multiple firings of single-unit MSNA. These findings suggest that AF per se leads to the instantaneous augmentation of single-unit MSNA induced by decreased diastolic pressure, which might partially contribute to disease progression in HF patients.

Attitudes to bystander cardiopulmonary resuscitation in Japan in 2010.

BACKGROUND: Early initiation of bystander cardiopulmonary resuscitation (CPR) improves the chances of successful resuscitation and survival. The aim of the present study was to identify the attitudes of Japanese subjects toward bystander CPR and to compare them with those observed in previous studies in 1998 and 2006. METHODS AND RESULTS: Participants were asked about their willingness to perform CPR in 5 different scenarios and their willingness to perform chest compression (CC) plus mouth-to-mouth ventilation (MMV) versus CC alone. A total of 2,785 individuals completed the questionnaire, including high school students, teachers, medical nurses, and medical students, whose characteristics were not statistically different from those in the previous studies. Only 15-30% of participants were likely to perform CC plus MMV, especially on a stranger or a trauma victim; these percentages in nurses and medical students were significantly lower than those in the previous studies. But 50-100% of them were likely to perform CC alone, consistent with the results obtained in 2006. The reasons for the unwillingness among laypeople to perform CC plus MMV were inadequate knowledge and/or doubt regarding whether they could perform the techniques effectively, while health-care providers reported a fear of disease transmission. CONCLUSIONS: Most participants are unlikely to perform CC plus MMV, especially on a stranger or trauma victim, but are more likely to perform CC alone, as also found in the previous studies.

Time point for transport initiation in out-of-hospital cardiac arrest cases with ongoing cardiopulmonary resuscitation: a nationwide cohort study in Japan.

Aim: This study aimed to investigate the time point of the decision to initiate transport with ongoing cardiopulmonary resuscitation (CPR) in Japan. Methods: We analyzed adult out-of-hospital cardiac arrest (OHCA) cases that achieved return of spontaneous circulation (ROSC) before hospital arrival from the All-Japan Utstein Registry during 2015-2017. We constructed receiver operating characteristics (ROC) curves to illustrate the ability of achieving ROSC as a predictor of neurologically favorable outcomes as a function of increasing time points of resuscitation before ROSC. Furthermore, a multivariable logistic regression analysis was carried out to identify factors associated with outcomes. Results: Of 373,993 OHCA patients with attempted resuscitation during 2015-2017, 22,067 patients with prehospital ROSC were included in our study. Patients were divided into the shockable initial rhythm (n = 5,580) and nonshockable initial rhythm (n = 16,487) cohorts. The ROC curves showed 10 min was the best test performance time point for a neurologically favorable outcome for shockable initial rhythm patients (sensitivity, 0.78; specificity, 0.53; area under the ROC curve [AUC], 0.70) and 8 min for nonshockable initial rhythm patients (sensitivity, 0.74; specificity, 0.77; AUC, 0.83). Multivariable logistic regression analyses revealed that CPR durations using the cut-off value were independently associated with better outcomes for both shockable initial rhythm patients (odds ratio, 2.09; 95% confidence interval, 1.81-2.42) and nonshockable initial rhythm patients (odds ratio, 3.34; 95% confidence interval, 2.92-3.82). Conclusion: When Japanese emergency medical service (EMS) providers attend OHCA cases, the decision to initiate transport with ongoing CPR should be made at approximately 10 min after EMS providers initiate CPR for shockable initial rhythm patients and at approximately 8 min for nonshockable initial rhythm patients.

Clinical and epidemiological features of healthcare workers after a coronavirus disease 2019 cluster infection in Japan and the effects of Kampo formulas-Hochuekkito and Kakkonto: A retrospective cohort study.

It is expected that a low-toxicity natural compound like Kampo formulas would exhibit a preventive effect on COVID-19, in a global outbreak of coronavirus disease 2019 (COVID-19). Although the biological properties and safety of the representative Kampo, Hochuekkito (HET), and Kakkonto (KKT) have been confirmed in various animal model experiments and clinical studies, and in a few human studies to induce biological effects on various infectious diseases without significant toxicity, it is unclear whether HET and KKT are safe and effective for COVID-19 prevention. We summarized the clinical characteristics of HCWs and the preventive effects of HET and KKT. We performed a retrospective, single-center, cohort study that included 175 HCWs (aged 21-77 years) from a total number of 217 in a hospital with a history of COVID-19 cluster infection. In total, 175 HCWs were tested for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies. We identified 27 patients (median age: 49 ± 10.7 years) who were diagnosed with COVID-19. The patients in the group that had a body mass index ≥ 25 had a high COVID-19 infection risk, while those in the group with a Kampo formula adherence rate ≥ 40% had a low COVID-19 risk. Patients in the group with an adherence rate ≥ 40%, as well as those in the current alcohol consumption group, were at a low risk of developing severe COVID-19. In conclusion, HET and KKT may have prevented the onset or worsening of COVID-19, which could be clinically used. Obesity might have increased the patients' susceptibility to COVID-19 and the disease severity.

Case Report: Myocarditis Associated With COVID-19 mRNA Vaccination Following Myocarditis Associated With Campylobacter Jejuni.

We herein present our experience with a case involving a 17-year-old Japanese boy suffering from acute myocarditis after his second coronavirus disease-2019 (COVID-19) messenger RNA (mRNA) vaccine shot. The patients had a history of myocarditis associated with Campylobacter jejuni 3 years prior. This has been the first-ever documented case of myocarditis associated with COVID-19 mRNA vaccination in a patient with a history of myocarditis. We present a series of images and blood biomarkers for different types of myocarditis that developed in this single patient.

Preexisting Humoral Immunity Cross-Reacting with SARS-CoV-2 Might Prevent Death Due to COVID-19 in Critical Patients.

The preexistence of humoral immunity, which cross-reacts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein due to prior endemic low-pathogenic human coronavirus infection, has been reported, but its role in coronavirus disease 2019 (COVID-19) outcomes remains elusive. We evaluated serum samples obtained from 368 patients before the pandemic and 1423 independent serum samples from patients during the pandemic. We found that approximately 6~13% and 1.5% of patients had IgG cross-reactivity to the SARS-CoV-2 spike and nucleocapsid proteins in both cohorts. We evaluated the IgG cross-reactivity to the SARS-CoV-2 spike and nucleocapsid proteins in 48 severe or critical COVID-19 patients to evaluate if the elevation of IgG was evoked as a primary response (IgG elevation from 10 days after antigen exposure) or boosted as a secondary response (IgG elevation immediately after antigen exposure). Approximately 50% of patients showed humoral immune responses to the nucleocapsid protein of SARS-CoV-2. Importantly, none of the critically ill patients with this humoral immunity died, whereas 40% of patients without this immunity did. Taken together, subjects had humoral immunity to SARS-CoV-2 nucleocapsid but not spike before the pandemic, which might prevent critically ill COVID-19 patients from dying.

Suicidal attempt with caffeine overdose treated with dexmedetomidine: a case report.

BACKGROUND: Caffeine is a widely used dietary stimulant, and cases of caffeine overdoses, sometimes leading to death, are increasing. We encountered a case of caffeine intoxication resolved with administration of the sedative agent dexmedetomidine. CASE PRESENTATION: We administered dexmedetomidine for sedation and to suppress sympathetic nerve stimulation in the case of an 18-year-old Japanese male who ingested a massive dose of caffeine with the intention of committing suicide. The patient was in an excited state and had hypertension, sinus tachycardia, and hypokalemia with prominent QT prolongation. After dexmedetomidine administration, the patient's mental state, hemodynamics, and electrolyte levels were improved immediately. He was discharged without any sequelae 3 days later. CONCLUSION: Cases of acute caffeine intoxication with agitation, sympathetic overactivity and adverse cardiac events would benefit with dexmedetomidine treatment.

Early Detection of Symptom Exacerbation in Patients With SARS-CoV-2 Infection Using the Fitbit Charge 3 (DEXTERITY): Pilot Evaluation.

BACKGROUND: Some patients with COVID-19 experienced sudden death due to rapid symptom deterioration. Thus, it is important to predict COVID-19 symptom exacerbation at an early stage prior to increasing severity in patients. Patients with COVID-19 could experience a unique "silent hypoxia" at an early stage of the infection when they are apparently asymptomatic, but with rather low SpO2 (oxygen saturation) levels. In order to continuously monitor SpO2 in daily life, a high-performance wearable device, such as the Apple Watch or Fitbit, has become commercially available to monitor several biometric data including steps, resting heart rate (RHR), physical activity, sleep quality, and estimated oxygen variation (EOV). OBJECTIVE: This study aimed to test whether EOV measured by the wearable device Fitbit can predict COVID-19 symptom exacerbation. METHODS: We recruited patients with COVID-19 from August to November 2020. Patients were asked to wear the Fitbit for 30 days, and biometric data including EOV and RHR were extracted. EOV is a relative physiological measure that reflects users' SpO2 levels during sleep. We defined a high EOV signal as a patient's oxygen level exhibiting a significant dip and recovery within the index period, and a high RHR signal as daily RHR exceeding 5 beats per day compared with the minimum RHR of each patient in the study period. We defined successful prediction as the appearance of those signals within 2 days before the onset of the primary outcome. The primary outcome was the composite of deaths of all causes, use of extracorporeal membrane oxygenation, use of mechanical ventilation, oxygenation, and exacerbation of COVID-19 symptoms, irrespective of readmission. We also assessed each outcome individually as secondary outcomes. We made weekly phone calls to discharged patients to check on their symptoms. RESULTS: We enrolled 23 patients with COVID-19 diagnosed by a positive SARS-CoV-2 polymerase chain reaction test. The patients had a mean age of 50.9 (SD 20) years, and 70% (n=16) were female. Each patient wore the Fitbit for 30 days. COVID-19 symptom exacerbation occurred in 6 (26%) patients. We were successful in predicting exacerbation using EOV signals in 4 out of 5 cases (sensitivity=80%, specificity=90%), whereas the sensitivity and specificity of high RHR signals were 50% and 80%, respectively, both lower than those of high EOV signals. Coincidental obstructive sleep apnea syndrome confirmed by polysomnography was detected in 1 patient via consistently high EOV signals. CONCLUSIONS: This pilot study successfully detected early COVID-19 symptom exacerbation by measuring EOV, which may help to identify the early signs of COVID-19 exacerbation. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000041421; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047290.

Immunological and Preventive Effects of Hochuekkito and Kakkonto Against Coronavirus Disease in Healthcare Workers: A Retrospective Observational Study.

Amid the global outbreak of coronavirus disease 2019 (COVID-19), it may be expected that low-toxicity natural compounds, such as Kampo formulas, will have a preventive effect on COVID-19. Although the biological properties and safety of the representative Kampo compounds, hochuekkito (HET) and kakkonto (KKT), have been confirmed in various animal model experiments, clinical studies, and a few human studies to induce biological effects on various infectious diseases without significant toxicity, it is unclear whether HET and KKT are safe and effective for COVID-19 prevention. The study population included healthcare workers (HCWs), as they are at a higher risk of infection than the other populations. We retrospectively investigated the immunological and preventive effects of HET and KTT against COVID-19. We included 27 HCWs (aged 21-72 years, F:M = 18:9) from hospitals and clinics of the Hokuriku-Tokai region. The HCWs received HET and KKT for general fatigue and myalgia during this period for 28 days. We obtained patient clinical data from electronic medical records. We analyzed the changes in immunomodulation before and after the administration of the formulas from residual specimens based on the expression of relevant surface markers. The specimens were also tested for the presence of antibodies against severe acute respiratory syndrome coronavirus 2. The following side effects were reported: abdominal discomfort in five patients, diarrhea in two, and loose or soft stool in three. All 27 HCWs tested negative for COVID-19 antibodies. HET and KKT administration significantly increased the absolute number of circulating lymphocytes expressing the activating receptors NKp46, NKp30, and suppressing receptor NKG2A. There was also a significant increase in the absolute number of circulating lymphocytes expressing the receptors TLR4, OX40, 4-1BB, GITR, PD-1, and ICOS. These data indicate that HET and KKT can enhance and modulate NK activity in circulating human immune cells. The immunomodulatory effects, such as activation and regulation of T cells, are consistent with a putative improvement in infectious immunosurveillance. An increase in the number of T cells and CD4/CD8-positive cells indicates an enhanced ability to protect against infection. HET and KKT may prevent the onset or worsening of COVID-19 through their immunomodulatory effects.

Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors inhibit SGLT2, which is expressed in the proximal renal tubule, and thus reduce blood glucose levels by enabling the urinary excretion of excess glucose. SGLT2 inhibitors have been reported to suppress the complications of diabetes and reduce overall mortality. However, little is known about the types of symptoms that may occur in response to an overdose of an SGLT2 inhibitor. Here, we describe a case of intoxication caused by an overdose of an SGLT2 inhibitor. CASE PRESENTATION: An otherwise physically healthy adult woman ingested an overdose of ipragliflozin, an SGLT2 inhibitor, and a polypill of olmesartan medoxomil, and azelnidipine in a suicide attempt. Although her blood ipragliflozin concentration was very high (9516.3 ng/mL) upon hospital arrival, her initial blood glucose level was normal, and she did not exhibit symptoms such as hypoglycemia or polyuria. Moderate renal dysfunction associated with an estimated glomerular filtration rate of 42.3 mL/min/1.73 m2 was observed. Thirty-six hours after ingestion, her blood ipragliflozin concentration decreased to a level equivalent to that observed after a therapeutic dose and her renal function improved almost simultaneously. After improvement in her renal function, the osmotic diuretic effect of the drug progressed. Her blood glucose level declined slightly but was in the normal range due to glucose administration. During the clinical course, fatal hypoglycemia was not observed. CONCLUSIONS: Our case showed that an overdose of an SGLT2 inhibitor caused toxic effects on renal function, but severe hypoglycemia was not observed. Additional cases of intoxication from SGLT2 inhibitors alone would be helpful to clarify the mechanism of intoxication.

Nafamostat mesylate-induced hyperkalemia in critically ill patients with COVID-19: Four case reports.

BACKGROUND: Nafamostat mesylate (NM) may prove to be one of the key drugs effective against coronavirus disease 2019 (COVID-19) because of its anti-viral properties and the potential to manage coagulopathy. However, NM tends to increase serum potassium levels. CASE SUMMARY: We observed hyperkalemia immediately after NM administration (200 mg/d) in four consecutive patients who were admitted to the Kanazawa University Hospital with severe COVID-19 pneumonia. Urinary potassium excretion decreased after NM administration in three patients who underwent urinalysis. CONCLUSION: NM is likely to produce hyperkalemia in patients with COVID-19. Therefore, it is necessary to monitor serum potassium values closely after NM initiation in COVID-19 patients who need respiratory support.

Efficacy and safety of landiolol, an ultra-short-acting ß1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Tachycardia and atrial fibrillation frequently occur in patients being treated for sepsis or septic shock and have a poor prognosis. Treatments for tachyarrhythmias are often ineffective or contraindicated in this setting. We aimed to investigate the efficacy and safety of landiolol, an ultra-short-acting ß-blocker, for treating sepsis-related tachyarrhythmias. METHODS: We did a multicentre, open-label, randomised controlled trial at 54 hospitals in Japan. Patients admitted to the intensive care units who received conventional treatment for sepsis, according to clinical guidelines for the management of sepsis, and who subsequently developed a tachyarrhythmia, were enrolled. The main inclusion criteria were 20 years of age or older, diagnosis of sepsis according to Third International Consensus Definitions for Sepsis and Septic Shock criteria, administration of catecholamine necessary to maintain mean arterial pressure at 65 mm Hg or more for at least 1 h, and heart rate of 100 beats per min (bpm) or more maintained for at least 10 min without a change in catecholamine dose with diagnosis of atrial fibrillation, atrial flutter, or sinus tachycardia. Only patients who developed these symptoms and signs within 24 h before randomisation, and within 72 h after entering an intensive care unit, were prospectively assigned to receive conventional sepsis therapy alone (control group) or conventional sepsis therapy plus landiolol (landiolol group) in an open-label manner. Landiolol hydrochloride was intravenously infused at an initial dose of 1 µg/kg per min within 2 h after randomisation and the dose could be increased per study protocol to a maximum of 20 µg/kg per min. Patients in both groups received conventional therapy (Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock 2016), including respiratory and fluid resuscitation, antimicrobials, and catecholamines. The treating physicians were required to stabilise the patient's haemodynamic status before randomisation. Randomisation was done using a central randomisation system and dynamic allocation with the minimisation method by institution, heart rate at randomisation (≥100 to <120 bpm or ≥120 bpm), and age (<70 years or ≥70 years). The primary outcome was the proportion of patients with heart rate of 60-94 bpm at 24 h after randomisation. Patients without heart rate data at 24 h after randomisation were handled as non-responders. The primary outcome was analysed using the full analysis set on an as-assigned basis, while safety was analysed using the safety analysis set according to the treatment received. This study was registered with the Japan Pharmaceutical Information Center Clinical Trials Information database, number JapicCTI-173767. FINDINGS: Between Jan 16, 2018 and Apr 22, 2019, 151 patients were randomly assigned, 76 to the landiolol group and 75 to the control group. A significantly larger proportion of patients in the landiolol group had a heart rate of 60-94 bpm 24 h after randomisation than in the control group (55% [41 of 75] vs 33% [25 of 75]), with a between-group difference of 23·1% (95% CI 7·1-37·5; p=0·0031). Adverse events were observed in 49 (64%) of 77 patients in the landiolol group and in 44 (59%) of 74 in the control group, with serious adverse events (including adverse events leading to death) in nine (12%) of 77 and eight (11%) of 74 patients. Serious adverse events related to landiolol occurred in five (6%) of 77 patients, including blood pressure decreases in three patients (4%) and cardiac arrest, heart rate decrease, and ejection fraction decrease occurred in one patient each (1%). INTERPRETATION: Landiolol resulted in significantly more patients with sepsis-related tachyarrhythmia achieving a heart rate of 60-94 bpm at 24 h and significantly reduced the incidence of new-onset arrhythmia. Landiolol was also well tolerated, but it should be used under appropriate monitoring of blood pressure and heart rate owing to the risk of hypotension in patients with sepsis and septic shock. FUNDING: Ono Pharmaceutical Co.

Impact of patient characteristics on the efficacy and safety of landiolol in patients with sepsis-related tachyarrhythmia: Subanalysis of the J-Land 3S randomised controlled study.

BACKGROUND: The J-Land 3S trial demonstrated that landiolol is effective and tolerated for treating sepsis-related tachyarrhythmias. Patient characteristics (e.g. baseline heart rate [HR], type of tachyarrhythmia, and concomitant disorders) may impact the outcomes of landiolol therapy. We performed subanalyses of J-Land 3S to evaluate the impact of patient characteristics on the efficacy and safety of landiolol for treating sepsis-related tachyarrhythmia. METHODS: Patients (≥20 years old; N = 151) hospitalised with sepsis at 54 participating hospitals in Japan with HR ≥100 beats/min for ≥10 min accompanied by diagnosis of tachyarrhythmia were randomised 1:1 to conventional sepsis therapy alone (control group) or conventional sepsis therapy plus landiolol (landiolol group). The efficacy and safety of landiolol were assessed in prespecified analyses of patients divided into subgroups by baseline characteristics and in post hoc, multivariate analyses with adjustment for age and HR at baseline. FINDINGS: The percentage of patients with HR of 60-94 beats/min at 24 h after randomisation (primary endpoint) was greater in the landiolol group in most subgroups in univariate unadjusted analyses and in multivariate logistic regression. The incidence of new-onset arrhythmia by 168 h and mortality by 28 days were also lower in the landiolol group in most subgroups in univariate and multivariate Cox proportional hazards models. No subgroups showed a markedly higher incidence of adverse events in univariate or multivariate logistic regression analyses. INTERPRETATION: These results of the J-Land 3S study suggest that the efficacy and safety of landiolol are generally unaffected by key patient characteristics. FUNDING: Ono Pharmaceutical Co., Ltd.