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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Association of Persistent Intense Thirst With Delirium Among Critically Ill Patients: A Cross-sectional Study.

CONTEXT: Thirst is a prevalent distressing symptom often reported by patients in the intensive care unit (ICU). Little is known about the association of thirst with delirium. OBJECTIVE: We aimed to investigate the relationship between thirst and delirium. METHODS: This retrospective cross-sectional study enrolled 401 patients who were evaluated for thirst intensity in the ICU between March 2017 and October 2017. We assessed thirst intensity on a scale of 0-10 (with 10 being the worst) and defined intense thirst as a score ≥8. If intense thirst persisted for more than 24 hours, we defined it as persistent intense thirst. Delirium was screened using the Intensive Care Delirium Screening Checklist. Propensity score matching and inverse probability of treatment weighting analyses were performed. RESULTS: Of 401 patients, 66 (16.5%) had intense thirst sensation for more than 24 hours. After matching, patients with persistent intense thirst showed an increased risk for delirium compared with those without persistent intense thirst (odds ratio, 4.95; 95% confidence interval, 2.58-9.48; P < 0.001). Propensity score weighted logistic regression analysis also indicated that persistent intense thirst was significantly associated with delirium (odds ratio, 5.74; 95% confidence interval, 2.53-12.99; P < 0.001). CONCLUSION: Intense thirst persisting for more than 24 hours was associated with increased risk for delirium.

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.

Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies.

BACKGROUND: Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown. METHODS: We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine. RESULTS: Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2. CONCLUSIONS: Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD. TRIAL REGISTRATION: UMIN, UMIN000004322. Registered 4 October 2010.

Sodium 4-Phenylbutyrate Attenuates Myocardial Reperfusion Injury by Reducing the Unfolded Protein Response.

BACKGROUND: The unfolded protein response (UPR) plays a pivotal role in ischemia-reperfusion (I/R) injury in various organs such as heart, brain, and liver. Sodium 4-phenylbutyrate (PBA) reportedly acts as a chemical chaperone that reduces UPR. In the present study, we evaluated the effect of PBA on reducing the UPR and protecting against myocardial I/R injury in mice. METHODS: Male C57BL/6 mice were subjected to 30-minute myocardial I/R, and were treated with phosphate-buffered saline (as a vehicle) or PBA. RESULTS: At 4 hours after reperfusion, mice treated with PBA had reduced serum cardiac troponin I levels and numbers of apoptotic cells in left ventricles (LVs) in myocardial I/R. Infarct size had also reduced in mice treated with PBA at 48 hours after reperfusion. At 2 hours after reperfusion, UPR markers, including eukaryotic initiation of the factor 2α-subunit, activating transcription factor-6, inositol-requiring enzyme-1, glucose-regulated protein 78, CCAAT/enhancer-binding protein (C/EBP) homologous protein, and caspase-12, were significantly increased in mice treated with vehicle compared to sham-operated mice. Administration of PBA significantly reduced the I/R-induced increases of these markers. Cardiac function and dimensions were assessed at 21 days after I/R. Sodium 4-phenylbutyrate dedicated to the improvement of cardiac parameters deterioration including LV end-diastolic diameter and LV fractional shortening. Consistently, PBA reduced messenger RNA expression levels of cardiac remodeling markers such as collagen type 1α1, brain natriuretic peptide, and α skeletal muscle actin in LV at 21 days after I/R. CONCLUSION: Unfolded protein response mediates myocardial I/R injury. Administration of PBA reduces the UPR, apoptosis, infarct size, and preserved cardiac function. Hence, PBA may be a therapeutic option to attenuate myocardial I/R injury in clinical practice.

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.

Landiolol, an ultra-short-acting ß1-blocker, is useful for managing supraventricular tachyarrhythmias in sepsis.

AIM: To investigate whether landiolol, an ultra-short-acting ß1-antagonist, can safely and effectively control heart rate in septic patients with supraventricular tachyarrhythmias. METHODS: We reviewed all patients with sepsis who admitted to our intensive care unit between January 2006 and December 2011. Sixty one septic patients suffered from supraventricular tachyarrhythmias (heart rate ≥ 120 bpm for > 1 h). Among 61 patients, 39 patients were treated with landiolol (landiolol group) and 22 patients were not treated with landiolol (control group). Arterial pressure, heart rate, cardiac rhythm, pulmonary arterial pressure and cardiac output (if a pulmonary arterial catheter was inserted) were compared between the 2 groups at 1, 8 and 24 h after the initiation of tachyarrhythmias. RESULTS: Mean age and Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were similar between the 2 groups. Paroxysmal atrial fibrillation/flutter (87%), paroxysmal atrial tachycardia (10%), and paroxysmal supraventricular tachycardia (3%) were observed. The initial landiolol dose administered was 6.3 ± 5.8 g/kg per minute. Rapid and substantial reduction of heart rate was observed in the landiolol group without any deterioration of hemodynamics. Landiolol significantly reduced heart rate (from 145 ± 14 bpm to 90 ± 20 bpm) compared to the control group (from 136 ± 21 bpm to 109 ± 18 bpm, P < 0.05). The conversion to sinus rhythm was observed more frequently in the landiolol group than in the control group at every point (P < 0.01 at 8 h; P < 0.05 at 1 and 24 h). CONCLUSION: Landiolol safely reduced heart rate and, in part, converted to sinus rhythm in septic patients with supraventricular tachyarrhythmias.